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Wang H, Ciccocioppo R, Terai S, Shoeibi S, Carnevale G, De Marchi G, Tsuchiya A, Ishii S, Tonouchi T, Furuyama K, Yang Y, Mito M, Abe H, Di Tinco R, Cardinale V. Targeted animal models for preclinical assessment of cellular and gene therapies in pancreatic and liver diseases: regulatory and practical insights. Cytotherapy 2025; 27:259-278. [PMID: 39755978 DOI: 10.1016/j.jcyt.2024.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 01/07/2025]
Abstract
Cellular and gene therapy (CGT) products have emerged as a popular approach in regenerative medicine, showing promise in treating various pancreatic and liver diseases in numerous clinical trials. Before these therapies can be tested in human clinical trials, it is essential to evaluate their safety and efficacy in relevant animal models. Such preclinical testing is often required to obtain regulatory approval for investigational new drugs. However, there is a lack of detailed guidance on selecting appropriate animal models for CGT therapies targeting specific pancreatic and liver conditions, such as pancreatitis and chronic liver diseases. In this review, the gastrointestinal committee for the International Society for Cell and Gene Therapy provides a summary of current recommendations for animal species and disease model selection, as outlined by the US Food and Drug Administration, with references to EU EMA and Japan PMDA. We discuss a range of small and large animal models, as well as humanized models, that are suitable for preclinical testing of CGT products aimed at treating pancreatic and liver diseases. For each model, we cover the associated pathophysiology, commonly used metrics for assessing disease status, the pros and limitations of the models, and the relevance of these models to human conditions. We also summarize the use and application of humanized mouse and other animal models in evaluating the safety and efficacy of CGT products. This review aims to provide comprehensive guidance for selecting appropriate animal species and models to help bridge the gap between the preclinical research and clinical trials using CGT therapies for specific pancreatic and liver diseases.
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Affiliation(s)
- Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA; Ralph H Johnson Veteran Medical Center, Charleston, South Carolina, USA.
| | - Rachele Ciccocioppo
- Department of Medicine, Gastroenterology Unit, Pancreas Institute, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Sara Shoeibi
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Gianluca Carnevale
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia De Marchi
- Department of Medicine, Gastroenterology Unit, Pancreas Institute, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Soichi Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Takafumi Tonouchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kaito Furuyama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuan Yang
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masaki Mito
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Rosanna Di Tinco
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, University of Rome, Rome, Italy.
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2
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Grattoni A, Korbutt G, Tomei AA, García AJ, Pepper AR, Stabler C, Brehm M, Papas K, Citro A, Shirwan H, Millman JR, Melero-Martin J, Graham M, Sefton M, Ma M, Kenyon N, Veiseh O, Desai TA, Nostro MC, Marinac M, Sykes M, Russ HA, Odorico J, Tang Q, Ricordi C, Latres E, Mamrak NE, Giraldo J, Poznansky MC, de Vos P. Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead. Nat Rev Endocrinol 2025; 21:14-30. [PMID: 39227741 PMCID: PMC11938328 DOI: 10.1038/s41574-024-01029-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/06/2024] [Indexed: 09/05/2024]
Abstract
Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable β cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment.
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Affiliation(s)
- Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA.
| | - Gregory Korbutt
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Alice A Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Andrew R Pepper
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Cherie Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, USA
- Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Michael Brehm
- Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Klearchos Papas
- Department of Surgery, The University of Arizona, Tucson, AZ, USA
| | - Antonio Citro
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Haval Shirwan
- Department of Pediatrics, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Juan Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Melanie Graham
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, USA
| | - Michael Sefton
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | - Norma Kenyon
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Omid Veiseh
- Department of Bioengineering, Rice University, Houston, TX, USA
| | - Tejal A Desai
- University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA
- Brown University, School of Engineering, Providence, RI, USA
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | | | - Megan Sykes
- Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
- Department of Surgery, Columbia University, New York, NY, USA
| | - Holger A Russ
- Diabetes Institute, University of Florida, Gainesville, FL, USA
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Jon Odorico
- UW Health Transplant Center, Madison, WI, USA
- Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Qizhi Tang
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
- Department of Surgery, University of California San Francisco, San Francisco, CA, US
- Gladstone Institute of Genomic Immunology, University of California San Francisco, San Francisco, CA, USA
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Esther Latres
- Research Department, Breakthrough T1D, New York, NY, USA
| | | | - Jaime Giraldo
- Research Department, Breakthrough T1D, New York, NY, USA.
| | - Mark C Poznansky
- Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Paul de Vos
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.
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Dong S, Fu C, Shu C, Xie M, Li Y, Zou J, Meng YZ, Xu P, Shan YH, Tian HM, He J, Yang YG, Hu Z. Development of a humanized mouse model with functional human materno-fetal interface immunity. JCI Insight 2024; 9:e176527. [PMID: 39435662 PMCID: PMC11529984 DOI: 10.1172/jci.insight.176527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 09/04/2024] [Indexed: 10/23/2024] Open
Abstract
Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.
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Affiliation(s)
- Shuai Dong
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Cong Fu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Chang Shu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
| | - Min Xie
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yan Li
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Jun Zou
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yi-Zi Meng
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Peng Xu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yan-Hong Shan
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
| | - Hui-Min Tian
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Jin He
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, Department of Obstetrics, Obstetrics and Gynaecology Center, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
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Robertson CC, Elgamal RM, Henry-Kanarek BA, Arvan P, Chen S, Dhawan S, Eizirik DL, Kaddis JS, Vahedi G, Parker SCJ, Gaulton KJ, Soleimanpour SA. Untangling the genetics of beta cell dysfunction and death in type 1 diabetes. Mol Metab 2024; 86:101973. [PMID: 38914291 PMCID: PMC11283044 DOI: 10.1016/j.molmet.2024.101973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. SCOPE OF REVIEW Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. MAJOR CONCLUSIONS We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We discuss how genetic risk prediction models can be used to address disease heterogeneity. Further, we present areas where investment will be critical for the future use of genetics to address open questions in the development of new treatment and prevention strategies for T1D.
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Affiliation(s)
- Catherine C Robertson
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Ruth M Elgamal
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Belle A Henry-Kanarek
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Peter Arvan
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Center for Genomic Health, Weill Cornell Medicine, New York, NY, USA
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Golnaz Vahedi
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Stephen C J Parker
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
| | - Kyle J Gaulton
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
| | - Scott A Soleimanpour
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA.
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Zhang T, Liu W, Yang YG. B cell development and antibody responses in human immune system mice: current status and future perspective. SCIENCE CHINA. LIFE SCIENCES 2024; 67:645-652. [PMID: 38270770 DOI: 10.1007/s11427-023-2462-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/28/2023] [Indexed: 01/26/2024]
Abstract
Humanized immune system (HIS) mice have been developed and used as a small surrogate model to study human immune function under normal or disease conditions. Although variations are found between models, most HIS mice show robust human T cell responses. However, there has been unsuccessful in constructing HIS mice that produce high-affinity human antibodies, primarily due to defects in terminal B cell differentiation, antibody affinity maturation, and development of primary follicles and germinal centers. In this review, we elaborate on the current knowledge about and previous attempts to improve human B cell development in HIS mice, and propose a potential strategy for constructing HIS mice with improved humoral immunity by transplantation of human follicular dendritic cells (FDCs) to facilitate the development of secondary follicles.
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Affiliation(s)
- Tao Zhang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, 130061, China
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, 130061, China.
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130061, China.
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, 130061, China.
- International Center of Future Science, Jilin University, Changchun, 130061, China.
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Xu L, Wang X, Zhang T, Meng X, Zhao W, Pi C, Yang YG. Expression of a mutant CD47 protects against phagocytosis without inducing cell death or inhibiting angiogenesis. Cell Rep Med 2024; 5:101450. [PMID: 38508139 PMCID: PMC10983038 DOI: 10.1016/j.xcrm.2024.101450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 11/22/2023] [Accepted: 02/09/2024] [Indexed: 03/22/2024]
Abstract
CD47 is a ligand of SIRPα, an inhibitory receptor expressed by macrophages, dendritic cells, and natural killer (NK) cells, and, therefore, transgenic overexpression of CD47 is considered an effective approach to inhibiting transplant rejection. However, the detrimental effect of CD47 signaling is overlooked when exploring this approach. Here, we construct a mutant CD47 by replacing the transmembrane and intracellular domains with a membrane anchor (CD47-IgV). In both human and mouse cells, CD47-IgV is efficiently expressed on the cell surface and protects against phagocytosis in vitro and in vivo but does not induce cell death or inhibit angiogenesis. Furthermore, hematopoietic stem cells expressing transgenic CD47-IgV show no detectable alterations in engraftment or differentiation. This study provides a potentially effective means of achieving transgenic CD47 expression that may help to produce gene-edited pigs for xenotransplantation and hypoimmunogenic pluripotent stem cells for regenerative medicine.
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Affiliation(s)
- Lu Xu
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China
| | - Xiaodan Wang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China
| | - Ting Zhang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China
| | - Xiandi Meng
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China
| | - Wenjie Zhao
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China
| | - Chenchen Pi
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, First Hospital of Jilin University, Changchun, Jilin 130062, China; National-Local Joint Engineering Laboratory of Animal Models for Human Disease, Jilin University, Changchun, Jilin 130062, China; International Center of Future Science, Jilin University, Changchun, Jilin 130062, China.
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7
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Mitchell AM, Baschal EE, McDaniel KA, Fleury T, Choi H, Pyle L, Yu L, Rewers MJ, Nakayama M, Michels AW. Tracking DNA-based antigen-specific T cell receptors during progression to type 1 diabetes. SCIENCE ADVANCES 2023; 9:eadj6975. [PMID: 38064552 PMCID: PMC10708189 DOI: 10.1126/sciadv.adj6975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023]
Abstract
T cells targeting self-proteins are important mediators in autoimmune diseases. T cells express unique cell-surface receptors (TCRs) that recognize peptides presented by major histocompatibility molecules. TCRs have been identified from blood and pancreatic islets of individuals with type 1 diabetes (T1D). Here, we tracked ~1700 known antigen-specific TCR sequences, islet antigen or viral reactive, in bulk TCRβ sequencing from longitudinal blood DNA samples in at-risk cases who progressed to T1D, age/sex/human leukocyte antigen-matched controls, and a new-onset T1D cohort. Shared and frequent antigen-specific TCRβ sequences were identified in all three cohorts, and viral sequences were present across all ages. Islet sequences had different patterns of accumulation based upon antigen specificity in the at-risk cases. Furthermore, 73 islet-antigen TCRβ sequences were present in higher frequencies and numbers in T1D samples relative to controls. The total number of these disease-associated TCRβ sequences inversely correlated with age at clinical diagnosis, indicating the potential to use disease-relevant TCR sequences as biomarkers in autoimmune disorders.
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Affiliation(s)
- Angela M. Mitchell
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Erin E. Baschal
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kristen A. McDaniel
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Theodore Fleury
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Hyelin Choi
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Laura Pyle
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO, USA
| | - Liping Yu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Marian J. Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Maki Nakayama
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Immunology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Aaron W. Michels
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Immunology, University of Colorado School of Medicine, Aurora, CO, USA
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James EA, Joglekar AV, Linnemann AK, Russ HA, Kent SC. The beta cell-immune cell interface in type 1 diabetes (T1D). Mol Metab 2023; 78:101809. [PMID: 37734713 PMCID: PMC10622886 DOI: 10.1016/j.molmet.2023.101809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge. SCOPE OF REVIEW Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology. MAJOR CONCLUSIONS The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.
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Affiliation(s)
- Eddie A James
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Alok V Joglekar
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amelia K Linnemann
- Center for Diabetes and Metabolic Diseases, and Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Holger A Russ
- Diabetes Institute, University of Florida, Gainesville, FL, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Sally C Kent
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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9
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Riaz F, Wei P, Pan F. PPARs at the crossroads of T cell differentiation and type 1 diabetes. Front Immunol 2023; 14:1292238. [PMID: 37928539 PMCID: PMC10623333 DOI: 10.3389/fimmu.2023.1292238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/11/2023] [Indexed: 11/07/2023] Open
Abstract
T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of T1D poses significant challenges to the healthcare system, particularly in countries with struggling economies. This review paper highlights the multifaceted roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the context of T1D, shedding light on their potential as regulators of immune responses and β-cell biology. Recent research has elucidated the intricate interplay between CD4+ T cell subsets, such as Tregs and Th17, in developing autoimmune diseases like T1D. Th17 cells drive inflammation, while Tregs exert immunosuppressive functions, highlighting the delicate balance crucial for immune homeostasis. Immunotherapy has shown promise in reinstating self-tolerance and restricting the destruction of autoimmune responses, but further investigations are required to refine these therapeutic strategies. Intriguingly, PPARs, initially recognized for their role in lipid metabolism, have emerged as potent modulators of inflammation in autoimmune diseases, particularly in T1D. Although evidence suggests that PPARs affect the β-cell function, their influence on T-cell responses and their potential impact on T1D remains largely unexplored. It was noted that PPARα is involved in restricting the transcription of IL17A and enhancing the expression of Foxp3 by minimizing its proteasomal degradation. Thus, antagonizing PPARs may exert beneficial effects in regulating the differentiation of CD4+ T cells and preventing T1D. Therefore, this review advocates for comprehensive investigations to delineate the precise roles of PPARs in T1D pathogenesis, offering innovative therapeutic avenues that target both the immune system and pancreatic function. This review paper seeks to bridge the knowledge gap between PPARs, immune responses, and T1D, providing insights that may revolutionize the treatment landscape for this autoimmune disorder. Moreover, further studies involving PPAR agonists in non-obese diabetic (NOD) mice hold promise for developing novel T1D therapies.
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Affiliation(s)
- Farooq Riaz
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Ping Wei
- Department of Otolaryngology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
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10
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Camaya I, O’Brien B, Donnelly S. How do parasitic worms prevent diabetes? An exploration of their influence on macrophage and β-cell crosstalk. Front Endocrinol (Lausanne) 2023; 14:1205219. [PMID: 37564976 PMCID: PMC10411736 DOI: 10.3389/fendo.2023.1205219] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/10/2023] [Indexed: 08/12/2023] Open
Abstract
Diabetes is the fastest growing chronic disease globally, with prevalence increasing at a faster rate than heart disease and cancer. While the disease presents clinically as chronic hyperglycaemia, two distinct subtypes have been recognised. Type 1 diabetes (T1D) is characterised as an autoimmune disease in which the insulin-producing pancreatic β-cells are destroyed, and type 2 diabetes (T2D) arises due to metabolic insufficiency, in which inadequate amounts of insulin are produced, and/or the actions of insulin are diminished. It is now apparent that pro-inflammatory responses cause a loss of functional β-cell mass, and this is the common underlying mechanism of both T1D and T2D. Macrophages are the central immune cells in the pathogenesis of both diseases and play a major role in the initiation and perpetuation of the proinflammatory responses that compromise β-cell function. Furthermore, it is the crosstalk between macrophages and β-cells that orchestrates the inflammatory response and ensuing β-cell dysfunction/destruction. Conversely, this crosstalk can induce immune tolerance and preservation of β-cell mass and function. Thus, specifically targeting the intercellular communication between macrophages and β-cells offers a unique strategy to prevent/halt the islet inflammatory events underpinning T1D and T2D. Due to their potent ability to regulate mammalian immune responses, parasitic worms (helminths), and their excretory/secretory products, have been examined for their potential as therapeutic agents for both T1D and T2D. This research has yielded positive results in disease prevention, both clinically and in animal models. However, the focus of research has been on the modulation of immune cells and their effectors. This approach has ignored the direct effects of helminths and their products on β-cells, and the modulation of signal exchange between macrophages and β-cells. This review explores how the alterations to macrophages induced by helminths, and their products, influence the crosstalk with β-cells to promote their function and survival. In addition, the evidence that parasite-derived products interact directly with endocrine cells to influence their communication with macrophages to prevent β-cell death and enhance function is discussed. This new paradigm of two-way metabolic conversations between endocrine cells and macrophages opens new avenues for the treatment of immune-mediated metabolic disease.
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Affiliation(s)
| | | | - Sheila Donnelly
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia
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11
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Peters LD, Yeh WI, Arnoletti JM, Brown ME, Posgai AL, Mathews CE, Brusko TM. Modeling cell-mediated immunity in human type 1 diabetes by engineering autoreactive CD8 + T cells. Front Immunol 2023; 14:1142648. [PMID: 37325626 PMCID: PMC10262917 DOI: 10.3389/fimmu.2023.1142648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 04/13/2023] [Indexed: 06/17/2023] Open
Abstract
The autoimmune pathogenesis of type 1 diabetes (T1D) involves cellular infiltration from innate and adaptive immune subsets into the islets of Langerhans within the pancreas; however, the direct cytotoxic killing of insulin-producing β-cells is thought to be mediated primarily by antigen-specific CD8+ T cells. Despite this direct pathogenic role, key aspects of their receptor specificity and function remain uncharacterized, in part, due to their low precursor frequency in peripheral blood. The concept of engineering human T cell specificity, using T cell receptor (TCR) and chimeric antigen receptor (CAR)-based approaches, has been demonstrated to improve adoptive cell therapies for cancer, but has yet to be extensively employed for modeling and treating autoimmunity. To address this limitation, we sought to combine targeted genome editing of the endogenous TCRα chain gene (TRAC) via CRISPR/Cas9 in combination with lentiviral vector (LV)-mediated TCR gene transfer into primary human CD8+ T cells. We observed that knockout (KO) of endogenous TRAC enhanced de novo TCR pairing, which permitted increased peptide:MHC-dextramer staining. Moreover, TRAC KO and TCR gene transfer increased markers of activation and effector function following activation, including granzyme B and interferon-γ production. Importantly, we observed increased cytotoxicity toward an HLA-A*0201+ human β-cell line by HLA-A*02:01 restricted CD8+ T cells engineered to recognize islet-specific glucose-6-phosphatase catalytic subunit (IGRP). These data support the notion of altering the specificity of primary human T cells for mechanistic analyses of autoreactive antigen-specific CD8+ T cells and are expected to facilitate downstream cellular therapeutics to achieve tolerance induction through the generation of antigen-specific regulatory T cells.
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Affiliation(s)
- Leeana D. Peters
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Wen-I Yeh
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Juan M. Arnoletti
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Matthew E. Brown
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Amanda L. Posgai
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Clayton E. Mathews
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Todd M. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
- Department of Pediatrics, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
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12
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van Tienhoven R, Kracht MJL, van der Slik AR, Thomaidou S, Wolters AHG, Giepmans BNG, Riojas JPR, Nelson MS, Carlotti F, de Koning EJP, Hoeben RC, Zaldumbide A, Roep BO. Presence of immunogenic alternatively spliced insulin gene product in human pancreatic delta cells. Diabetologia 2023; 66:884-896. [PMID: 36884057 PMCID: PMC10036285 DOI: 10.1007/s00125-023-05882-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/23/2022] [Indexed: 03/09/2023]
Abstract
AIMS/HYPOTHESIS Transcriptome analyses revealed insulin-gene-derived transcripts in non-beta endocrine islet cells. We studied alternative splicing of human INS mRNA in pancreatic islets. METHODS Alternative splicing of insulin pre-mRNA was determined by PCR analysis performed on human islet RNA and single-cell RNA-seq analysis. Antisera were generated to detect insulin variants in human pancreatic tissue using immunohistochemistry, electron microscopy and single-cell western blot to confirm the expression of insulin variants. Cytotoxic T lymphocyte (CTL) activation was determined by MIP-1β release. RESULTS We identified an alternatively spliced INS product. This variant encodes the complete insulin signal peptide and B chain and an alternative C-terminus that largely overlaps with a previously identified defective ribosomal product of INS. Immunohistochemical analysis revealed that the translation product of this INS-derived splice transcript was detectable in somatostatin-producing delta cells but not in beta cells; this was confirmed by light and electron microscopy. Expression of this alternatively spliced INS product activated preproinsulin-specific CTLs in vitro. The exclusive presence of this alternatively spliced INS product in delta cells may be explained by its clearance from beta cells by insulin-degrading enzyme capturing its insulin B chain fragment and a lack of insulin-degrading enzyme expression in delta cells. CONCLUSIONS/INTERPRETATION Our data demonstrate that delta cells can express an INS product derived from alternative splicing, containing both the diabetogenic insulin signal peptide and B chain, in their secretory granules. We propose that this alternative INS product may play a role in islet autoimmunity and pathology, as well as endocrine or paracrine function or islet development and endocrine destiny, and transdifferentiation between endocrine cells. INS promoter activity is not confined to beta cells and should be used with care when assigning beta cell identity and selectivity. DATA AVAILABILITY The full EM dataset is available via www.nanotomy.org (for review: http://www.nanotomy.org/OA/Tienhoven2021SUB/6126-368/ ). Single-cell RNA-seq data was made available by Segerstolpe et al [13] and can be found at https://sandberglab.se/pancreas . The RNA and protein sequence of INS-splice was uploaded to GenBank (BankIt2546444 INS-splice OM489474).
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Affiliation(s)
- René van Tienhoven
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Maria J L Kracht
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Arno R van der Slik
- Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sofia Thomaidou
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Anouk H G Wolters
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Ben N G Giepmans
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | | | - Michael S Nelson
- Light Microscopy Core, City of Hope National Medical Center, Duarte, CA, USA
| | - Françoise Carlotti
- Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Eelco J P de Koning
- Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Rob C Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Bart O Roep
- Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
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13
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Ackun-Farmmer MA, Jewell CM. Delivery route considerations for designing antigen-specific biomaterial strategies to combat autoimmunity. ADVANCED NANOBIOMED RESEARCH 2023; 3:2200135. [PMID: 36938103 PMCID: PMC10019031 DOI: 10.1002/anbr.202200135] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Disease modifying drugs and biologics used to treat autoimmune diseases, although promising, are non-curative. As the field moves towards development of new approaches to treat autoimmune disease, antigen-specific therapies immunotherapies (ASITs) have emerged. Despite clinical approval of ASITs for allergies, clinical trials using soluble ASITs for autoimmunity have been largely unsuccessful. A major effort to address this shortcoming is the use of biomaterials to harness the features unique to specific delivery routes. This review focuses on biomaterials being developed for delivery route-specific strategies to induce antigen-specific responses in autoimmune diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and celiac disease. We first discuss the delivery strategies used in ongoing and completed clinical trials in autoimmune ASITs. Next, we highlight pre-clinical biomaterial approaches from the most recent 3 years in the context of these same delivery route considerations. Lastly, we provide discussion on the gaps remaining in biomaterials development and comment on the need to consider delivery routes in the process of designing biomaterials for ASITs.
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Affiliation(s)
- Marian A Ackun-Farmmer
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Christopher M Jewell
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
- US Department of Veterans Affairs, VA Maryland Health Care System, Baltimore, MD, 21201, USA
- Robert E. Fischell Institute for Biomedical Devices, College Park, MD, 20742, USA
- Department of Microbiology and Immunology, University of Maryland Medical School, Baltimore, MD, 21201, USA
- Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA
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14
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Roep BO. The need and benefit of immune monitoring to define patient and disease heterogeneity, mechanisms of therapeutic action and efficacy of intervention therapy for precision medicine in type 1 diabetes. Front Immunol 2023; 14:1112858. [PMID: 36733487 PMCID: PMC9887285 DOI: 10.3389/fimmu.2023.1112858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
The current standard of care for type 1 diabetes patients is limited to treatment of the symptoms of the disease, insulin insufficiency and its complications, not its cause. Given the autoimmune nature of type 1 diabetes, immunology is critical to understand the mechanism of disease progression, patient and disease heterogeneity and therapeutic action. Immune monitoring offers the key to all this essential knowledge and is therefore indispensable, despite the challenges and costs associated. In this perspective, I attempt to make this case by providing evidence from the past to create a perspective for future trials and patient selection.
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15
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Guo J, Wang S, Gao Q. Can next-generation humanized mice that reconstituted with both functional human immune system and hepatocytes model the progression of viral hepatitis to hepatocarcinogenesis? Front Med (Lausanne) 2022; 9:1002260. [PMID: 36213658 PMCID: PMC9537463 DOI: 10.3389/fmed.2022.1002260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/08/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatitis B virus (HBV) and Hepatitis C virus (HCV) chronic infections cause liver immunopathological diseases such as hepatitis, fibrosis, cirrhosis, and hepatocellular carcinomas, which are difficult to treat and continue to be major health problems globally. Due to the species-specific hepato-tropism of HBV and HCV, conventional rodent models are limited in their utility for studying the infection and associated liver immunopathogenesis. Humanized mice reconstituted with both functional human immune system and hepatocytes (HIS-HuHEP mice) have been extremely instrumental for in vivo studies of HBV or HCV infection and human-specific aspects of the progression of liver immunopathogenesis. However, none of the current HIS-HuHEP mice can model the progression of viral hepatitis to hepatocarcinogenesis which may be a notorious result of HBV or HCV chronic infection in patients, suggesting that they were functionally compromised and that there is still significant space to improve and establish next-generation of HIS-HuHEP mice with more sophisticated functions. In this review, we first summarize the principal requirements to establish HIS-HuHEP mice. We then discuss the respective protocols for current HIS-HuHEP mice and their applications, as well as their advantages and disadvantages. We also raise perspectives for further improving and establishing next-generation HIS-HuHEP mice.
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Affiliation(s)
- Jinglong Guo
- Department of Cardiovascular Disease, The First Hospital of Jilin University, Changchun, China
| | - Siyue Wang
- Graduate Program in Immunology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, United States
| | - Qi Gao
- Department of Cardiovascular Disease, The First Hospital of Jilin University, Changchun, China
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16
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Mallone R, Halliez C, Rui J, Herold KC. The β-Cell in Type 1 Diabetes Pathogenesis: A Victim of Circumstances or an Instigator of Tragic Events? Diabetes 2022; 71:1603-1610. [PMID: 35881836 PMCID: PMC9490354 DOI: 10.2337/dbi21-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022]
Abstract
Recent reports have revived interest in the active role that β-cells may play in type 1 diabetes pathogenesis at different stages of disease. In some studies, investigators suggested an initiating role and proposed that type 1 diabetes may be primarily a disease of β-cells and only secondarily a disease of autoimmunity. This scenario is possible and invites the search for environmental triggers damaging β-cells. Another major contribution of β-cells may be to amplify autoimmune vulnerability and to eventually drive it into an intrinsic, self-detrimental state that turns the T cell-mediated homicide into a β-cell suicide. On the other hand, protective mechanisms are also mounted by β-cells and may provide novel therapeutic targets to combine immunomodulatory and β-cell protective agents. This integrated view of autoimmunity as a disease of T-cell/β-cell cross talk will ultimately advance our understanding of type 1 diabetes pathogenesis and improve our chances of preventing or reversing disease progression.
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Affiliation(s)
- Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
| | - Clémentine Halliez
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
| | - Jinxiu Rui
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
| | - Kevan C. Herold
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
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17
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Tan S, Fang M, Fan W, Wang Z, Lv Y, Zou J, Wang X, Liu B, Yang YG, Hu Z. Improvement of human myeloid and natural killer cell development in humanized mice via hydrodynamic injection of transposon plasmids containing multiple human cytokine genes. Immunol Cell Biol 2022; 100:624-635. [PMID: 35662247 DOI: 10.1111/imcb.12564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 05/12/2021] [Accepted: 06/03/2022] [Indexed: 11/29/2022]
Abstract
Humanized mice reconstituted with a functional human immune system (HIS) are instrumental in studying human immunity and immune disorders in vivo. The poor or lack of cross-reactivity between mouse cytokines and human cells limits the development and/or function of human immune cell subsets including human myeloid, natural killer and B cells. Here we explored the potential to achieve long-term production of human cytokines in immunodeficient mice using a transposon-plasmid-based hydrodynamic injection approach. We constructed a transposon-plasmid carrying five human cytokine coding sequences (named PB-5F), and observed that four of the cytokines (granulocyte-macrophage colony-stimulating factor, interleukin (IL)-15, IL-6 and IL-3) were detectable in sera and three (granulocyte-macrophage colony-stimulating factor, IL-15 and IL-6) showed long-term production in immunodeficient mice that received a single hydrodynamic injection of PB-5F plus the transposase plasmid (Super PB). Furthermore, a single injection of PB-5F/Super PB markedly enhanced the reconstitution of human myeloid cells and natural killer cells, and promoted human B-cell maturation in HIS mice. Taken together, our data revealed that hydrodynamic injection of the PB-5F/Super PB vectors may serve as a convenient and efficacious means to promote human immune function in HIS mice.
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Affiliation(s)
- Shulian Tan
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Minghui Fang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Wei Fan
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Zhaowei Wang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Yanan Lv
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Jun Zou
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Xue Wang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
| | - Bin Liu
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China.,International Center of Future Science, Jilin University, Changchun, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, The First Hospital of Jilin University, Changchun, China
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18
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Vecchione A, Madley R, Danzl N, Borsotti C, Marharlooei MK, Li HW, Nauman G, Ding X, Ho SH, Fousteri G, Sykes M. T1D patient-derived hematopoietic stem cells are programmed to generate Tph, Tfh, and autoimmunity-associated B cell subsets in human immune system mice. Clin Immunol 2022; 240:109048. [PMID: 35644520 PMCID: PMC9564152 DOI: 10.1016/j.clim.2022.109048] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 11/03/2022]
Abstract
Interactions between B cells and CD4+ T cells play a central role in the development of Type 1 Diabetes (T1D). Two helper cell subsets, follicular (Tfh) and peripheral (Tph) helper T cells, are increased in patients with T1D but their role in driving B cell autoimmunity is undefined. We used a personalized immune (PI) mouse model to generate human immune systems de novo from hematopoietic stem cells (HSCs) of patients with T1D or from healthy controls (HCs). Both groups developed Tfh and Tph-like cells, and those with T1D-derived immune systems demonstrated increased numbers of Tph-like and Tfh cells compared to HC-derived PI mice. T1D-derived immune systems included increased proportions of unconventional memory CD27-IgD- B cells and reduced proportions of naïve B cells compared to HC PI mice, resembling changes reported for patients with systemic lupus erythematosus. Our findings suggest that T1D HSCs are genetically programmed to produce increased proportions of T cells that promote the development of unconventional, possibly autoreactive memory B cells. PI mice provide an avenue for further understanding of the immune abnormalities that drive autoantibody pathogenesis and T1D.
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19
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Nauman G, Danzl NM, Lee J, Borsotti C, Madley R, Fu J, Hölzl MA, Dahmani A, Dorronsoro Gonzalez A, Chavez É, Campbell SR, Yang S, Satwani P, Liu K, Sykes M. Defects in Long-Term APC Repopulation Ability of Adult Human Bone Marrow Hematopoietic Stem Cells (HSCs) Compared with Fetal Liver HSCs. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1652-1663. [PMID: 35315788 PMCID: PMC8976823 DOI: 10.4049/jimmunol.2100966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 01/25/2022] [Indexed: 04/28/2023]
Abstract
Immunodeficient mice reconstituted with immune systems from patients, or personalized immune (PI) mice, are powerful tools for understanding human disease. Compared with immunodeficient mice transplanted with human fetal thymus tissue and fetal liver-derived CD34+ cells administered i.v. (Hu/Hu mice), PI mice, which are transplanted with human fetal thymus and adult bone marrow (aBM) CD34+ cells, demonstrate reduced levels of human reconstitution. We characterized APC and APC progenitor repopulation in human immune system mice and detected significant reductions in blood, bone marrow (BM), and splenic APC populations in PI compared with Hu/Hu mice. APC progenitors and hematopoietic stem cells (HSCs) were less abundant in aBM CD34+ cells compared with fetal liver-derived CD34+ cell preparations, and this reduction in APC progenitors was reflected in the BM of PI compared with Hu/Hu mice 14-20 wk posttransplant. The number of HSCs increased in PI mice compared with the originally infused BM cells and maintained functional repopulation potential, because BM from some PI mice 28 wk posttransplant generated human myeloid and lymphoid cells in secondary recipients. Moreover, long-term PI mouse BM contained functional T cell progenitors, evidenced by thymopoiesis in thymic organ cultures. Injection of aBM cells directly into the BM cavity, transgenic expression of hematopoietic cytokines, and coinfusion of human BM-derived mesenchymal stem cells synergized to enhance long-term B cell and monocyte levels in PI mice. These improvements allow a sustained time frame of 18-22 wk where APCs and T cells are present and greater flexibility for modeling immune disease pathogenesis and immunotherapies in PI mice.
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Affiliation(s)
- Grace Nauman
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Nichole M Danzl
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Jaeyop Lee
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Chiara Borsotti
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Rachel Madley
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Jianing Fu
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Markus A Hölzl
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Alexander Dahmani
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Akaitz Dorronsoro Gonzalez
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Éstefania Chavez
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Sean R Campbell
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Suxiao Yang
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Prakash Satwani
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Pediatrics, Columbia University Medical Center, Columbia University, New York, NY
| | - Kang Liu
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; and
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY;
- Department of Microbiology and Immunology, Columbia University Medical Center, Columbia University, New York, NY
- Columbia University Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Surgery, Columbia University Medical Center, Columbia University, New York, NY
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20
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Abstract
As medical and pharmacological technology advances, new and complex modalities of disease treatment that are more personalized and targeted are being developed. Often these modalities must be validated in the presence of critical components of the human biological system. Given the incongruencies between murine and human biology, as well as the human-tropism of certain drugs and pathogens, the selection of animal models that accurately recapitulate the intricacies of the human biological system becomes more salient for disease modeling and preclinical testing. Immunodeficient mice engrafted with functional human tissues (so-called humanized mice), which allow for the study of physiologically relevant disease mechanisms, have thus become an integral aspect of biomedical research. This review discusses the recent advancements and applications of humanized mouse models on human immune system and liver humanization in modeling human diseases, as well as how they can facilitate translational medicine.
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Affiliation(s)
- Weijian Ye
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; ,
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21
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Khosravi-Maharlooei M, Madley R, Borsotti C, Ferreira LMR, Sharp RC, Brehm MA, Greiner DL, Parent AV, Anderson MS, Sykes M, Creusot RJ. Modeling human T1D-associated autoimmune processes. Mol Metab 2022; 56:101417. [PMID: 34902607 PMCID: PMC8739876 DOI: 10.1016/j.molmet.2021.101417] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/19/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. SCOPE OF REVIEW Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. MAJOR CONCLUSIONS To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.
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Affiliation(s)
- Mohsen Khosravi-Maharlooei
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Rachel Madley
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Chiara Borsotti
- Department of Health Sciences, Histology laboratory, Università del Piemonte Orientale, Novara, Italy
| | - Leonardo M R Ferreira
- Departments of Microbiology & Immunology, and Regenerative Medicine & Cell Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Robert C Sharp
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Michael A Brehm
- Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Dale L Greiner
- Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA
| | - Audrey V Parent
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | - Mark S Anderson
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Remi J Creusot
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
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22
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Martens PJ, Ellis D, Bruggeman Y, Viaene M, Laureys J, Teyton L, Mathieu C, Gysemans C. Preventing type 1 diabetes in late-stage pre-diabetic NOD mice with insulin: A central role for alum as adjuvant. Front Endocrinol (Lausanne) 2022; 13:1023264. [PMID: 36339431 PMCID: PMC9630573 DOI: 10.3389/fendo.2022.1023264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/04/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Restoration of immune tolerance to disease-relevant antigens is an appealing approach to prevent or arrest an organ-specific autoimmune disease like type 1 diabetes (T1D). Numerous studies have identified insulin as a key antigen of interest to use in such strategies, but to date, the success of these interventions in humans has been inconsistent. The efficacy of antigen-specific immunotherapy may be enhanced by optimising the dose, timing, and route of administration, and perhaps by the inclusion of adjuvants like alum. The aim of our study was to evaluate the effect of an insulin peptide vaccine formulated with alum to prevent T1D development in female non-obese diabetic (NOD) mice when administered during late-stage pre-diabetes. METHODS Starting at 10 weeks of age, female NOD mice received four weekly subcutaneous injections of an insulin B:8-24 (InsB:8-24) peptide with (Ins+alum) or without Imject® alum (Ins) as adjuvant. Diabetes incidence was assessed for up to 30 weeks of age. Insulin autoantibodies and C-peptide concentrations were measured in plasma and flow cytometric analysis was performed on pancreatic-draining lymph nodes (PLN) and pancreas using an InsB:12-20-reactive tetramer. RESULTS InsB:8-24 peptide formulated in alum reduced diabetes incidence (39%), compared to mice receiving the InsB:8-24 peptide without alum (71%, P < 0.05), mice receiving alum alone (76%, P < 0.01), or mice left untreated (70%, P < 0.01). This was accompanied by reduced insulitis severity, and preservation of C-peptide. Ins+alum was associated with reduced frequencies of pathogenic effector memory CD4+ and CD8+ T cells in the pancreas and increased frequencies of insulin-reactive FoxP3+ Tregs in the PLN. Of interest, insulin-reactive Tregs were enriched amongst populations of Tregs expressing markers indicative of stable FoxP3 expression and enhanced suppressive function. CONCLUSION An InsB:8-24 peptide vaccine prevented the onset of T1D in late-stage pre-diabetic NOD mice, but only when formulated in alum. These findings support the use of alum as adjuvant to optimise the efficacy of antigen-specific immunotherapy in future trials.
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Affiliation(s)
- Pieter-Jan Martens
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Darcy Ellis
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Ylke Bruggeman
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Marijke Viaene
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Jos Laureys
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Luc Teyton
- Scripps Research Institute, Department of Immunology and Microbiology, La Jolla, CA, United States
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
| | - Conny Gysemans
- Clinical and Experimental Endocrinology (CEE), Campus Gasthuisberg O&N1, Leuven, Belgium
- *Correspondence: Conny Gysemans,
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23
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Santini-González J, Castro-Gutierrez R, Becker MW, Rancourt C, Russ HA, Phelps EA. Human stem cell derived beta-like cells engineered to present PD-L1 improve transplant survival in NOD mice carrying human HLA class I. Front Endocrinol (Lausanne) 2022; 13:989815. [PMID: 36506044 PMCID: PMC9732725 DOI: 10.3389/fendo.2022.989815] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/19/2022] [Indexed: 11/27/2022] Open
Abstract
There is a critical need for therapeutic approaches that combine renewable sources of replacement beta cells with localized immunomodulation to counter recurrence of autoimmunity in type 1 diabetes (T1D). However, there are few examples of animal models to study such approaches that incorporate spontaneous autoimmunity directed against human beta cells rather than allogenic rejection. Here, we address this critical limitation by demonstrating rejection and survival of transplanted human stem cell-derived beta-like cells clusters (sBCs) in a fully immune competent mouse model with matching human HLA class I and spontaneous diabetes development. We engineered localized immune tolerance toward transplanted sBCs via inducible cell surface overexpression of PD-L1 (iP-sBCs) with and without deletion of all HLA class I surface molecules via beta-2 microglobulin knockout (iP-BKO sBCs). NOD.HLA-A2.1 mice, which lack classical murine MHC I and instead express human HLA-A*02:01, underwent transplantation of 1,000 human HLA-A*02:01 sBCs under the kidney capsule and were separated into HLA-A2 positive iP-sBC and HLA-class I negative iP-BKO sBC groups, each with +/- doxycycline (DOX) induced PD-L1 expression. IVIS imaging showed significantly improved graft survival in mice transplanted with PD-L1 expressing iP-sBC at day 3 post transplantation compared to controls. However, luciferase signal dropped below in vivo detection limits by day 14 for all groups in this aggressive immune competent diabetes model. Nonetheless, histological examination revealed significant numbers of surviving insulin+/PD-L1+ sBCs cells for DOX-treated mice at day 16 post-transplant despite extensive infiltration with high numbers of CD3+ and CD45+ immune cells. These results show that T cells rapidly infiltrate and attack sBC grafts in this model but that significant numbers of PD-L1 expressing sBCs manage to survive in this harsh immunological environment. This investigation represents one of the first in vivo studies recapitulating key aspects of human autoimmune diabetes to test immune tolerance approaches with renewable sources of beta cells.
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Affiliation(s)
- Jorge Santini-González
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Roberto Castro-Gutierrez
- Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Matthew W. Becker
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Chad Rancourt
- Animal Care Services, University of Florida, Gainesville, FL, United States
| | - Holger A. Russ
- Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Edward A. Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
- *Correspondence: Edward A. Phelps,
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24
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Current Status, Barriers, and Future Directions for Humanized Mouse Models to Evaluate Stem Cell–Based Islet Cell Transplant. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1387:89-106. [DOI: 10.1007/5584_2022_711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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25
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Houeiss P, Boitard C, Luce S. Preclinical Models to Evaluate the Human Response to Autoantigen and Antigen-Specific Immunotherapy in Human Type 1 Diabetes. Front Endocrinol (Lausanne) 2022; 13:883000. [PMID: 35498419 PMCID: PMC9044628 DOI: 10.3389/fendo.2022.883000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Type 1 Diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic islet β-cells by auto-reactive T cells. The clinical management of T1D faces the lack of fully predictive biomarkers in its preclinical stage and of antigen-specific therapies to induce or re-induce immune tolerance to β-cell autoantigens and prevent its development. From a therapeutic standpoint, preclinical models of T1D have fallen short of directly translating into humans. To circumvent this limitation, preclinical models are being optimized to allow defining autoantigen epitopes that are presented to T cells and directly apply to the human. In this review, we propose to make a point on the latest available models such as humanized immunodeficient NOD mice models and HLA and autoantigen transgenic mice and their application in the context of T1D.
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Affiliation(s)
- Pamela Houeiss
- Laboratory Immunology of Diabetes, Cochin Institute, Department Endocrinology, Metabolism and Diabetologia (EMD), Institut Nationale de la Santé et de la Recherche Médicale, Unité 1016 (INSERMU1016), Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, Cochin Institute, Department Endocrinology, Metabolism and Diabetologia (EMD), Institut Nationale de la Santé et de la Recherche Médicale, Unité 1016 (INSERMU1016), Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Sandrine Luce
- Laboratory Immunology of Diabetes, Cochin Institute, Department Endocrinology, Metabolism and Diabetologia (EMD), Institut Nationale de la Santé et de la Recherche Médicale, Unité 1016 (INSERMU1016), Paris, France
- Medical Faculty, Paris University, Paris, France
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26
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Nakayama M, Michels AW. Using the T Cell Receptor as a Biomarker in Type 1 Diabetes. Front Immunol 2021; 12:777788. [PMID: 34868047 PMCID: PMC8635517 DOI: 10.3389/fimmu.2021.777788] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/26/2021] [Indexed: 12/20/2022] Open
Abstract
T cell receptors (TCRs) are unique markers that define antigen specificity for a given T cell. With the evolution of sequencing and computational analysis technologies, TCRs are now prime candidates for the development of next-generation non-cell based T cell biomarkers, which provide a surrogate measure to assess the presence of antigen-specific T cells. Type 1 diabetes (T1D), the immune-mediated form of diabetes, is a prototypical organ specific autoimmune disease in which T cells play a pivotal role in targeting pancreatic insulin-producing beta cells. While the disease is now predictable by measuring autoantibodies in the peripheral blood directed to beta cell proteins, there is an urgent need to develop T cell markers that recapitulate T cell activity in the pancreas and can be a measure of disease activity. This review focuses on the potential and challenges of developing TCR biomarkers for T1D. We summarize current knowledge about TCR repertoires and clonotypes specific for T1D and discuss challenges that are unique for autoimmune diabetes. Ultimately, the integration of large TCR datasets produced from individuals with and without T1D along with computational 'big data' analysis will facilitate the development of TCRs as potentially powerful biomarkers in the development of T1D.
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MESH Headings
- Alleles
- Animals
- Biomarkers
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/etiology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/therapy
- Disease Susceptibility
- Epitopes/chemistry
- Epitopes/immunology
- Epitopes/metabolism
- Genetic Predisposition to Disease
- Genetic Variation
- Histocompatibility Antigens/genetics
- Histocompatibility Antigens/immunology
- Humans
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Peptides/immunology
- Peptides/metabolism
- Protein Binding
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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Affiliation(s)
- Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Aaron W. Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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27
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Efficient adoptive transfer of autologous modified B cells: a new humanized platform mouse model for testing B cells reprogramming therapies. Cancer Immunol Immunother 2021; 71:1771-1775. [PMID: 34748076 PMCID: PMC9188505 DOI: 10.1007/s00262-021-03101-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/26/2021] [Indexed: 11/17/2022]
Abstract
Here, we report a novel experimental setup to perform adoptive transfer of gene-edited B cells using humanized immune system mice by infusing autologous HIS mouse-derived human B cells “educated” in a murine context and thus rendered tolerant to the host. The present approach presents two advantages over the conventional humanized PBMC mouse models: (i) it circumvents the risk of xenogeneic graft-versus-host reaction and (ii) it mimics more closely human immune responses, thus favoring clinical translation. We show that the frequencies and numbers of transduced B cells in recipient’s spleens one week post-transfer are within the range of the size of the pre-immune B cell population specific for a given protein antigen in the mouse. They are also compatible with the B cell numbers required to elicit a sizeable immune response upon immunization. Altogether, our findings pave the way for future studies aiming at assessing therapeutic interventions involving B cell reprogramming for instance by an antibody transgene in a “humanized” hematopoietic setting.
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28
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Luce S, Guinoiseau S, Gadault A, Letourneur F, Nitschke P, Bras M, Vidaud M, Charneau P, Larger E, Colli ML, Eizirik DL, Lemonnier F, Boitard C. A Humanized Mouse Strain That Develops Spontaneously Immune-Mediated Diabetes. Front Immunol 2021; 12:748679. [PMID: 34721418 PMCID: PMC8551915 DOI: 10.3389/fimmu.2021.748679] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/22/2021] [Indexed: 12/03/2022] Open
Abstract
To circumvent the limitations of available preclinical models for the study of type 1 diabetes (T1D), we developed a new humanized model, the YES-RIP-hB7.1 mouse. This mouse is deficient of murine major histocompatibility complex class I and class II, the murine insulin genes, and expresses as transgenes the HLA-A*02:01 allele, the diabetes high-susceptibility HLA-DQ8A and B alleles, the human insulin gene, and the human co-stimulatory molecule B7.1 in insulin-secreting cells. It develops spontaneous T1D along with CD4+ and CD8+ T-cell responses to human preproinsulin epitopes. Most of the responses identified in these mice were validated in T1D patients. This model is amenable to characterization of hPPI-specific epitopes involved in T1D and to the identification of factors that may trigger autoimmune response to insulin-secreting cells in human T1D. It will allow evaluating peptide-based immunotherapy that may directly apply to T1D in human and complete preclinical model availability to address the issue of clinical heterogeneity of human disease.
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Affiliation(s)
- Sandrine Luce
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France.,Medical Faculty, Paris University, Paris, France
| | - Sophie Guinoiseau
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France.,Medical Faculty, Paris University, Paris, France
| | - Alexis Gadault
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France.,Medical Faculty, Paris University, Paris, France
| | - Franck Letourneur
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France
| | | | - Marc Bras
- Medical Faculty, Paris University, Paris, France
| | - Michel Vidaud
- Biochemistry and Molecular Genetics Department, Cochin Hospital, Paris, France
| | - Pierre Charneau
- Molecular Virology and Vaccinology, Pasteur Institute, Paris, France
| | - Etienne Larger
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France.,Diabetology Department, Cochin Hospital, Paris, France
| | - Maikel L Colli
- Université Libre de Bruxelles (ULB) Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Decio L Eizirik
- Université Libre de Bruxelles (ULB) Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.,Diabetes Center, Indiana Biosciences Research Institute (IBRI), Indianapolis, IN, United States
| | - François Lemonnier
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France.,Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, INSERMU1016, Department EMD, Cochin Institute, Paris, France.,Medical Faculty, Paris University, Paris, France.,Diabetology Department, Cochin Hospital, Paris, France
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29
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Wang X, Brown NK, Wang B, Shariati K, Wang K, Fuchs S, Melero‐Martin JM, Ma M. Local Immunomodulatory Strategies to Prevent Allo-Rejection in Transplantation of Insulin-Producing Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2003708. [PMID: 34258870 PMCID: PMC8425879 DOI: 10.1002/advs.202003708] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 05/12/2021] [Indexed: 05/02/2023]
Abstract
Islet transplantation has shown promise as a curative therapy for type 1 diabetes (T1D). However, the side effects of systemic immunosuppression and limited long-term viability of engrafted islets, together with the scarcity of donor organs, highlight an urgent need for the development of new, improved, and safer cell-replacement strategies. Induction of local immunotolerance to prevent allo-rejection against islets and stem cell derived β cells has the potential to improve graft function and broaden the applicability of cellular therapy while minimizing adverse effects of systemic immunosuppression. In this mini review, recent developments in non-encapsulation, local immunomodulatory approaches for T1D cell replacement therapies, including islet/β cell modification, immunomodulatory biomaterial platforms, and co-transplantation of immunomodulatory cells are discussed. Key advantages and remaining challenges in translating such technologies to clinical settings are identified. Although many of the studies discussed are preliminary, the growing interest in the field has led to the exploration of new combinatorial strategies involving cellular engineering, immunotherapy, and novel biomaterials. Such interdisciplinary research will undoubtedly accelerate the development of therapies that can benefit the whole T1D population.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Natalie K. Brown
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Bo Wang
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Kaavian Shariati
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Kai Wang
- Department of Cardiac SurgeryBoston Children's HospitalBostonMA02115USA
- Department of SurgeryHarvard Medical SchoolBostonMA02115USA
| | - Stephanie Fuchs
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Juan M. Melero‐Martin
- Department of Cardiac SurgeryBoston Children's HospitalBostonMA02115USA
- Department of SurgeryHarvard Medical SchoolBostonMA02115USA
- Harvard Stem Cell InstituteCambridgeMA02138USA
| | - Minglin Ma
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
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30
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Erdem N, Montero E, Roep BO. Breaking and restoring immune tolerance to pancreatic beta-cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2021; 28:397-403. [PMID: 34183540 DOI: 10.1097/med.0000000000000646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) results from the loss of immune tolerance to pancreatic beta-cells leading to their destruction. Immune intervention therapies tested in T1D so far delayed progression but failed to restore tolerance, which partly explains their lack of durable clinical efficacy. RECENT FINDINGS The role of beta-cells and islets themselves in dialogue with their micro- and macro-environment including the immune system and the intestinal microbiome is increasingly evident. Indeed, islets can both maintain and break immune tolerance. Some recent immune therapies in cancer that block immune regulation also break tolerance. Induction of immune tolerance requires activating immune activation too, whereas immune suppression precludes this process. Immunotherapy alone my not suffice without engaging islets to restore tolerance and preserve beta-cell function. SUMMARY New insight into the role of islet tissue and its interaction with its environment in preserving or breaking tolerance has contributed to understand the development of islet autoimmunity and T1D. Knowing which factors in islets and the immune system contribute to maintaining, breaking, and restoring the balance in the immune system is critical to prevent initiation and reverse disease progression, and guides the design of novel tolerogenic strategies for durable therapeutic intervention and remission that target both the immune system and distressed islets.
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Affiliation(s)
- Neslihan Erdem
- The Arthur Riggs Diabetes & Metabolism Research Institute at the Beckman Research Institute
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Enrique Montero
- The Arthur Riggs Diabetes & Metabolism Research Institute at the Beckman Research Institute
| | - Bart O Roep
- The Arthur Riggs Diabetes & Metabolism Research Institute at the Beckman Research Institute
- Department Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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31
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Ríos-Ríos WDJ, Sosa-Luis SA, Torres-Aguilar H. Current advances in using tolerogenic dendritic cells as a therapeutic alternative in the treatment of type 1 diabetes. World J Diabetes 2021; 12:603-615. [PMID: 33995848 PMCID: PMC8107985 DOI: 10.4239/wjd.v12.i5.603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/26/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells of the pancreatic islets by autoreactive T cells, leading to high blood glucose levels and severe long-term complications. The typical treatment indicated in T1D is exogenous insulin administration, which controls glucose levels; however, it does not stop the autoimmune process. Various strategies have been implemented aimed at stopping β-cell destruction, such as cellular therapy. Dendritic cells (DCs) as an alternative in cellular therapy have gained great interest for autoimmune disease therapy due to their plasticity to acquire immunoregulatory properties both in vivo and in vitro, performing functions such as anti-inflammatory cytokine secretion and suppression of autoreactive lymphocytes, which are dependent of their tolerogenic phenotype, displayed by features such as semimature phenotype, low surface expression of stimulatory molecules to prime T cells, as well as the elevated expression of inhibitory markers. DCs may be obtained and propagated easily in optimal amounts from peripheral blood or bone marrow precursors, such as monocytes or hematopoietic stem cells, respectively; therefore, various protocols have been established for tolerogenic (tol)DCs manufacturing for therapeutic research in the treatment of T1D. In this review, we address the current advances in the use of tolDCs for T1D therapy, encompassing protocols for their manufacturing, the data obtained from preclinical studies carried out, and the status of clinical research evaluating the safety, feasibility, and effectiveness of tolDCs.
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Affiliation(s)
- William de Jesús Ríos-Ríos
- Department of Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico
| | - Sorely Adelina Sosa-Luis
- Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City 07360, Mexico
| | - Honorio Torres-Aguilar
- Department of Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca, Oaxaca 68120, Mexico
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Roep BO, Thomaidou S, van Tienhoven R, Zaldumbide A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nat Rev Endocrinol 2021; 17:150-161. [PMID: 33293704 PMCID: PMC7722981 DOI: 10.1038/s41574-020-00443-4] [Citation(s) in RCA: 306] [Impact Index Per Article: 76.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/04/2020] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing β-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that autoreactive T cells mistakenly destroy healthy ('innocent') β-cells. We propose an alternative view in which the β-cell is the key contributor to the disease. By their nature and function, β-cells are prone to biosynthetic stress with limited measures for self-defence. β-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone. This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize β-cells, in combination with immune intervention strategies, to reverse the disease. We present the case that dysfunction occurs in both the immune system and β-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus. Next, we build the case for the β-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity. Finally, we synthesize a model ('connecting the dots') in which both β-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.
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Affiliation(s)
- Bart O Roep
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute at City of Hope, Los Angeles, CA, USA.
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
| | - Sofia Thomaidou
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - René van Tienhoven
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute at City of Hope, Los Angeles, CA, USA
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
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33
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Hosszu A, Kaucsar T, Seeliger E, Fekete A. Animal Models of Renal Pathophysiology and Disease. Methods Mol Biol 2021; 2216:27-44. [PMID: 33475992 DOI: 10.1007/978-1-0716-0978-1_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Renal diseases remain devastating illnesses with unacceptably high rates of mortality and morbidity worldwide. Animal models are essential tools to better understand the pathomechanisms of kidney-related illnesses and to develop new, successful therapeutic strategies. Magnetic resonance imaging (MRI) has been actively explored in the last decades for assessing renal function, perfusion, tissue oxygenation as well as the degree of fibrosis and inflammation. This chapter aims to provide a comprehensive overview of animal models of acute and chronic kidney diseases, highlighting MRI-specific considerations, advantages, and pitfalls, and thus assisting the researcher in experiment planning.This publication is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers.
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Affiliation(s)
- Adam Hosszu
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Tamas Kaucsar
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Erdmann Seeliger
- Working Group Integrative Kidney Physiology, Institute of Physiology, Charité-University Medicine Berlin, Berlin, Germany
| | - Andrea Fekete
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
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Carré A, Richardson SJ, Larger E, Mallone R. Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset? Diabetologia 2021; 64:15-25. [PMID: 33084970 PMCID: PMC7717061 DOI: 10.1007/s00125-020-05298-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 08/20/2020] [Indexed: 12/31/2022]
Abstract
Available evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo 'humanised' mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the 'benign' islet autoimmunity of healthy individuals. Graphical abstract.
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Affiliation(s)
- Alexia Carré
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Sarah J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
| | - Etienne Larger
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Cochin Hospital, Service de Diabétologie et Immunologie Clinique, Paris, France
| | - Roberto Mallone
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France.
- Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Cochin Hospital, Service de Diabétologie et Immunologie Clinique, Paris, France.
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35
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Sun L, Jin CH, Tan S, Liu W, Yang YG. Human Immune System Mice With Autologous Tumor for Modeling Cancer Immunotherapies. Front Immunol 2020; 11:591669. [PMID: 33133105 PMCID: PMC7578411 DOI: 10.3389/fimmu.2020.591669] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 09/22/2020] [Indexed: 12/30/2022] Open
Abstract
Mouse models are the most commonly used in vivo system for biomedical research, in which immune-related diseases and therapies can be investigated in syngeneic and immunologically intact hosts. However, because there are significant differences between rodent and human, most findings from conventional mouse models cannot be applied to humans. The humanized mouse with a functional human immune system, also referred to as human immune system (HIS) mouse, is the only model available to date for in vivo studies in real-time of human immune function under physiological and pathological conditions. HIS mice with human tumor xenografts are considered an emerging and promising in vivo model for modeling human cancer immunotherapy. In this review, we briefly discuss the protocols to construct HIS mice and elaborate their pros and cons. Particular attention is given to HIS mouse models with human tumor that is autologous or genetically identical to the human immune system, which are discussed with examples of their usefulness in modeling human cancer immunotherapies.
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Affiliation(s)
- Liguang Sun
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Chun-Hui Jin
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,Department of Pathology, The First Hospital of Jilin University, Changchun, China
| | - Shulian Tan
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China.,International Center of Future Science, Jilin University, Changchun, China
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36
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Ma H, Jeppesen JF, Jaenisch R. Human T Cells Expressing a CD19 CAR-T Receptor Provide Insights into Mechanisms of Human CD19-Positive β Cell Destruction. CELL REPORTS MEDICINE 2020; 1:100097. [PMID: 33205073 PMCID: PMC7659530 DOI: 10.1016/j.xcrm.2020.100097] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/24/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022]
Abstract
Autoimmune destruction of pancreatic β cells underlies type 1 diabetes (T1D). To understand T cell-mediated immune effects on human pancreatic β cells, we combine β cell-specific expression of a model antigen, CD19, and anti-CD19 chimeric antigen receptor T (CAR-T) cells. Coculturing CD19-expressing β-like cells and CD19 CAR-T cells results in T cell-mediated β-like cell death with release of activated T cell cytokines. Transcriptome analysis of β-like cells and human islets treated with conditioned medium of the immune reaction identifies upregulation of immune reaction genes and the pyroptosis mediator GSDMD as well as its activator CASP4. Caspase-4-mediated cleaved GSDMD is detected in β-like cells under inflammation and endoplasmic reticulum (ER) stress conditions. Among immune-regulatory genes, PDL1 is one of the most upregulated, and PDL1 overexpression partially protects human β-like cells transplanted into mice. This experimental platform identifies potential mechanisms of β cell destruction and may allow testing of therapeutic strategies.
CD19-expressing β-like cells differentiated from human ES cells are functional Tractable in vitro and in vivo killing of CD19-expressing β-like cells by CAR-T cells Upregulation of pyroptosis factors GSDMD and CAPS4 during β-like cell inflammation PDL1-overexpressing in β-like cells partially protects against reactive T cells
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Affiliation(s)
- Haiting Ma
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Jacob F Jeppesen
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Global Drug Discovery, Novo Nordisk, Cambridge, MA 02142, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142
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37
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Lombardi A, Concepcion E, Hou H, Arib H, Mezei M, Osman R, Tomer Y. Retro-inverso D-peptides as a novel targeted immunotherapy for Type 1 diabetes. J Autoimmun 2020; 115:102543. [PMID: 32951964 DOI: 10.1016/j.jaut.2020.102543] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 08/29/2020] [Accepted: 08/30/2020] [Indexed: 02/07/2023]
Abstract
Over the past four decades, the number of people with Type 1 Diabetes (T1D) has increased by 4% per year, making it an important public health challenge. Currently, no curative therapy exists for T1D and the only available treatment is insulin replacement. HLA-DQ8 has been shown to present antigenic islet peptides driving the activation of CD4+ T-cells in T1D patients. Specifically, the insulin peptide InsB:9-23 activates self-reactive CD4+ T-cells, causing pancreatic beta cell destruction. The aim of the current study was to identify retro-inverso-d-amino acid based peptides (RI-D-peptides) that can suppress T-cell activation by blocking the presentation of InsB:9-23 peptide within HLA-DQ8 pocket. We identified a RI-D-peptide (RI-EXT) that inhibited InsB:9-23 binding to recombinant HLA-DQ8 molecule, as well as its binding to DQ8 expressed on human B-cells. RI-EXT prevented T-cell activation in a cellular antigen presentation assay containing human DQ8 cells loaded with InsB:9-23 peptide and murine T-cells expressing a human T-cell receptor specific for the InsB:9-23-DQ8 complex. Moreover, RI-EXT blocked T-cell activation by InsB:9-23 in a humanized DQ8 mice both ex vivo and in vivo, as shown by decreased production of IL-2 and IFN-γ and reduced lymphocyte proliferation. Interestingly, RI-EXT also blocked lymphocyte activation and proliferation by InsB:9-23 in PBMCs isolated from recent onset DQ8-T1D patients. In summary, we discovered a RI-D-peptide that blocks InsB:9-23 binding to HLA-DQ8 and its presentation to T-cells in T1D. These findings set the stage for using our approach as a novel therapy for patients with T1D and potentially other autoimmune diseases.
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Affiliation(s)
- Angela Lombardi
- Department of Medicine, Division of Endocrinology, Department of Microbiology and Immunology, The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Erlinda Concepcion
- Department of Medicine, Division of Endocrinology, Department of Microbiology and Immunology, The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Hanxi Hou
- Department of Medicine, Division of Endocrinology, Department of Microbiology and Immunology, The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Hanane Arib
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mihaly Mezei
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Roman Osman
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yaron Tomer
- Department of Medicine, Division of Endocrinology, Department of Microbiology and Immunology, The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA
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38
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Tian H, Lyu Y, Yang YG, Hu Z. Humanized Rodent Models for Cancer Research. Front Oncol 2020; 10:1696. [PMID: 33042811 PMCID: PMC7518015 DOI: 10.3389/fonc.2020.01696] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 07/30/2020] [Indexed: 12/18/2022] Open
Abstract
As one of the most popular laboratory animal models, rodents have been playing crucial roles in mechanistic investigations of oncogenesis as well as anticancer drug or regimen discoveries. However, rodent tumors show different or no responses to therapies against human cancers, and thus, in recent years, increased attention has been given to mouse models with xenografted or spontaneous human cancer cells. By combining with the human immune system (HIS) mice, these models have become more sophisticated and robust, enabling in vivo exploration of human cancer immunology and immunotherapy. In this review, we summarize the pros and cons of these humanized mouse models, with a focus on their potential as an in vivo platform for human cancer research. We also discuss the strategies for further improving these models.
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Affiliation(s)
- Huimin Tian
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yanan Lyu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China.,International Center of Future Science, Jilin University, Changchun, China
| | - Zheng Hu
- Key Laboratory of Organ Regeneration & Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China.,National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
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Madley R, Nauman G, Danzl N, Borsotti C, Khosravi Maharlooei M, Li HW, Chavez E, Creusot RJ, Nakayama M, Roep B, Sykes M. Negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen in the human thymus. J Transl Autoimmun 2020; 3:100061. [PMID: 32875283 PMCID: PMC7451786 DOI: 10.1016/j.jtauto.2020.100061] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/02/2020] [Indexed: 12/15/2022] Open
Abstract
During T cell development in mice, thymic negative selection deletes cells with the potential to recognize and react to self-antigens. In human T cell-dependent autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, T cells reactive to autoantigens are thought to escape negative selection, traffic to the periphery and attack self-tissues. However, physiological thymic negative selection of autoreactive human T cells has not been previously studied. We now describe a human T-cell receptor-transgenic humanized mouse model that permits the study of autoreactive T-cell development in a human thymus. Our studies demonstrate that thymocytes expressing the autoreactive Clone 5 TCR, which recognizes insulin B:9-23 presented by HLA-DQ8, are efficiently negatively selected at the double and single positive stage in human immune systems derived from HLA-DQ8+ HSCs. In the absence of hematopoietic expression of the HLA restriction element, negative selection of Clone 5 is less efficient and restricted to the single positive stage. To our knowledge, these data provide the first demonstration of negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen. Intrathymic antigen presenting cells are required to delete less mature thymocytes, while presentation by medullary thymic epithelial cells may be sufficient to delete more mature single positive cells. These observations set the stage for investigation of putative defects in negative selection in human autoimmune diseases.
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Affiliation(s)
- Rachel Madley
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA,Columbia University Department of Microbiology and Immunology, New York, NY, 10032, USA
| | - Grace Nauman
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA,Columbia University Department of Microbiology and Immunology, New York, NY, 10032, USA
| | - Nichole Danzl
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Chiara Borsotti
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Mohsen Khosravi Maharlooei
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Hao Wei Li
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Estefania Chavez
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Remi J. Creusot
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Bart Roep
- Department of Immunohaematology & Blood Transfusion, Leiden University Medical Center, 2300 RC, Leiden, the Netherlands,Department of Diabetes Immunology, Diabetes & Metabolism Research Institute at the Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA,Columbia University Department of Microbiology and Immunology, New York, NY, 10032, USA,Columbia University Department of Surgery, New York, NY, 10032, USA,Corresponding author. Columbia Center for Translational Immunology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, 10032, USA.
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Stripecke R, Münz C, Schuringa JJ, Bissig K, Soper B, Meeham T, Yao L, Di Santo JP, Brehm M, Rodriguez E, Wege AK, Bonnet D, Guionaud S, Howard KE, Kitchen S, Klein F, Saeb‐Parsy K, Sam J, Sharma AD, Trumpp A, Trusolino L, Bult C, Shultz L. Innovations, challenges, and minimal information for standardization of humanized mice. EMBO Mol Med 2020; 12:e8662. [PMID: 32578942 PMCID: PMC7338801 DOI: 10.15252/emmm.201708662] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 04/29/2020] [Accepted: 05/14/2020] [Indexed: 12/12/2022] Open
Abstract
Mice xenotransplanted with human cells and/or expressing human gene products (also known as "humanized mice") recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo context for understanding of human-specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring different facets of humanized mouse models has steadily increased in past years, it is becoming evident that standardized reporting is needed in the field. Therefore, an international community-driven resource called "Minimal Information for Standardization of Humanized Mice" (MISHUM) has been created for the purpose of enhancing rigor and reproducibility of studies in the field. Within MISHUM, we propose comprehensive guidelines for reporting critical information generated using humanized mice.
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Affiliation(s)
- Renata Stripecke
- Regenerative Immune Therapies AppliedHannover Medical SchoolHannoverGermany
- German Center for Infection Research (DZIF)Hannover RegionGermany
| | - Christian Münz
- Viral ImmunobiologyInstitute of Experimental ImmunologyUniversity of ZurichZurichSwitzerland
| | - Jan Jacob Schuringa
- Department of HematologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | | | | | | | | | | | - Michael Brehm
- University of Massachusetts Medical SchoolWorcesterMAUSA
| | | | - Anja Kathrin Wege
- Department of Gynecology and ObstetricsUniversity Cancer Center RegensburgRegensburgGermany
| | | | | | | | - Scott Kitchen
- University of California, Los AngelesLos AngelesCAUSA
| | | | | | | | - Amar Deep Sharma
- Regenerative Immune Therapies AppliedHannover Medical SchoolHannoverGermany
| | - Andreas Trumpp
- Division of Stem Cells and CancerGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH)HeidelbergGermany
| | - Livio Trusolino
- Department of OncologyUniversity of Torino Medical SchoolTurinItaly
- Candiolo Cancer Institute FPO IRCCSCandioloItaly
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de Groot PF, Nikolic T, Imangaliyev S, Bekkering S, Duinkerken G, Keij FM, Herrema H, Winkelmeijer M, Kroon J, Levin E, Hutten B, Kemper EM, Simsek S, Levels JHM, van Hoorn FA, Bindraban R, Berkvens A, Dallinga-Thie GM, Davids M, Holleman F, Hoekstra JBL, Stroes ESG, Netea M, van Raalte DH, Roep BO, Nieuwdorp M. Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial. Diabetologia 2020; 63:597-610. [PMID: 31915895 DOI: 10.1007/s00125-019-05073-8] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 11/06/2019] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.
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Affiliation(s)
- Pieter F de Groot
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands.
| | - Tatjana Nikolic
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Sultan Imangaliyev
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Siroon Bekkering
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Gaby Duinkerken
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Fleur M Keij
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Hilde Herrema
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Maaike Winkelmeijer
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Jeffrey Kroon
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Evgeni Levin
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Barbara Hutten
- Department of Epidemiology, Amsterdam University Medical Centers, Academic Medical Centre, Amsterdam, the Netherlands
| | - Elles M Kemper
- Clinical Pharmacy, Amsterdam University Medical Centers, Academic Medical Centre, Amsterdam, the Netherlands
| | - Suat Simsek
- Department of Internal Medicine, Alkmaar Medical Center (MCA), Alkmaar, the Netherlands
| | - Johannes H M Levels
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Flora A van Hoorn
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Renuka Bindraban
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Alicia Berkvens
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Geesje M Dallinga-Thie
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Mark Davids
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Frits Holleman
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Joost B L Hoekstra
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Erik S G Stroes
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
| | - Mihai Netea
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Daniël H van Raalte
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, VU University Medical Centre, Amsterdam, the Netherlands
| | - Bart O Roep
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute at the Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Academic Medical Center, Meibergdreef 9, Room D3-316, 1105 AZ, Amsterdam, the Netherlands
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, VU University Medical Centre, Amsterdam, the Netherlands
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Martinov T, Fife BT. Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance. Ann N Y Acad Sci 2020; 1461:73-103. [PMID: 31025378 PMCID: PMC6994200 DOI: 10.1111/nyas.14106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/25/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) affects over a million Americans, and disease incidence is on the rise. Despite decades of research, there is still no cure for this disease. Exciting beta cell replacement strategies are being developed, but in order for such approaches to work, targeted immunotherapies must be designed. To selectively halt the autoimmune response, researchers must first understand how this response is regulated and which tolerance checkpoints fail during T1D development. Herein, we discuss the current understanding of T1D pathogenesis in humans, genetic and environmental risk factors, presumed roles of CD4+ and CD8+ T cells as well as B cells, and implicated autoantigens. We also highlight studies in non-obese diabetic mice that have demonstrated the requirement for CD4+ and CD8+ T cells and B cells in driving T1D pathology. We present an overview of central and peripheral tolerance mechanisms and comment on existing controversies in the field regarding central tolerance. Finally, we discuss T cell- and B cell-intrinsic tolerance mechanisms, with an emphasis on the roles of inhibitory receptors in maintaining islet tolerance in humans and in diabetes-prone mice, and strategies employed to date to harness inhibitory receptor signaling to prevent or reverse T1D.
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Affiliation(s)
- Tijana Martinov
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Brian T Fife
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota
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43
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Liu B, Xiang Y, Liu Z, Zhou Z. Past, present and future of latent autoimmune diabetes in adults. Diabetes Metab Res Rev 2020; 36:e3205. [PMID: 31318117 DOI: 10.1002/dmrr.3205] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 06/14/2019] [Accepted: 07/11/2019] [Indexed: 12/14/2022]
Abstract
Latent autoimmune diabetes in adults (LADA) is the most common form of autoimmune diabetes diagnosed in adults. Similar to type 1 diabetes, the prevalence of LADA is impacted by ethnicity and geography. LADA is characterized by β cell loss due to autoimmunity and insulin resistance and has highly heterogeneous clinical features, autoimmunity, and genetics in a glutamic acid decarboxylase antibody (GADA) titre-dependent manner, suggesting LADA is part of a continuum spectrum between type 1 and type 2 diabetes. Although LADA is the most frequent form of autoimmune diabetes diagnosed in adults, clinical trials involving LADA are scarce. Here we review the recent advancements in LADA epidemiology, clinical features, pathogenesis, and interventions. We also highlight the environmental factors that are thought to play an important role in addition to genetics in the pathogenesis of LADA. In the future, high-throughput molecular profiles might shed light on the nature of LADA among the wide spectrum of diabetes and offer new opportunities to identify novel LADA-specific biomarkers.
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Affiliation(s)
- Bingwen Liu
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, China
| | - Yufei Xiang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, China
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Central South University, Changsha, China
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44
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Replacing murine insulin 1 with human insulin protects NOD mice from diabetes. PLoS One 2019; 14:e0225021. [PMID: 31821343 PMCID: PMC6903741 DOI: 10.1371/journal.pone.0225021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 11/21/2019] [Indexed: 12/11/2022] Open
Abstract
Type 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (Ins) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15–20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.
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45
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Alves da Costa T, Lang J, Torres RM, Pelanda R. The development of human immune system mice and their use to study tolerance and autoimmunity. J Transl Autoimmun 2019; 2:100021. [PMID: 32743507 PMCID: PMC7388352 DOI: 10.1016/j.jtauto.2019.100021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 11/04/2019] [Indexed: 12/26/2022] Open
Abstract
Autoimmune diseases evolve from complex interactions between the immune system and self-antigens and involve several genetic attributes, environmental triggers and diverse cell types. Research using experimental mouse models has contributed key knowledge on the mechanisms that underlie these diseases in humans, but differences between the mouse and human immune systems can and, at times, do undermine the translational significance of these findings. The use of human immune system (HIS) mice enables the utility of mouse models with greater relevance for human diseases. As the name conveys, these mice are reconstituted with mature human immune cells transferred directly from peripheral blood or via transplantation of human hematopoietic stem cells that nucleate the generation of a complex human immune system. The function of the human immune system in HIS mice has improved over the years with the stepwise development of better models. HIS mice exhibit key benefits of the murine animal model, such as small size, robust and rapid reproduction and ease of experimental manipulation. Importantly, HIS mice also provide an applicable in vivo setting that permit the investigation of the physiological and pathological functions of the human immune system and its response to novel treatments. With the gaining popularity of HIS mice in the last decade, the potential of this model has been exploited for research in basic science, infectious diseases, cancer, and autoimmunity. In this review we focus on the use of HIS mice in autoimmune studies to stimulate further development of these valuable models.
Human immune system (HIS) mice bear components of the human immune system. HIS mice engraft with human blood or hematopoietic stem cells, and sometimes thymus. HIS mice are used to investigate development and function of the human immune system. Immunological tolerance and autoimmune responses can be studied in HIS mice. HIS models of autoimmunity vary in complexity and in ability to represent disease.
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Affiliation(s)
- Thiago Alves da Costa
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Julie Lang
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Raul M. Torres
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA
| | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA
- Corresponding author. University of Colorado School of Medicine, 12800 East 19th Avenue Mail Stop 8333, Aurora, CO, 80045-2508, USA.
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46
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Platt JL, Cascalho M, Piedrahita JA. Xenotransplantation: Progress Along Paths Uncertain from Models to Application. ILAR J 2019; 59:286-308. [PMID: 30541147 DOI: 10.1093/ilar/ily015] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 08/23/2018] [Indexed: 12/18/2022] Open
Abstract
For more than a century, transplantation of tissues and organs from animals into man, xenotransplantation, has been viewed as a potential way to treat disease. Ironically, interest in xenotransplantation was fueled especially by successful application of allotransplantation, that is, transplantation of human tissue and organs, as a treatment for a variety of diseases, especially organ failure because scarcity of human tissues limited allotransplantation to a fraction of those who could benefit. In principle, use of animals such as pigs as a source of transplants would allow transplantation to exert a vastly greater impact than allotransplantation on medicine and public health. However, biological barriers to xenotransplantation, including immunity of the recipient, incompatibility of biological systems, and transmission of novel infectious agents, are believed to exceed the barriers to allotransplantation and presently to hinder clinical applications. One way potentially to address the barriers to xenotransplantation is by genetic engineering animal sources. The last 2 decades have brought progressive advances in approaches that can be applied to genetic modification of large animals. Application of these approaches to genetic engineering of pigs has contributed to dramatic improvement in the outcome of experimental xenografts in nonhuman primates and have encouraged the development of a new type of xenograft, a reverse xenograft, in which human stem cells are introduced into pigs under conditions that support differentiation and expansion into functional tissues and potentially organs. These advances make it appropriate to consider the potential limitation of genetic engineering and of current models for advancing the clinical applications of xenotransplantation and reverse xenotransplantation.
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Affiliation(s)
- Jeffrey L Platt
- Surgery, Microbiology & Immunology, and Transplantation Biology, University of Michigan, Ann Arbor, Michigan
| | - Marilia Cascalho
- Surgery, Microbiology & Immunology, and Transplantation Biology, University of Michigan, Ann Arbor, Michigan
| | - Jorge A Piedrahita
- Translational Medicine and The Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina
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47
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Peters L, Posgai A, Brusko TM. Islet-immune interactions in type 1 diabetes: the nexus of beta cell destruction. Clin Exp Immunol 2019; 198:326-340. [PMID: 31309537 DOI: 10.1111/cei.13349] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2019] [Indexed: 12/12/2022] Open
Abstract
Recent studies in Type 1 Diabetes (T1D) support an emerging model of disease pathogenesis that involves intrinsic β-cell fragility combined with defects in both innate and adaptive immune cell regulation. This combination of defects induces systematic changes leading to organ-level atrophy and dysfunction of both the endocrine and exocrine portions of the pancreas, ultimately culminating in insulin deficiency and β-cell destruction. In this review, we discuss the animal model data and human tissue studies that have informed our current understanding of the cross-talk that occurs between β-cells, the resident stroma, and immune cells that potentiate T1D. Specifically, we will review the cellular and molecular signatures emerging from studies on tissues derived from organ procurement programs, focusing on in situ defects occurring within the T1D islet microenvironment, many of which are not yet detectable by standard peripheral blood biomarkers. In addition to improved access to organ donor tissues, various methodological advances, including immune receptor repertoire sequencing and single-cell molecular profiling, are poised to improve our understanding of antigen-specific autoimmunity during disease development. Collectively, the knowledge gains from these studies at the islet-immune interface are enhancing our understanding of T1D heterogeneity, likely to be an essential component for instructing future efforts to develop targeted interventions to restore immune tolerance and preserve β-cell mass and function.
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Affiliation(s)
- L Peters
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - A Posgai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - T M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
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48
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Chaperones may cause the focus of diabetes autoimmunity on distinct (pro)insulin peptides. J Autoimmun 2019; 105:102304. [PMID: 31327552 DOI: 10.1016/j.jaut.2019.102304] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/09/2019] [Accepted: 07/14/2019] [Indexed: 12/25/2022]
Abstract
It is still an enigma why T cell autoreactivity in type 1 diabetes targets few beta cell antigens only. Among these, one primary autoantigen is pro(insulin). Autoimmune T cells preferentially recognise three epitopes on the proinsulin molecule, of which the peptide region B:11-23 is the dominant one. Interestingly, the three regions superimpose with binding sites of the chaperone hsp70, the region B:11-23 being the strongest binding one. Absence of an intact core region B:15-17 prevents autoimmune diabetes in NOD as well as binding of hsp70. A role of hsp70 in selecting autoimmune epitopes is supported by the ability of this and other chaperones to deliver bound peptides to MHC class I and II molecules for efficient antigen presentation. Binding of hsp70 to receptors on antigen presenting cells such as TLR4 results in costimulatory signals for T cell activation. Strongest effects are seen for the mixture of hsp70 with the peptide B:11-23. Thus, hsp70 may assist in proinsulin epitope selection and efficient presentation to autoreactive T cells. The concept of chaperone guided immune reactivity may also apply to other autoimmune diseases.
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49
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Allen TM, Brehm MA, Bridges S, Ferguson S, Kumar P, Mirochnitchenko O, Palucka K, Pelanda R, Sanders-Beer B, Shultz LD, Su L, PrabhuDas M. Humanized immune system mouse models: progress, challenges and opportunities. Nat Immunol 2019; 20:770-774. [PMID: 31160798 PMCID: PMC7265413 DOI: 10.1038/s41590-019-0416-z] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Over 30 key leaders in the field participated in a 1-day workshop entitled ‘Recent Advances and Opportunities in the Development and Use of Humanized Immune System Mouse Models’ to discuss the benefits and limitations of using human fetal tissue versus non-fetal tissue sources to generate mice with a humanized immune system. This Comment summarizes the workshop discussions, including highlights of some of the key advances made through the use of humanized mice in improving the understanding of immune system function and developing novel therapeutics for the treatment of infectious, immunological and allergic diseases, as well as current challenges in the production, characterization and utilization of these animal models.
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Affiliation(s)
- Todd M Allen
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Michael A Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Sandra Bridges
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institutes of Health, Rockville, MD, USA
| | - Stacy Ferguson
- Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Priti Kumar
- Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Oleg Mirochnitchenko
- Office of Research Infrastructure Programs, Division of Program Coordination, Planning, and Strategic Initiatives, Office of the Director, National Institutes of Health, Bethesda, MD, USA
| | | | - Roberta Pelanda
- Department of Immunology and Microbiology, University of Colorado, Aurora, CO, USA
| | - Brigitte Sanders-Beer
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institutes of Health, Rockville, MD, USA
| | | | - Lishan Su
- University of North Carolina, Chapel Hill, Chapel Hill, NC, USA
| | - Mercy PrabhuDas
- Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
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50
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Shultz LD, Keck J, Burzenski L, Jangalwe S, Vaidya S, Greiner DL, Brehm MA. Humanized mouse models of immunological diseases and precision medicine. Mamm Genome 2019; 30:123-142. [PMID: 30847553 PMCID: PMC6610695 DOI: 10.1007/s00335-019-09796-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 03/02/2019] [Indexed: 12/25/2022]
Abstract
With the increase in knowledge resulting from the sequencing of the human genome, the genetic basis for the underlying differences in individuals, their diseases, and how they respond to therapies is starting to be understood. This has formed the foundation for the era of precision medicine in many human diseases that is beginning to be implemented in the clinic, particularly in cancer. However, preclinical testing of therapeutic approaches based on individual biology will need to be validated in animal models prior to translation into patients. Although animal models, particularly murine models, have provided significant information on the basic biology underlying immune responses in various diseases and the response to therapy, murine and human immune systems differ markedly. These fundamental differences may be the underlying reason why many of the positive therapeutic responses observed in mice have not translated directly into the clinic. There is a critical need for preclinical animal models in which human immune responses can be investigated. For this, many investigators are using humanized mice, i.e., immunodeficient mice engrafted with functional human cells, tissues, and immune systems. We will briefly review the history of humanized mice, the remaining limitations, approaches to overcome them and how humanized mouse models are being used as a preclinical bridge in precision medicine for evaluation of human therapies prior to their implementation in the clinic.
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Affiliation(s)
- Leonard D Shultz
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
| | - James Keck
- The Jackson Laboratory, 1650 Santa Ana Avenue, Sacramento, CA, 95838, USA
| | - Lisa Burzenski
- The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA
| | - Sonal Jangalwe
- Diabetes Center of Excellence, The University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
| | - Shantashri Vaidya
- Diabetes Center of Excellence, The University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
| | - Dale L Greiner
- Diabetes Center of Excellence, The University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
| | - Michael A Brehm
- Diabetes Center of Excellence, The University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA, 01605, USA
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