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1
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McGonigle P. How Biologics Have Changed the Drug Discovery Landscape. Annu Rev Pharmacol Toxicol 2025; 65:29-46. [PMID: 39389098 DOI: 10.1146/annurev-pharmtox-061724-080811] [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] [Indexed: 10/12/2024]
Abstract
Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA-based therapeutics and the application of artificial intelligence.
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Affiliation(s)
- Paul McGonigle
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA;
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2
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Han JW, Park SH. Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:257-272. [PMID: 39696994 PMCID: PMC11732766 DOI: 10.4285/ctr.24.0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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3
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Chauhan K, Tyagi M. Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond. FRONTIERS IN OPHTHALMOLOGY 2024; 4:1412930. [PMID: 39157460 PMCID: PMC11327136 DOI: 10.3389/fopht.2024.1412930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/16/2024] [Indexed: 08/20/2024]
Abstract
Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.
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Affiliation(s)
- Khushboo Chauhan
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
| | - Mudit Tyagi
- Saroja A Rao Centre for Uveitis, L V Prasad Eye Institute, Hyderabad, India
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
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4
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Symmonds J, Gaufin T, Xu C, Raehtz KD, Ribeiro RM, Pandrea I, Apetrei C. Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection. Viruses 2024; 16:972. [PMID: 38932264 PMCID: PMC11209256 DOI: 10.3390/v16060972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/31/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.
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Affiliation(s)
- Jen Symmonds
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Thaidra Gaufin
- Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA;
| | - Cuiling Xu
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Kevin D. Raehtz
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ruy M. Ribeiro
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
| | - Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Cristian Apetrei
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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5
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Sharma P, Joshi RV, Pritchard R, Xu K, Eicher MA. Therapeutic Antibodies in Medicine. Molecules 2023; 28:6438. [PMID: 37764213 PMCID: PMC10535987 DOI: 10.3390/molecules28186438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/05/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10-15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery.
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Affiliation(s)
- Prerna Sharma
- Geisinger Commonwealth School of Medicine, Scranton, PA 18509, USA
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Abou-Jaoudé M, Akiki D, Moussawi A, Abou-Jaoudé W. The impact of induction therapy in low-immunological risk kidney transplant recipients regardless of HLA matching. Transpl Immunol 2023; 76:101773. [PMID: 36526105 DOI: 10.1016/j.trim.2022.101773] [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: 07/14/2022] [Revised: 11/30/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Induction agents have proved to reduce the rate of acute rejection (AR) in kidney transplant recipients (KTRs) without improving long-term graft and patient survival (PS). OBJECTIVE This study evaluates the utility of induction therapy in low immunological risk KTRs regardless of donor-to-recipient HLA matching. METHODS We retrospectively reviewed the records of 218 patients undergoing kidney transplantation (KT). These patients were divided into two groups according to the usage of induction therapy: 82 did not receive any induction therapy (Group I), and 136 patients received either Anti-IL2 receptor antibodies or anti-thymocyte globulin (Group II). All patients had panel reactive antibody (PRA) < 20% and absence of donor-specific antibodies (DSA). The difference in outcomes were assessed at different intervals following KT. RESULTS The rate of bacterial infections at one year (p-value = 0.032) and the frequency of CMV disease (p-value = 0.044) were significantly higher in Group II (with induction therapy). The duration of hospital stay, the rate and severity of acute rejection, the occurrence of delayed graft function, the rate and type of surgical complications at one year, and the graft function and survival at one and three years were similar between the two groups (p-value = NS). In addition, the financial burden is much less in Group I (without induction therapy), reducing the total cost of the transplant procedure. CONCLUSION We conclude that induction therapy in low-immunological risk kidney transplant patients is not a must regardless of donor-to-recipient HLA matching. Therefore, induction therapy did not yield significant health results, but had negative financial consequences.
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Affiliation(s)
- Maroun Abou-Jaoudé
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; Department of Surgery, Middle East Institute of Health, Bsalim, Lebanon; Department of Surgery, Saint-George Hospital-UMC, Beirut, Lebanon.
| | - Dany Akiki
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Ali Moussawi
- Department of Nephrology, Middle East Institute of Health, Bsalim, Lebanon
| | - Walid Abou-Jaoudé
- Department of Nephrology, Middle East Institute of Health, Bsalim, Lebanon
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7
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Wang Z, Wang G, Lu H, Li H, Tang M, Tong A. Development of therapeutic antibodies for the treatment of diseases. MOLECULAR BIOMEDICINE 2022; 3:35. [PMID: 36418786 PMCID: PMC9684400 DOI: 10.1186/s43556-022-00100-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/24/2022] [Indexed: 11/25/2022] Open
Abstract
Since the first monoclonal antibody drug, muromonab-CD3, was approved for marketing in 1986, 165 antibody drugs have been approved or are under regulatory review worldwide. With the approval of new drugs for treating a wide range of diseases, including cancer and autoimmune and metabolic disorders, the therapeutic antibody drug market has experienced explosive growth. Monoclonal antibodies have been sought after by many biopharmaceutical companies and scientific research institutes due to their high specificity, strong targeting abilities, low toxicity, side effects, and high development success rate. The related industries and markets are growing rapidly, and therapeutic antibodies are one of the most important research and development areas in the field of biology and medicine. In recent years, great progress has been made in the key technologies and theoretical innovations provided by therapeutic antibodies, including antibody-drug conjugates, antibody-conjugated nuclides, bispecific antibodies, nanobodies, and other antibody analogs. Additionally, therapeutic antibodies can be combined with technologies used in other fields to create new cross-fields, such as chimeric antigen receptor T cells (CAR-T), CAR-natural killer cells (CAR-NK), and other cell therapy. This review summarizes the latest approved or in regulatory review therapeutic antibodies that have been approved or that are under regulatory review worldwide, as well as clinical research on these approaches and their development, and outlines antibody discovery strategies that have emerged during the development of therapeutic antibodies, such as hybridoma technology, phage display, preparation of fully human antibody from transgenic mice, single B-cell antibody technology, and artificial intelligence-assisted antibody discovery.
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Affiliation(s)
- Zeng Wang
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Guoqing Wang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Huaqing Lu
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjian Li
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Mei Tang
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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8
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Cheung J, Zahorowska B, Suranyi M, Wong JKW, Diep J, Spicer ST, Verma ND, Hodgkinson SJ, Hall BM. CD4 +CD25 + T regulatory cells in renal transplantation. Front Immunol 2022; 13:1017683. [PMID: 36426347 PMCID: PMC9681496 DOI: 10.3389/fimmu.2022.1017683] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/13/2022] [Indexed: 09/14/2023] Open
Abstract
The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4+CD25+Foxp3+T regulatory cells (Treg) can down-regulate allograft rejection and can induce immune tolerance to the allograft. Treg represent <10% of peripheral CD4+T cells and do not markedly increase in tolerant hosts. CD4+CD25+Foxp3+T cells include both resting and activated Treg that can be distinguished by several markers, many of which are also expressed by effector T cells. More detailed characterization of Treg to identify increased activated antigen-specific Treg may allow reduction of non-specific immunosuppression. Natural thymus derived resting Treg (tTreg) are CD4+CD25+Foxp3+T cells and only partially inhibit alloantigen presenting cell activation of effector cells. Cytokines produced by activated effector cells activate these tTreg to more potent alloantigen-activated Treg that may promote a state of operational tolerance. Activated Treg can be distinguished by several molecules they are induced to express, or whose expression they have suppressed. These include CD45RA/RO, cytokine receptors, chemokine receptors that alter pathways of migration and transcription factors, cytokines and suppression mediating molecules. As the total Treg population does not increase in operational tolerance, it is the activated Treg which may be the most informative to monitor. Here we review the methods used to monitor peripheral Treg, the effect of immunosuppressive regimens on Treg, and correlations with clinical outcomes such as graft survival and rejection. Experimental therapies involving ex vivo Treg expansion and administration in renal transplantation are not reviewed.
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Affiliation(s)
- Jason Cheung
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
| | | | - Michael Suranyi
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | | | - Jason Diep
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Stephen T. Spicer
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Nirupama D. Verma
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Suzanne J. Hodgkinson
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Bruce M. Hall
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
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9
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Lim SW, Shin YJ, Cui S, Ko EJ, Yoo SH, Chung BH, Yang CW. Therapeutic effect of multiple functional minicircle vector encoding anti-CD25/IL-10/CXCR3 in allograft rejection model. Korean J Intern Med 2022; 37:1031-1049. [PMID: 35725307 PMCID: PMC9449213 DOI: 10.3904/kjim.2021.299] [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: 06/30/2021] [Accepted: 01/04/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND/AIMS We previously proposed minicircle vector technology as the potential platform for the development and production of new biologics. In this study, we have designed a novel target molecule for the treatment of allograft rejection and evaluated its feasibility as the therapeutic agent in this disease using the minicircle vector system. METHODS We engineered vectors to carry cassette sequences for anti-CD25, interleukin-10 (IL-10), and C-X-C motif chemokine receptor 3 (CXCR3) fusion protein, and then isolated minicircle vectors from the parent vectors. We verified the substantial production of anti-CD25/IL-10/CXCR3 fusion protein from minicircles and their duration in HEK293T cells and mice models. We also evaluated whether minicircle-derived anti-CD25/IL-10/CXCR3 has therapeutic effects in a skin allograft in mice model. RESULTS We confirmed the production of anti-CD25/IL-10/CXCR3 from minicircle by its significant availability in cells transfected with the minicircle and in its conditioned media. After a single injection of minicircle by hydrodynamic injection via mouse tail vein, luminescence or red fluorescence was maintained until 40 days in the liver tissue, suggesting the production of anti-CD25/IL-10/CXCR3 protein from minicircles via protein synthesis machinery in the liver. Mice treated with the minicircle encoding anti-CD25/IL-10/CXCR3 showed prolonged skin allograft survival times accompanied by improved immunologic regulation e.g., reduction of the lymphocyte population of Th1, Th2, and Th17 and an induction of regulatory T cells. CONCLUSION These findings implied that self-generated anti-CD25/IL-10/CXCR3 protein drug by minicircle technology is functionally active and relevant for reducing allograft rejection. The minicircle vector system may be useful for developing new biological drugs, avoiding manufacturing or practical problems.
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Affiliation(s)
- Sun Woo Lim
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Yoo Jin Shin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Sheng Cui
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Eun Jeong Ko
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | | | - Byung Ha Chung
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Chul Woo Yang
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
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10
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Yélamos J. Current innovative engineered antibodies. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 369:1-43. [PMID: 35777861 DOI: 10.1016/bs.ircmb.2022.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Antibody engineering has developed very intensively since the invention of the hybridoma technology in 1975, and it now can generate therapeutic agents with high specificity and reduced adverse effects. Indeed, antibodies have become one of the most innovative therapeutic agents in recent years, with some landing in the top 10 bestselling pharmaceutical drugs. New antibodies are being approved every year, in different formats and for treating various illnesses, including cancer, autoimmune inflammatory diseases, metabolic diseases and infectious diseases. In this review, I summarize current progress in innovative engineered antibodies. Overall, this progress has led to the approval by regulatory authorities of more than 100 antibody-based molecules, with many others at various stages of clinical development, indicating the high growth potential of the field.
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Affiliation(s)
- José Yélamos
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain; Immunology Unit, Department of Pathology, Hospital del Mar, Barcelona, Spain.
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11
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Seron D, Rabant M, Becker JU, Roufosse C, Bellini MI, Böhmig GA, Budde K, Diekmann F, Glotz D, Hilbrands L, Loupy A, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation. Transpl Int 2022; 35:10135. [PMID: 35669975 PMCID: PMC9163314 DOI: 10.3389/ti.2022.10135] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/11/2022] [Indexed: 12/14/2022]
Abstract
The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.
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Affiliation(s)
- Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
| | - Marion Rabant
- Department of Pathology, Hôpital Necker–Enfants Malades, Paris, France
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Candice Roufosse
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | | | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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12
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Krämer J, Wiendl H. What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us? Neurotherapeutics 2022; 19:785-807. [PMID: 35794296 PMCID: PMC9294122 DOI: 10.1007/s13311-022-01246-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2022] [Indexed: 12/13/2022] Open
Abstract
In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II-III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these 'negative' experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte 'outside-in' traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood-brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for 'proof of concept', time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs.
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Affiliation(s)
- Julia Krämer
- Department of Neurology With Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany
| | - Heinz Wiendl
- Department of Neurology With Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149 Muenster, Germany
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13
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Evans RD, Lan JH, Kadatz M, Brar S, Chang DT, McMichael L, Gill J, Gill JS. Use and Outcomes of Induction Therapy in Well-Matched Kidney Transplant Recipients. Clin J Am Soc Nephrol 2022; 17:271-279. [PMID: 35131930 PMCID: PMC8823946 DOI: 10.2215/cjn.09170721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 11/30/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND OBJECTIVES The optimal induction treatment in low-immune risk kidney transplant recipients is uncertain. We therefore investigated the use and outcomes of induction immunosuppression in a low-risk cohort of patients who were well matched with their donor at HLA-A, -B, -DR, -DQB1 on the basis of serologic typing. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Our study was an observational study of first adult kidney-only transplant recipients in the United States recorded by the Organ Procurement and Transplant Network. RESULTS Among 2976 recipients, 57% were treated with T cell-depleting antibodies, 28% were treated with an IL-2 receptor antagonist, and 15% were treated without induction. There was no difference in allograft survival, death-censored graft survival, or death with function between patients treated with an IL-2 receptor antagonist and no induction therapy. In multivariable models, patients treated with T cell-depleting therapy had a similar risk of graft loss from any cause, including death (hazard ratio, 1.19; 95% confidence interval, 0.98 to 1.45), compared with patients treated with an IL-2 receptor antagonist or no induction. The findings were consistent in subgroup analyses of Black recipients, patients grouped by calculated panel reactive antibody, and donor source. The incidence of acute rejection at 1 year was low (≤5%) and did not vary between treatment groups. CONCLUSIONS Use of induction therapy with T cell-depleting therapy or IL-2 receptor antagonists in first kidney transplant recipients who are well matched with their donor at the HLA-A, -B, -DR, -DQB1 gene loci is not associated with improved post-transplant outcomes.
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Affiliation(s)
- Rhys D.R. Evans
- Division of Nephrology, Kidney Transplant Program, University of British Columbia, Vancouver, British Columbia, Canada
| | - James H. Lan
- Division of Nephrology, Kidney Transplant Program, University of British Columbia, Vancouver, British Columbia, Canada,Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Matthew Kadatz
- Division of Nephrology, Kidney Transplant Program, University of British Columbia, Vancouver, British Columbia, Canada,Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Sandeep Brar
- Division of Nephrology, Kidney Transplant Program, University of British Columbia, Vancouver, British Columbia, Canada
| | - Doris T. Chang
- Providence Health Research Institute, Vancouver, British Columbia, Canada
| | - Lachlan McMichael
- Division of Nephrology, Kidney Transplant Program, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jagbir Gill
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada,Providence Health Research Institute, Vancouver, British Columbia, Canada,Centre for Health Evaluation and Outcomes Sciences, Vancouver, British Columbia, Canada,University of British Columbia School of Population and Public Health, Vancouver, British Columbia, Canada
| | - John S. Gill
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada,Providence Health Research Institute, Vancouver, British Columbia, Canada,Department of Nephrology, Tufts–New England Medical Center, Boston, Massachusetts
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14
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Dehbashi M, Hojati Z, Motovali-bashi M, Ganjalikhany MR, Cho WC, Shimosaka A, Navabi P, Ganjalikhani-Hakemi M. A Novel CAR Expressing NK Cell Targeting CD25 With the Prospect of Overcoming Immune Escape Mechanism in Cancers. Front Oncol 2021; 11:649710. [PMID: 34055618 PMCID: PMC8160382 DOI: 10.3389/fonc.2021.649710] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023] Open
Abstract
For many years, high-affinity subunit of IL-2 receptor (CD25) has been considered as a promising therapeutic target for different pathologic conditions like allograft rejection, autoimmunity, and cancers. Although CD25 is transiently expressed by newly-activated T cells, it is the hallmark of regulatory T (Treg) cells which are the most important immunosuppressive elements in tumor microenvironment. Thus, Tregs can be considered as a potential target for chimeric antigen receptor (CAR)-based therapeutic approaches. On the other hand, due to some profound adverse effects pertaining to the use of CAR T cells, CAR NK cells have caught researchers' attention as a safer choice. Based on these, the aim of this study was to design and develop a CAR NK cell against CD25 as the most prominent biomarker of Tregs with the prospect of overcoming immune escape mechanism in solid and liquid cancers. In the current study, an anti-CD25 CAR was designed and evaluated by comprehensive in silico analyses. Then, using lentiviral transduction system, NK-92 cell line was engineered to express this anti-CD25 CAR construct. In vitro functional analyses of anti-CD25 CAR for its reactivity against CD25 antigen as well as for cytotoxicity and cytokine production assays against CD25 bearing Jurkat cell line were done. In silico analyses demonstrated that the anti-CD25 CAR transcript and scFv protein structures were stable and had proper interaction with the target. Also, in vitro analyses showed that the anti-CD25 CAR-engineered NK-92 cells were able to specifically detect and lyse target cells with an appropriate cytokine production and cytotoxic activity. To conclude, the results showed that this novel CAR NK cell is functional and warrant further investigations.
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Affiliation(s)
- Moein Dehbashi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Zohreh Hojati
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Majid Motovali-bashi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mohamad Reza Ganjalikhany
- Division of Biochemistry, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
| | - Akihiro Shimosaka
- Institute of Hematology, Peking Union Medical College, Beijing, China
| | - Parnian Navabi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mazdak Ganjalikhani-Hakemi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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15
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Kathirvel M, Mallick S, Sethi P, Thillai M, Durairaj MS, Nair K, Sunny A, Mathew JS, Varghese CT, Chandran B, Pillai Thankamony Amma BS, Menon RN, Balakrishnan D, Gopalakrishnan U, Surendran S. Randomized trial of steroid free immunosuppression with basiliximab induction in adult live donor liver transplantation (LDLT). HPB (Oxford) 2021; 23:666-674. [PMID: 33032883 DOI: 10.1016/j.hpb.2020.09.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Corticosteroids are an integral part of immunosuppression following solid organ transplantation, despite their metabolic complications. We conducted a randomized trial to evaluate the efficacy of steroid-free immunosuppression following live donor liver transplantation (LDLT). METHODS We randomized 104 patients stratified based on pre-transplant diabetic status to either a steroid-free arm (SF-arm) (Basiliximab + Tacrolimus and Azathioprine,n = 52) or Steroid arm (S-Arm) (Steroid + Tacrolimus + Azathioprine,n = 52). The primary endpoint was the occurrence of metabolic complications (new-onset diabetes after transplant (NODAT), new-onset systemic hypertension after transplant (NOSHT), post-transplant dyslipidemia) within 6 months after transplant. Secondary endpoints included biopsy-proven acute rejection (BPAR) within six months, patient and graft survival at 6 months. RESULTS The incidence NODAT was significantly higher in S-arm at 3 months (64.5%vs. 28.1%,p-0.004) and 6 months (51.6% vs. 15.6%,p-0.006). Likewise, the incidence of NOSHT (27.8% vs. 4.8%,p-0.01) and hypertriglyceridemia (26.7% vs. 8%,p-0.03) at six months was significantly higher in S-arm. However, there were no differences in BPAR (19.2% vs. 21.2%, p-0.81), time to first rejection (58 vs. 53 days, p-0.78), patient and graft survival (610 vs. 554 days,p- 0.22). CONCLUSION Following LDLT, basiliximab induction with tacrolimus and azathioprine maintenance resulted in significantly lower metabolic complications compared to the triple-drug regimen of steroid, tacrolimus, and azathioprine.
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Affiliation(s)
- Manikandan Kathirvel
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India.
| | - Shweta Mallick
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Pulkit Sethi
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Manoj Thillai
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Madhu S Durairaj
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Krishnanunni Nair
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Aleena Sunny
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Johns S Mathew
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Christi T Varghese
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Biju Chandran
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Binoj S Pillai Thankamony Amma
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Ramachandran N Menon
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Dinesh Balakrishnan
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Unnikrishnan Gopalakrishnan
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
| | - Sudhindran Surendran
- Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India
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16
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Li X, Lau SK, Woo PC. Fungal infection risks associated with the use of cytokine antagonists and immune checkpoint inhibitors. Exp Biol Med (Maywood) 2020; 245:1104-1114. [PMID: 32640893 DOI: 10.1177/1535370220939862] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
IMPACT STATEMENT The risk of opportunistic infections due to fungi is relatively less well addressed in patients receiving biologic agents, compared with other opportunistic bacterial and viral infections. There is a lack of consensus guideline on the screening, prophylaxis, and management of fungal infection in patients anticipated to receive or actively receiving biologic therapy. In addition, invasive mycosis in immunocompromised patients is associated with high mortality and morbidity. This review highlighted the risk of fungal infection in patients receiving cytokine antagonists and immune checkpoint inhibitors, two big categories of biologic agents that are widely used in the treatment of various autoimmune and malignant conditions, often in combination with other immunomodulatory or immunosuppressive agents but also as standalone therapy. The adverse outcomes of opportunistic fungal infection in these patients can be reduced by heightened awareness, active case finding, and prompt treatment.
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Affiliation(s)
- Xin Li
- Department of Microbiology, The University of Hong Kong, Hong Kong
| | - Susanna Kp Lau
- Department of Microbiology, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong
| | - Patrick Cy Woo
- Department of Microbiology, The University of Hong Kong, Hong Kong.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong.,Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong
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17
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Conlon KC, Sportes C, Brechbiel MW, Fowler DH, Gress R, Miljkovic MD, Chen CC, Whatley MA, Bryant BR, Corcoran EM, Kurdziel KA, Pittaluga S, Paik CH, Lee JH, Fleisher TA, Carrasquillo JA, Waldmann TA. 90Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma. Cancer Biother Radiopharm 2020; 35:249-261. [PMID: 32275165 DOI: 10.1089/cbr.2019.3298] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled 90Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq 90Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq 90Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with 90Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and 90Y-daclizumab provided strong enough β emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong β irradiation killed normal cells in the tumor microenvironment. Conclusions: 90Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of 90Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. 90Y provided strong β emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong β radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of 90Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.
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Affiliation(s)
- Kevin C Conlon
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Claude Sportes
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Martin W Brechbiel
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Daniel H Fowler
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Ronald Gress
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Milos D Miljkovic
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Clara C Chen
- Nuclear Medicine Department, Radiation and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Millie A Whatley
- Nuclear Medicine Department, Radiation and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Bonita R Bryant
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Erin M Corcoran
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Karen A Kurdziel
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Chang H Paik
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jae Ho Lee
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Thomas A Fleisher
- Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Jorge A Carrasquillo
- Nuclear Medicine Department, Radiation and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Thomas A Waldmann
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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18
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Allen SJ, Lumb KJ. Protein-protein interactions: a structural view of inhibition strategies and the IL-23/IL-17 axis. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 121:253-303. [PMID: 32312425 DOI: 10.1016/bs.apcsb.2019.12.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Protein-protein interactions are central to biology and provide opportunities to modulate disease with small-molecule or protein therapeutics. Recent developments in the understanding of the tractability of protein-protein interactions are discussed with a focus on the ligandable nature of protein-protein interaction surfaces. General principles of inhibiting protein-protein interactions are illustrated with structural biology examples from six members of the IL-23/IL-17 signaling family (IL-1, IL-6, IL-17, IL-23 RORγT and TNFα). These examples illustrate the different approaches to discover protein-protein interaction inhibitors on a target-specific basis that has proven fruitful in terms of discovering both small molecule and biologic based protein-protein interaction inhibitors.
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Affiliation(s)
- Samantha J Allen
- Lead Discovery & Profiling, Discovery Sciences, Janssen R&D LLC, Spring House, PA, United States
| | - Kevin J Lumb
- Lead Discovery & Profiling, Discovery Sciences, Janssen R&D LLC, Spring House, PA, United States
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19
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Mitchell K, Steidl U. Targeting Immunophenotypic Markers on Leukemic Stem Cells: How Lessons from Current Approaches and Advances in the Leukemia Stem Cell (LSC) Model Can Inform Better Strategies for Treating Acute Myeloid Leukemia (AML). Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036251. [PMID: 31451539 DOI: 10.1101/cshperspect.a036251] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Therapies targeting cell-surface antigens in acute myeloid leukemia (AML) have been tested over the past 20 years with limited improvement in overall survival. Recent advances in the understanding of AML pathogenesis support therapeutic targeting of leukemia stem cells as the most promising avenue toward a cure. In this review, we provide an overview of the evolving leukemia stem cell (LSC) model, including evidence of the cell of origin, cellular and molecular disease architecture, and source of relapse in AML. In addition, we explore limitations of current targeted strategies utilized in AML and describe the various immunophenotypic antigens that have been proposed as LSC-directed therapeutic targets. We draw lessons from current approaches as well as from the (pre)-LSC model to suggest criteria that immunophenotypic targets should meet for more specific and effective elimination of disease-initiating clones, highlighting in detail a few targets that we suggest fit these criteria most completely.
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Affiliation(s)
- Kelly Mitchell
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
| | - Ulrich Steidl
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.,Department of Medicine (Oncology), Division of Hemato-Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, New York 10461, USA.,Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.,Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA
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20
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Kim W, Kim HJ. Monoclonal Antibody Therapies for Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder. J Clin Neurol 2020; 16:355-368. [PMID: 32657055 PMCID: PMC7354979 DOI: 10.3988/jcn.2020.16.3.355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/01/2019] [Accepted: 12/02/2019] [Indexed: 12/21/2022] Open
Abstract
Considerable progress has been made in treatments for multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) over the last several decades. However, the present treatments do not show satisfactory efficacy or safety in a considerable proportion of patients, who experience relapse or disability progression despite receiving treatment and suffer from side effects, which can be severe. Improvements in the understanding of the pathophysiologies of MS and NMOSD have led to numerous therapeutic approaches being proposed and developed. Monoclonal antibodies (mAbs) are receiving increasing attention because of their specificity of action and likelihood of high efficacy with fewer side effects. Many mAbs have been evaluated, and some have been approved for MS or NMOSD treatment. This article reviews the use of mAbs for treating MS and NMOSD, including summarizing their mechanisms of action, efficacy, and safety profiles.
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Affiliation(s)
- Woojun Kim
- Department of Neurology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ho Jin Kim
- Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Korea.
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21
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Verma A, Mathur R, Farooque A, Kaul V, Gupta S, Dwarakanath BS. T-Regulatory Cells In Tumor Progression And Therapy. Cancer Manag Res 2019; 11:10731-10747. [PMID: 31920383 PMCID: PMC6935360 DOI: 10.2147/cmar.s228887] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/06/2019] [Indexed: 12/24/2022] Open
Abstract
Regulatory T cells (Tregs) are important members of the immune system regulating the host responses to infection and neoplasms. Tregs prevent autoimmune disorders by protecting the host-cells from an immune response, related to the peripheral tolerance. However, tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response. Thus, Tregs are a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. This has prompted the development of novel adjuvant therapies that obviate their negative effects thereby enhancing the therapeutic efficacy. Our earlier studies have shown the efficacy of the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) by reducing the induced Tregs pool and enhance immune stimulation as well as local tumor control. These findings have suggested its potential for enhancing the efficacy of immunotherapy, besides radiotherapy and chemotherapy. This review provides a brief account of the current status of Tregs as a component of the immune-biology of tumors and various preclinical and clinical strategies pursued to obviate the limitations imposed by them in achieving therapeutic efficacy.
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Affiliation(s)
- Amit Verma
- Armed Forces Radiobiology Research Institute, Uniformed Services University, Bethesda, MD, USA
| | - Rohit Mathur
- Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Vandana Kaul
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, USA
| | - Seema Gupta
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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22
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Okada R, Maruoka Y, Furusawa A, Inagaki F, Nagaya T, Fujimura D, Choyke PL, Kobayashi H. The Effect of Antibody Fragments on CD25 Targeted Regulatory T Cell Near-Infrared Photoimmunotherapy. Bioconjug Chem 2019; 30:2624-2633. [PMID: 31498995 DOI: 10.1021/acs.bioconjchem.9b00547] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Regulatory T (Treg) cells play a major role in immune suppression permitting tumors to evade immune surveillance. Depletion of intratumoral Treg cells can result in tumor regression. However, systemic depletion of Tregs may also induce autoimmune adverse events. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cell-specific cancer therapy that locally kills specific cells in the tumor. Antibody-photoabsorber (IRDye700DX) conjugates (APC) are injected and bind to the tumor, and subsequent administration of NIR light to the tumor results in rapid cell death only in targeted cells. CD25-targeted NIR-PIT has been shown to induce spatially selective depletion of tumor-associated Treg cells. In this study, we compared the efficacy of an antibody fragment, anti-CD25-F(ab')2, and a full antibody, anti-CD25-IgG, as agents for NIR-PIT. Tumor-bearing mice were divided into four groups: (1) no treatment; (2) anti-CD25-IgG-IR700 i.v. only; (3) anti-CD25-F(ab')2-IR700 i.v. with NIR light exposure; and (4) anti-CD25-IgG-IR700 i.v. with NIR light exposure. Although both CD25-targeted NIR-PITs resulted in significant tumor growth inhibition, the anti-CD25-F(ab')2-IR700 based NIR-PIT was superior to the anti-CD25-IgG-IR700 NIR-PIT. The anti-CD25-F(ab')2-IR700 demonstrated faster clearance from the body than the anti-CD25-IgG-IR700. Sustained circulation of anti-CD25-IgG-IR700 may block IL-2 binding on the activated effector T-cells decreasing immune response. In conclusion, anti-CD25-F(ab')2 based NIR-PIT was more effective in reducing tumor growth than anti-CD25-IgG based NIR-PIT. Absence of the Fc portion of the APC leads to faster clearance and therefore promotes a superior activated T cell response in tumors.
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Affiliation(s)
- Ryuhei Okada
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Yasuhiro Maruoka
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Aki Furusawa
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Fuyuki Inagaki
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Tadanobu Nagaya
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Daiki Fujimura
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Peter L Choyke
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
| | - Hisataka Kobayashi
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States of America
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23
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Zhu H, Mathew E, Connelly SM, Zuber J, Sullivan M, Piepenbrink MS, Kobie JJ, Dumont ME. Identification of variant HIV envelope proteins with enhanced affinities for precursors to anti-gp41 broadly neutralizing antibodies. PLoS One 2019; 14:e0221550. [PMID: 31504041 PMCID: PMC6736307 DOI: 10.1371/journal.pone.0221550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/09/2019] [Indexed: 11/19/2022] Open
Abstract
HIV envelope protein (Env) is the sole target of broadly neutralizing antibodies (BNAbs) that are capable of neutralizing diverse strains of HIV. While BNAbs develop spontaneously in a subset of HIV-infected patients, efforts to design an envelope protein-based immunogen to elicit broadly neutralizing antibody responses have so far been unsuccessful. It is hypothesized that a primary barrier to eliciting BNAbs is the fact that HIV envelope proteins bind poorly to the germline-encoded unmutated common ancestor (UCA) precursors to BNAbs. To identify variant forms of Env with increased affinities for the UCA forms of BNAbs 4E10 and 10E8, which target the Membrane Proximal External Region (MPER) of Env, libraries of randomly mutated Env variants were expressed in a yeast surface display system and screened using fluorescence activated cell sorting for cells displaying variants with enhanced abilities to bind the UCA antibodies. Based on analyses of individual clones obtained from the screen and on next-generation sequencing of sorted libraries, distinct but partially overlapping sets of amino acid substitutions conferring enhanced UCA antibody binding were identified. These were particularly enriched in substitutions of arginine for highly conserved tryptophan residues. The UCA-binding variants also generally exhibited enhanced binding to the mature forms of anti-MPER antibodies. Mapping of the identified substitutions into available structures of Env suggest that they may act by destabilizing both the initial pre-fusion conformation and the six-helix bundle involved in fusion of the viral and cell membranes, as well as providing new or expanded epitopes with increased accessibility for the UCA antibodies.
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Affiliation(s)
- Hong Zhu
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Elizabeth Mathew
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Sara M. Connelly
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Jeffrey Zuber
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Mark Sullivan
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, United States of America
| | - Michael S. Piepenbrink
- Infectious Diseases Division, University of Rochester Medical Center, Rochester, NY United States of America
| | - James J. Kobie
- Infectious Diseases Division, University of Rochester Medical Center, Rochester, NY United States of America
| | - Mark E. Dumont
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, United States of America
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24
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Ali H, Mohiuddin A, Sharma A, Shaheen I, Kim JJ, El Kosi M, Halawa A. Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis. Clin Kidney J 2019; 12:592-599. [PMID: 31384453 PMCID: PMC6671558 DOI: 10.1093/ckj/sfy132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Indexed: 12/30/2022] Open
Abstract
Background Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection. Methods We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis. Results Of the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I 2 = 21.8%, P = 0.27). The overall risk difference was -0.02 [95% confidence interval (CI) -0.05-0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was -0.01 (95% CI -0.04-0.01) and 0.00 (95% CI -0.00-0.01), respectively. Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group. Conclusion IL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.
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Affiliation(s)
- Hatem Ali
- Department of Renal Medicine, Royal Stoke University Hospital, NHS Foundation Trust, Stoke-on-Trent, UK.,Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK
| | - Atif Mohiuddin
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Department of Transplantation, Liverpool University Teaching Hospital, NHS Foundation Trust, Liverpool, UK
| | - Ajay Sharma
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Department of Transplantation, Liverpool University Teaching Hospital, NHS Foundation Trust, Liverpool, UK
| | - Ihab Shaheen
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Royal Hospital for Sick Children, Glasgow, UK
| | - Jon Jin Kim
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Nottingham Children Hospital, Nottingham, UK
| | - Mohsen El Kosi
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Renal Department, Doncaster Royal Infirmary, Doncaster, UK
| | - Ahmed Halawa
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Department of Renal Medicine, Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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25
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Immunosuppression after renal transplantation. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2019. [DOI: 10.1007/s12254-019-0507-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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26
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Xu L, Song X, Su L, Zheng Y, Li R, Sun J. New therapeutic strategies based on IL-2 to modulate Treg cells for autoimmune diseases. Int Immunopharmacol 2019; 72:322-329. [PMID: 31005777 DOI: 10.1016/j.intimp.2019.03.064] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/29/2019] [Accepted: 03/29/2019] [Indexed: 02/06/2023]
Abstract
Interleukin-2 (IL-2) is a multifunctional cytokine in immune regulation. It is essential for the differentiation, expansion and stability of CD25+Foxp3+ regulatory T (Treg) cells, which is an important factor in immune suppression and self-tolerance. Meanwhile, IL-2 also stimulate effector T (Teff) cells to promote immune responses. The opposite and diverse function of IL-2 impedes its application to boost Treg cell populations in autoimmune disease treatment. Thus, it became focus of the research to modulate IL-2 activities to enhance Treg cell functions selectively. Based on the characteristic properties of Treg cells such as constitutively expression of high affinity IL-2 receptors (IL-2Rs), multiple approaches, including IL-2/mAb complexes, IL-2 muteins and low-dose of IL-2 have emerged in recent years to selectively target Treg cells and treat autoimmunity. These therapeutic approaches have achieved favorable results in both clinical trials and experimental animal models, and provided engineering blueprints to develop novel strategies of IL-2 treatments for autoimmune diseases.
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Affiliation(s)
- Le Xu
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 30072, PR China
| | - Xiaolei Song
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 30072, PR China
| | - Lili Su
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 30072, PR China
| | - Yong Zheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, PR China.
| | - Ru Li
- Department of Rheumatology & Immunology, Peking University People's Hospital and Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing 100044, PR China.
| | - Jian Sun
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 30072, PR China.
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27
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Cohan SL, Lucassen EB, Romba MC, Linch SN. Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis. Biomedicines 2019; 7:biomedicines7010018. [PMID: 30862055 PMCID: PMC6480729 DOI: 10.3390/biomedicines7010018] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/06/2019] [Accepted: 03/06/2019] [Indexed: 01/07/2023] Open
Abstract
Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease.
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Affiliation(s)
- Stanley L Cohan
- Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR 97225, USA.
| | - Elisabeth B Lucassen
- Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR 97225, USA.
| | - Meghan C Romba
- Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR 97225, USA.
| | - Stefanie N Linch
- Providence Health and Services, Regional Research Department, Portland, OR 97213, USA.
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28
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Xu M, Garcia-Aroz S, Banan B, Wang X, Rabe BJ, Zhou F, Nayak DK, Zhang Z, Jia J, Upadhya GA, Manning PT, Gaut JP, Lin Y, Chapman WC. Enhanced immunosuppression improves early allograft function in a porcine kidney transplant model of donation after circulatory death. Am J Transplant 2019; 19:713-723. [PMID: 30152136 DOI: 10.1111/ajt.15098] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 07/30/2018] [Accepted: 08/14/2018] [Indexed: 01/25/2023]
Abstract
It remains controversial whether renal allografts from donation after circulatory death (DCD) have a higher risk of acute rejection (AR). In the porcine large animal kidney transplant model, we investigated the AR and function of DCD renal allografts compared to the non-DCD renal allografts and the effects of increased immunosuppression. We found that the AR was significantly increased along with elevated MHC-I expression in the DCD transplants receiving low-dose immunosuppression; however, AR and renal function were significantly improved when given high-dose immunosuppressive therapy postoperatively. Also, high-dose immunosuppression remarkably decreased the mRNA levels of ifn-g, il-6, tgf-b, il-4, and tnf-a in the allograft at day 5 and decreased serum cytokines levels of IFN-g and IL-17 at day 4 and day 5 after operation. Furthermore, Western blot analysis showed that higher immunosuppression decreased phosphorylation of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells-p65, increased phosphorylation of extracellular-signal-regulated kinase, and reduced the expression of Bcl-2-associated X protein and caspase-3 in the renal allografts. These results suggest that the DCD renal allograft seems to be more vulnerable to AR; enhanced immunosuppression reduces DCD-associated AR and improves early allograft function in a preclinical large animal model.
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Affiliation(s)
- Min Xu
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Sandra Garcia-Aroz
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Babak Banan
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Xuanchuan Wang
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Brian J Rabe
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Fangyu Zhou
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Deepak K Nayak
- University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - Zhengyan Zhang
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Jianluo Jia
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - Gundumi A Upadhya
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Joseph P Gaut
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yiing Lin
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
| | - William C Chapman
- Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA
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29
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Bone Marrow Mast Cell Antibody-Targetable Cell Surface Protein Expression Profiles in Systemic Mastocytosis. Int J Mol Sci 2019; 20:ijms20030552. [PMID: 30696068 PMCID: PMC6387409 DOI: 10.3390/ijms20030552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 12/30/2022] Open
Abstract
Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and FcεRI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM.
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Abstract
Since the approval of the first monoclonal antibody (mAb), rituximab, for hematological malignancies, almost 30 additional mAbs have been approved in oncology. Despite remarkable advances, relatively weak responses and resistance to antibody monotherapy remain major open issue. Overcoming resistance might require combinations of drugs blocking both the major target and the emerging secondary target. We review clinically approved combinations of antibodies and either cytotoxic regimens (chemotherapy and irradiation) or kinase inhibitors. Thereafter, we focus on the most promising and currently very active arena that combines mAbs inhibiting immune checkpoints or growth factor receptors. Clinically approved and experimental oligoclonal mixtures of mAbs targeting different antigens (hetero-combinations) or different epitopes of the same antigen (homo-combinations) are described. Effective oligoclonal mixtures of antibodies that mimic the polyclonal immune response will likely become a mainstay of cancer therapy.
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Affiliation(s)
- Ilaria Marrocco
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Donatella Romaniello
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
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31
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Abstract
In the age of personalized medicine, an efficient method to generate monoclonal antibodies (mAbs) is essential for biomedical and immunotherapeutic research. Numerous aspects of basic B-cell biology can be studied at the monoclonal level, including B-cell development, antibody responses to infection or vaccination, and autoimmune responses. Single-cell B-cell receptor cloning allows for the rapid generation of antigen-specific mAbs in a matter of several weeks. In this chapter, we provide an efficient method to generate mAbs from peripheral blood plasmablasts and memory B cells induced by infection and vaccination. Additionally, we provide a protocol on how to optimize single-cell B-cell sorting for both single-cell B-cell receptor cloning and single-cell RNA-sequencing, for the application of studying B-cell specificity and function (spec-seq). This protocol can be easily adapted for other B-cell populations, B cells in tissues, and B cells from other organisms.
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32
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Abstract
Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell leukemia, and interleukin (IL)-2 for the treatment of advanced melanoma and metastatic renal cancer. In addition, IL-12, IL-15, IL-21, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been evaluated in clinical trials. However, the cytokines as monotherapy have not fulfilled their early promise because cytokines administered parenterally do not achieve sufficient concentrations in the tumor, are often associated with severe toxicities, and induce humoral or cellular checkpoints. To circumvent these impediments, cytokines are being investigated clinically in combination therapy with checkpoint inhibitors, anticancer monoclonal antibodies to increase the antibody-dependent cellular cytotoxicity (ADCC) of these antibodies, antibody cytokine fusion proteins, and anti-CD40 to facilitate tumor-specific immune responses.
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Affiliation(s)
- Thomas A Waldmann
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Clinical Center, Bethesda, Maryland 20892-1374
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33
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Xue M, Zhao C, Lv C, Chen M, Xu M, Rong R, Zhang Y, Liang J, Gao J, Yu M, Zhu T, Gao X. Interleukin-2 receptor antagonists: Protective factors against new-onset diabetes after renal transplantation. J Diabetes 2018; 10:857-865. [PMID: 29577632 DOI: 10.1111/1753-0407.12663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 03/12/2018] [Accepted: 03/20/2018] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The aim of the present study was to examine the association between interleukin-2 receptor antagonists (IL-2Ra) and new-onset diabetes after transplantation (NODAT) among renal transplant recipients (RTRs). METHODS Between January 1993 and March 2014, 915 patients underwent renal transplantation at Zhongshan Hospital. In all, 557 RTRs were included in the present retrospective cohort study. The incidence of NODAT in this cohort was determined and multivariate Cox regression analysis was used to evaluate the risk factors for NODAT and to show the association between IL-2Ra use and NODAT development among RTRs. The cumulative incidence of NODAT was compared between groups treated with or without IL-2Ra. RESULTS The mean ±SD postoperative follow-up was 5.08 ±3.17 years. The incidence of NODAT at the end of follow-up was 20.3%. After adjusting for potential confounders in the multivariate logistic regression (i.e. age, sex, body mass index, history of smoking, family history of diabetes, duration of dialysis, type of dialysis, donor type, recovery of graft function, acute rejection, hepatitis B or C or cytomegalovirus infection, fasting plasma glucose levels before and 1 week after transplantation, preoperative total cholesterol and triglyceride levels, daily dose of glucocorticoid, immunosuppressive regimen type, and immunosuppressant concentration after transplantation), IL-2Ra use was found to be related to a reduced incidence of NODAT. CONCLUSIONS Use of IL-2Ra is associated with protection against the development of NODAT in RTRs.
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Affiliation(s)
- Mengjuan Xue
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Elderly Endocrinology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Chenhe Zhao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chaoyang Lv
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism, The Seventh People's Hospital of Zhengzhou, Zhengzhou, China
| | - Minling Chen
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Endocrinology and Metabolism, People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine (The People's Hospital of Fujian Province), Fuzhou, China
| | - Ming Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yao Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Infectious Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Liang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Gao
- Evidence Base Medicine Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mingxiang Yu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
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Mathews DV, Dong Y, Higginbotham LB, Kim SC, Breeden CP, Stobert EA, Jenkins J, Tso JY, Larsen CP, Adams AB. CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J Clin Invest 2018; 128:4557-4572. [PMID: 30222140 PMCID: PMC6159972 DOI: 10.1172/jci95914] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 07/31/2018] [Indexed: 12/30/2022] Open
Abstract
Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell-mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor β-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122.
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Affiliation(s)
- David V. Mathews
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | - Ying Dong
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | | | - Steven C. Kim
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | | | | | | | - J. Yun Tso
- JN Biosciences, Mountain View, California, USA
| | - Christian P. Larsen
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
- Yerkes National Primate Center, Atlanta, Georgia, USA
| | - Andrew B. Adams
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
- Yerkes National Primate Center, Atlanta, Georgia, USA
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Lim S, Kirkiles-Smith NC, Pober JS, Bothwell ALM, Choi JM. Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection. Biomaterials 2018; 183:128-138. [PMID: 30165256 DOI: 10.1016/j.biomaterials.2018.08.049] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 08/14/2018] [Accepted: 08/20/2018] [Indexed: 12/30/2022]
Abstract
Manipulation of human T cell functioning by delivery of macromolecules such as DNA, RNA, or protein is limited, unless the human T cells have been stimulated or electropermeabilized. To achieve successful adaptation and survival of a grafted organ, the alloreactive T cells that induce graft rejection must be regulated. Corticosteroids, calcineurin inhibitors, and mTOR inhibitors, which are systemic immunosuppressants, are currently used for transplantation, with significant side effects. In this study, we demonstrated that a cell-permeable peptide (CPP), dNP2, could efficiently deliver proteins into human CD4 and CD8 T cells. We confirmed regulatory functioning of the cytoplasmic domain of CTLA-4 conjugated with dNP2 (dNP2-ctCTLA-4) in human T cell activation, proliferation, and chemokine receptor expression. We utilized a human skin allograft system in SCID/beige mice to examine whether dNP2-ctCTLA-4 could inhibit allograft rejection by controlling T cell responses. The grafted skin tissue inflammation, allogeneic T cell infiltration, and blood cytokine level was markedly reduced by dNP2-ctCTLA-4, resulting in successful transplantation. In addition, it also inhibited T cell alloresponses against microvessels formed form Bcl-2-transduced human umbilical vein endothelial cells implanted into Balb/c Rag1-/-/IL-2Rγ-/- double knockout (DKO) mice, assessed as reduced T cell infiltration and granzyme B expression. These results collectively suggest that dNP2 peptide conjugation offers a valuable tool for delivering macromolecules like proteins into human T cells, and dNP2-ctCTLA-4 is a novel agent that shows potential in controlling human T cell responses to allow successful adaptation of grafted tissues.
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Affiliation(s)
- Sangho Lim
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 04763, Korea; Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Korea
| | - Nancy C Kirkiles-Smith
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Jordan S Pober
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Alfred L M Bothwell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Je-Min Choi
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 04763, Korea; Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Korea.
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Zhu D, McCague K, Lin W, Rong R, Xu M, Chan L, Zhu T. Outcome of Kidney Transplantation From Donor After Cardiac Death: Reanalysis of the US Mycophenolic Renal Transplant Registry. Transplant Proc 2018; 50:1258-1263. [DOI: 10.1016/j.transproceed.2018.01.051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 12/17/2017] [Accepted: 01/23/2018] [Indexed: 12/19/2022]
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Kleinman AJ, Sivanandham R, Pandrea I, Chougnet CA, Apetrei C. Regulatory T Cells As Potential Targets for HIV Cure Research. Front Immunol 2018; 9:734. [PMID: 29706961 PMCID: PMC5908895 DOI: 10.3389/fimmu.2018.00734] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/23/2018] [Indexed: 12/19/2022] Open
Abstract
T regulatory cells (Tregs) are a key component of the immune system, which maintain a delicate balance between overactive responses and immunosuppression. As such, Treg deficiencies are linked to autoimmune disorders and alter the immune control of pathogens. In HIV infection, Tregs play major roles, both beneficial and detrimental. They regulate the immune system such that inflammation and spread of virus through activated T cells is suppressed. However, suppression of immune activation also limits viral clearance and promotes reservoir formation. Tregs can be directly targeted by HIV, thereby harboring a fraction of the viral reservoir. The vital role of Tregs in the pathogenesis and control of HIV makes them a subject of interest for manipulation in the search of an HIV cure. Here, we discuss the origin and generation, homeostasis, and functions of Tregs, particularly their roles and effects in HIV infection. We also present various Treg manipulation strategies, including Treg depletion techniques and interventions that alter Treg function, which may be used in different cure strategies, to simultaneously boost HIV-specific immune responses and induce reactivation of the latent virus.
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Affiliation(s)
- Adam J Kleinman
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ranjit Sivanandham
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ivona Pandrea
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Claire A Chougnet
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati University, Cincinnati, OH, United States
| | - Cristian Apetrei
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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Serrano-Alonso M, Guillen-Grima F, Martin-Moreno P, Rabago G, Manrique J, Garcia-del-Barrio M, Reina G, Torre-Cisneros J, Fernandez-Alonso M, Herrero J. Reduction in mortality associated with secondary cytomegalovirus prophylaxis after solid organ transplantation. Transpl Infect Dis 2018; 20:e12873. [DOI: 10.1111/tid.12873] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 01/02/2018] [Accepted: 01/14/2018] [Indexed: 01/06/2023]
Affiliation(s)
| | - F. Guillen-Grima
- Preventive Medicine Department; Clínica Universidad de Navarra; Pamplona Spain
- Department of Health Sciences; Public University of Navarra; Pamplona Spain
- Navarra's Health Research Institute (IdiSNA); Pamplona Spain
| | - P. Martin-Moreno
- Navarra's Health Research Institute (IdiSNA); Pamplona Spain
- Nephrology Department; Clínica Universidad de Navarra; Pamplona Spain
| | - G. Rabago
- Cardiac Surgery Department; Clínica Universidad de Navarra; Pamplona Spain
| | - J. Manrique
- Navarra's Health Research Institute (IdiSNA); Pamplona Spain
- Nephrology Department; Complejo Hospitalario de Navarra; Pamplona Spain
| | | | - G. Reina
- Navarra's Health Research Institute (IdiSNA); Pamplona Spain
- Microbiology Department; Clínica Universidad de Navarra; Pamplona Spain
| | - J. Torre-Cisneros
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC); Reina Sofía University Hospital; University of Cordoba; Cordoba Spain
| | - M. Fernandez-Alonso
- Navarra's Health Research Institute (IdiSNA); Pamplona Spain
- Microbiology Department; Clínica Universidad de Navarra; Pamplona Spain
| | - J.I. Herrero
- Navarra's Health Research Institute (IdiSNA); Pamplona Spain
- Liver Unit; Clínica Universidad de Navarra; Pamplona Spain
- Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBERehd); Madrid Spain
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Early Conversion to Belatacept in Kidney Transplant Recipients With Low Glomerular Filtration Rate. Transplantation 2018; 102:478-483. [DOI: 10.1097/tp.0000000000001985] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Haasova M, Snowsill T, Jones-Hughes T, Crathorne L, Cooper C, Varley-Campbell J, Mujica-Mota R, Coelho H, Huxley N, Lowe J, Dudley J, Marks S, Hyde C, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation. Health Technol Assess 2018; 20:1-324. [PMID: 27557331 DOI: 10.3310/hta20610] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013544. FUNDING The National Institute for Health Research HTA programme.
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Affiliation(s)
- Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jan Dudley
- Department of Paediatric Nephrology, Bristol Royal Hospital for Children (University Hospitals Bristol NHS Foundation Trust), Bristol, UK
| | - Stephen Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
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Ratay ML, Bellotti E, Gottardi R, Little SR. Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation. Adv Healthc Mater 2017; 6:10.1002/adhm.201700733. [PMID: 29034584 PMCID: PMC5915344 DOI: 10.1002/adhm.201700733] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 07/25/2017] [Indexed: 12/12/2022]
Abstract
Dry eye disease, age-related macular degeneration, and uveitis are ocular diseases that significantly affect the quality of life of millions of people each year. In these diseases, the action of chemokines, proinflammatory cytokines, and immune cells drives a local inflammatory response that results in ocular tissue damage. Multiple therapeutic strategies are developed to either address the symptoms or abate the underlying cause of these diseases. Herein, the challenges to deliver drugs to the relevant location in the eye for each of these diseases are reviewed along with current and innovative therapeutic approaches that attempt to restore homeostasis within the ocular microenvironment.
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Affiliation(s)
- Michelle L. Ratay
- Department of Bioengineering, University of Pittsburgh, 427 Benedum Hall 3700 O’Hara Street Pittsburgh, Pa 15261
| | - Elena Bellotti
- Department of Chemical Engineering, University of Pittsburgh, 427 Benedum Hall 3700 O’Hara Street Pittsburgh, Pa 15261
| | - Riccardo Gottardi
- Department of Chemical Engineering, Department of Orthopedic Surgery, Ri.MED Foundation, 427 Benedum Hall 3700 O’Hara Street Pittsburgh, Pa 15261
| | - Steven R. Little
- Department of Chemical Engineering, Department of Bioengineering, Department of Ophthalmology, Department of Immunology, Department of Pharmaceutical Sciences, The McGowan Institute for Regenerative Medicine, 940 Benedum Hall 3700 O’Hara Street Pittsburgh Pa 15261
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Ilyas M, Colegio OR, Kaplan B, Sharma A. Cutaneous Toxicities From Transplantation-Related Medications. Am J Transplant 2017; 17:2782-2789. [PMID: 28452165 DOI: 10.1111/ajt.14337] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 03/22/2017] [Accepted: 04/22/2017] [Indexed: 01/25/2023]
Abstract
Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding nonmalignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant-related medications that can vary in presentation, severity, and prognosis. To limit associated morbidity and mortality, solid organ transplant recipient care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant-related medications will be discussed: antithymocyte globulins, systemic steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mammalian target of rapamycin inhibitors sirolimus and everolimus, basiliximab and daclizumab, belatacept, and voriconazole.
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Affiliation(s)
- M Ilyas
- Department of Dermatology, Mayo Clinic Arizona, Scottsdale, AZ
| | - O R Colegio
- Departments of Dermatology, Pathology and Surgery, Yale University, New Haven, CT
| | - B Kaplan
- Department of Nephrology, Mayo Clinic Arizona, Scottsdale, AZ
| | - A Sharma
- Department of Dermatology, Mayo Clinic Arizona, Scottsdale, AZ
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Weng PL, Alejos JC, Halnon N, Zhang Q, Reed EF, Tsai-Chambers E. Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients. Pediatr Transplant 2017; 21:10.1111/petr.13023. [PMID: 28727227 PMCID: PMC5638697 DOI: 10.1111/petr.13023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/08/2017] [Indexed: 11/30/2022]
Abstract
Pediatric sHKTx has become an effective therapy for patients with combined cardiac and renal failure. Often, these patients develop human leukocyte antigen antibodies from their previous allografts and are therefore more difficult to re-transplant. We describe the largest case series of a predominantly sensitized pediatric sHKTx with emphasis on medical management and patient outcomes. Demographics, clinical characteristics, antibody, and biopsy data were retrospectively collected from University of California, Los Angeles database and correlated with short- and long-term patient and allograft outcomes of all sHKTx performed between 2002 and 2015. We identified seven pediatric patients who underwent sHKTx at our center. Mean age at time of sHKTx was 13.7 years and 85.7% were re-graft patients. 57.1% were sensitized with cPRA >50% and another 57.1% had preformed donor-specific antibody. Five-year renal allograft survival and patient survival was 85.7% for both end-points. The remaining six patients are all alive (mean follow-up 78.5 months) with good kidney and heart function. sHKTx in a population with increased immunological risk can be associated with good long-term outcomes and offers potential guidance to the pediatric transplant community where data are limited.
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Affiliation(s)
- Patricia L. Weng
- Division of Pediatric Nephrology, Mattel Children's Hospital UCLA, Los Angeles, CA, USA
| | - Juan Carlos Alejos
- Division of Pediatric Cardiology, Mattel Children's Hospital UCLA, Los Angeles, CA, USA
| | - Nancy Halnon
- Division of Pediatric Cardiology, Mattel Children's Hospital UCLA, Los Angeles, CA, USA
| | - Qiuheng Zhang
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Elaine F. Reed
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA
| | - Eileen Tsai-Chambers
- Division of Pediatric Nephrology, Duke University Medical Center, Durham, NC, USA
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Shahdordizadeh M, Taghdisi SM, Sankian M, Ramezani M, Abnous K. Design, isolation and evaluation of the binding efficiency of a DNA aptamer against interleukin 2 receptor alpha, in vitro. Int Immunopharmacol 2017; 53:96-104. [PMID: 29055191 DOI: 10.1016/j.intimp.2017.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 10/07/2017] [Accepted: 10/10/2017] [Indexed: 01/19/2023]
Abstract
High levels of CD25, as part of the IL-2 receptor, are expressed on the surface of the activated T lymphocytes and regulatory T cells, indicating that the soluble CD25 (sCD25) could be a clinically valuable tool for treating several diseases. Moreover, progress has been achieved in targeting the IL-2 receptor to treat autoimmune diseases, organ transplantation and certain hematological malignancies. In the current study, generation of an ssDNA aptamer (Apt51) against CD25 is reported. Apt51 bound to CD25 with high affinity (Kd=13.4nM) and specificity. Furthermore, Apt51 was truncated to two shortened variants that almost retained their high affinity for the CD25 protein. Moreover, Apt51 showed good affinity and selectivity for the recognition of CD25 on the cell surface. Importantly, the study showed that Apt51 interfered with the binding of CD25 to its ligand (IL 2) and consequently decreased the IL-2-induced Akt activation.
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Affiliation(s)
- Mahin Shahdordizadeh
- Pharmaceutical Research Center, Advanced Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mohammad Taghdisi
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Targeted Drug Delivery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojtaba Sankian
- Immunology Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Advanced Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Khalil Abnous
- Pharmaceutical Research Center, Advanced Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers and Subjects with Multiple Sclerosis: Analysis of Phase I-III Clinical Trials. Clin Pharmacokinet 2017; 55:943-55. [PMID: 26873229 DOI: 10.1007/s40262-016-0366-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND OBJECTIVES Daclizumab high-yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit (CD25) of the interleukin-2 receptor. The present work characterized the population pharmacokinetics of daclizumab HYP in healthy volunteers (HVs) and subjects with relapsing-remitting multiple sclerosis (RRMS) and evaluated the effects of covariates on daclizumab HYP exposure. METHODS Measurable serum concentrations (n = 17,139) from 1670 subjects in seven clinical studies (three phase I, one immunogenicity, one phase II with extension, and one phase III) were included in this pharmacokinetic analysis using non-linear mixed-effects modeling. The three phase I studies evaluated single or multiple doses that ranged from 50 to 400 mg with either intravenous or subcutaneous (SC) administration in HVs (n = 71). The phase II with extension studies evaluated doses of 150 or 300 mg SC every 4 weeks (n = 567), and the immunogenicity (n = 113) and the phase III (n = 919) studies evaluated 150 mg SC every 4 weeks, all in RRMS patients. RESULTS A two-compartment model with first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Clearance (CL) was 0.212 L/day and the central volume of distribution was 3.92 L, scaled by [body weight (kg)/68] with exponents of 0.87 and 1.12, respectively. The peripheral volume of distribution was 2.42 L. Absorption lag time, mean absorption time, and absolute bioavailability (100-300 mg SC) were 1.61 h, 7.2 days, and 88 %, respectively. The daclizumab HYP terminal half-life was 21 days. Baseline CD25, age, and sex did not influence daclizumab HYP pharmacokinetics. Body weight explained 37 and 27 % of the inter-individual variability for CL and central volume of distribution, respectively. Neutralizing antibody (NAb)-positive status (included as a time-varying covariate) increased daclizumab HYP CL by 19 %. CONCLUSIONS Consistent with previous findings in HVs, this analysis including extensive data from RRMS patients demonstrates that daclizumab HYP is characterized by slow CL, linear pharmacokinetics at doses above 100 mg, and high SC bioavailability. The pharmacokinetics of daclizumab HYP were not influenced by age (range 18-66 years), the sex of adult subjects, or the baseline CD4+CD25+ T cells (target level). The impact of covariates (body weight, NAb) on daclizumab HYP pharmacokinetics is unlikely to be clinically relevant.
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Baldassari LE, Rose JW. Daclizumab: Development, Clinical Trials, and Practical Aspects of Use in Multiple Sclerosis. Neurotherapeutics 2017; 14:842-858. [PMID: 28707278 PMCID: PMC5722760 DOI: 10.1007/s13311-017-0553-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Daclizumab is a humanized monoclonal antibody directed towards CD25, the alpha subunit of the high-affinity interleukin (IL)-2 receptor. Daclizumab exerts its effects via multiple mechanisms, including reduction of IL-2-mediated lymphocyte activation and upregulation of CD56-bright natural killer cells. Intravenous daclizumab (Zenapax™) was initially approved for prevention of rejection in renal transplant. In subsequent early testing, followed by larger-scale phase II and phase III trials, both intravenous and subcutaneous daclizumab have demonstrated clinical efficacy in the treatment of multiple sclerosis. The subcutaneous daclizumab prepared by high-yield process was utilized in the advanced phase II and phase III trials (SELECT and DECIDE). High-yield process daclizumab is now approved by the US Food and Drug Administration for relapsing-remitting multiple sclerosis, and is now formally termed daclizumab beta (DAC-beta; Zinbryta™). In this review, the early development of anti-IL-2 receptor alpha monoclonal antibodies and the properties of IL-2 and its receptor are discussed, and diverse mechanisms of action for daclizumab are presented. Results of the CHOICE, SELECT, and DECIDE clinical trials are discussed in detail. Adverse events observed in clinical trials included cutaneous reactions, liver enzyme elevations, infections, and autoimmune phenomena. DAC-beta is a monthly, patient-administered subcutaneous injection that requires enrollment in a safety monitoring (REMS) program for monthly liver function testing. Prescribers should be aware of the potential adverse events, as early recognition and management is important, particularly in cutaneous and hepatic reactions. Continued clinical experience with DAC-beta, including observations from the REMS program, will define its place in the armamentarium of immunotherapeutics for relapsing-remitting multiple sclerosis.
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Affiliation(s)
- Laura E Baldassari
- Division of Neuroimmunology, Department of Neurology, University of Utah, Imaging and Neurosciences Center, 729 Arapeen Drive, Salt Lake City, UT, 84108, USA
| | - John W Rose
- Division of Neuroimmunology, Department of Neurology, University of Utah, Imaging and Neurosciences Center, 729 Arapeen Drive, Salt Lake City, UT, 84108, USA.
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Comparative efficacy and safety of antibody induction therapy for the treatment of kidney: a network meta-analysis. Oncotarget 2017; 8:66426-66437. [PMID: 29029524 PMCID: PMC5630424 DOI: 10.18632/oncotarget.19815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/12/2017] [Indexed: 12/22/2022] Open
Abstract
To evaluate the efficacy and safety of antibody induction therapies in kidney transplantation. Systematic literature searches were undertaken using MEDLINE, Embase, and Cochrane Library database from 1980 to 2016. Randomized controlled trials (RCTs) comparing three antibody induction therapies (alemtuzumab, interleukin-2 receptor antibodies and antithymocyte globulin) between each other were identified. Bayesian network meta-analysis was used to combine both the direct and indirect evidence on treatment efficacy and its safety. Antibody induction therapy studies, comprising of 18 RCTs (3444 kidney transplant recipients), were included. Overall, alemtuzumab treatment was superior to the ATG group (OR: 0.49, 95% CI: 0.32 to 0.71) and IL-2RAs group (OR: 0.36, 95% CI: 0.25 to 0.52) for reducing the 1-year acute rejection in kidney transplant recipients. Although alemtuzumab treatment was nearly same with ATG group and IL-2RAs group in improving patient survival and renal function, it can reduce the adverse effects of cytomegalovirus infection more efficiently than ATG group (OR: 0.59, 95% CI: 0.32 to 0.95) and IL-2RAs group (OR: 1.08, 95% CI: 0.61 to 1.73). Alemtuzumab was not associated with increased other adverse effects. Alemtuzumab treatment is safe and effective for kidney transplant recipients. No serious adverse effects were observed in trials or in general populations.
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Martin R, Sospedra M, Rosito M, Engelhardt B. Current multiple sclerosis treatments have improved our understanding of MS autoimmune pathogenesis. Eur J Immunol 2017; 46:2078-90. [PMID: 27467894 DOI: 10.1002/eji.201646485] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 07/14/2016] [Accepted: 07/22/2016] [Indexed: 12/23/2022]
Abstract
Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults. When MS is not treated, it leads to irreversible and severe disability. The etiology of MS and its pathogenesis are not fully understood. The recent discovery that MS-associated genetic variants code for molecules related to the function of specific immune cell subsets is consistent with the concept of MS as a prototypic, T-cell-mediated autoimmune disease targeting the CNS. While the therapeutic efficacy of the currently available immunomodulatory therapies further strengthen this concept, differences observed in responses to MS treatment as well as additional clinical and imaging observations have also shown that the autoimmune pathogenesis underlying MS is much more complex than previously thought. There is therefore an unmet need for continued detailed phenotypic and functional analysis of disease-relevant adaptive immune cells and tissues directly derived from MS patients to unravel the immune etiology of MS in its entire complexity. In this review, we will discuss the currently available MS treatment options and approved drugs, including how they have contributed to the understanding of the immune pathology of this autoimmune disease.
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Affiliation(s)
- Roland Martin
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Mireia Sospedra
- Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, Zurich, Switzerland
| | - Maria Rosito
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
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Stephen-Victor E, Bosschem I, Haesebrouck F, Bayry J. The Yin and Yang of regulatory T cells in infectious diseases and avenues to target them. Cell Microbiol 2017; 19. [DOI: 10.1111/cmi.12746] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 04/03/2017] [Accepted: 04/04/2017] [Indexed: 12/26/2022]
Affiliation(s)
- Emmanuel Stephen-Victor
- Institut National de la Santé et de la Recherche Médicale; Paris France
- Centre de Recherche des Cordeliers; Equipe-Immunopathologie et Immunointervention Thérapeutique; Paris France
- Sorbonne Universités; Université Pierre et Marie Curie; Paris France
| | - Iris Bosschem
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Freddy Haesebrouck
- Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine; Ghent University; Merelbeke Belgium
| | - Jagadeesh Bayry
- Institut National de la Santé et de la Recherche Médicale; Paris France
- Centre de Recherche des Cordeliers; Equipe-Immunopathologie et Immunointervention Thérapeutique; Paris France
- Sorbonne Universités; Université Pierre et Marie Curie; Paris France
- Université Paris Descartes; Sorbonne Paris Cité; Paris France
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Herwerth M, Hemmer B. Daclizumab for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Biol Ther 2017; 17:747-753. [PMID: 28286970 DOI: 10.1080/14712598.2017.1304913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Over the last two decades, the number of therapeutic options for the treatment of relapsing remitting MS (RRMS) has been constantly growing, providing new treatment options to patients. Areas covered: Herein, the authors review the recently approved monoclonal antibody daclizumab for the treatment of RRMS. Based on original articles, they discuss its mode of action and evaluate its efficacy and safety profile compared to other available agents. Expert opinion: The IL-2 receptor modulator daclizumab is a new highly effective agent for the treatment of RRMS with novel immunomodulatory properties. Compared to interferon-beta i.m., daclizumab is more effective in reducing relapse rates and MRI activity. However, its use is limited by the risk of autoimmune disorders and hepatotoxicity. Similar to other monoclonal antibodies for RRMS, therapy with daclizumab needs a strict preselection and monitoring of patients based on individual risk benefit assessment. Given its substantial effectiveness, daclizumab can be an attractive option for patients with highly active MS.
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Affiliation(s)
- Marina Herwerth
- a Department of Neurology , Klinikum rechts der Isar, Technical University of Munich , Munich , Germany.,b Institute of Neuronal Cell Biology , Technical University of Munich , Munich , Germany
| | - Bernhard Hemmer
- a Department of Neurology , Klinikum rechts der Isar, Technical University of Munich , Munich , Germany.,c Munich Cluster for Systems Neurology (SyNergy) , Munich , Germany
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