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1
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Yakubu I, Moinuddin I, Brown A, Sterling S, Sinhmar P, Kumar D. Costimulation blockade: the next generation. Curr Opin Organ Transplant 2025; 30:96-102. [PMID: 39882641 DOI: 10.1097/mot.0000000000001206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
PURPOSE OF REVIEW Calcineurin inhibitors (CNIs) are central to immunosuppression in kidney transplantation (KT), improving short-term outcomes but falling short in enhancing long-term outcomes due to cardiovascular, metabolic, and renal complications. Belatacept, an FDA-approved costimulation blocker, offers a less toxic alternative to CNIs but is limited by its intravenous administration and reduced efficacy in high-immunological-risk patients. RECENT FINDINGS Emerging therapies target more specific pathways to improve efficacy and accessibility. Abatacept, a first-generation cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immunoglobulin, has shown favorable outcomes in small studies. VEL-101 and Lulizumab selectively block CD28 while preserving CTLA-4 signaling, showing promise in early trials. In the CD40/CD40L pathway, results have been mixed. Iscalimab (CD40 antibody) was inferior to tacrolimus in Phase 2 trials, and Bleselumab (CD40 antibody) showed variable rejection rates despite being noninferior to tacrolimus. CD40L-targeting agents such as TNX-1500, Tegoprubart, and Dazodalibep have demonstrated promising efficacy and safety in rejection prophylaxis. SUMMARY The focus in transplantation is shifting toward safer, long-term therapies with greater accessibility. Investigational agents with subcutaneous delivery methods could overcome logistical challenges, improve adherence, and redefine posttransplant care. These advancements in costimulation blockade may enhance long-term graft survival and transform the management of KT recipients.
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Affiliation(s)
- Idris Yakubu
- Department of Pharmacy, Virginia Commonwealth University Health System
| | - Irfan Moinuddin
- Division of Nephrology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Andrew Brown
- Department of Pharmacy, Virginia Commonwealth University Health System
| | - Sara Sterling
- Department of Pharmacy, Virginia Commonwealth University Health System
| | - Pawan Sinhmar
- Division of Nephrology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University, Richmond, Virginia, USA
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2
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de Graav GN, Udomkarnjananun S, Baan CC, Reinders MEJ, Roodnat JI, de Winter BCM, Hesselink DA. New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review. Ther Drug Monit 2025; 47:64-76. [PMID: 39570574 DOI: 10.1097/ftd.0000000000001275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/31/2024] [Indexed: 11/22/2024]
Abstract
PURPOSE In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents. METHODS Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014-2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov . RESULTS Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies. CONCLUSIONS The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents.
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Affiliation(s)
- Gretchen N de Graav
- Department of Internal Medicine, Division of Nephrology, Reinier de Graaf Gasthuis, Delft, the Netherlands
| | - Suwasin Udomkarnjananun
- Department of Medicine, Division of Nephrology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Carla C Baan
- Transplant Laboratory & Research Center, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Marlies E J Reinders
- Department of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands ; and
| | - Joke I Roodnat
- Department of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands ; and
| | - Brenda C M de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands ; and
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Mahgoub M, Zand L. Recurrent FSGS Post-Kidney Transplantations: Where Do We Stand? Transplantation 2025:00007890-990000000-00988. [PMID: 39828914 DOI: 10.1097/tp.0000000000005335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Affiliation(s)
- Mohammed Mahgoub
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN
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4
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Du X, Chang Y, Song J. Use of Brain Death Recipients in Xenotransplantation: A Double-Edged Sword. Xenotransplantation 2025; 32:e70010. [PMID: 39825621 DOI: 10.1111/xen.70010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/06/2024] [Accepted: 12/10/2024] [Indexed: 01/20/2025]
Abstract
Organ transplants are used to treat many end-stage diseases, but a shortage of donors means many patients cannot be treated. Xenogeneic organs have become an important part of filling the donor gap. Many current studies of kidney, heart, and liver xenotransplantation have used gene-edited pig organs on brain-dead recipients. However, the endocrine system, immune system, and nervous system of brain-dead people are changed, which are different from that of real patients transplanted, and the current research results of brain death (BD) recipients are also different. So there are drawbacks to using brain-dead people for xenotransplantation. In addition, although the policy requires the use of non-human primate (NHP) experiments as the research standard for xenotransplantation, there are still differences between NHP and humans in terms of immunity. Therefore, to better study xenotransplantation, new models may be needed in addition to NHP and brain-dead individuals. Humanized animal models or organoids may be able to fill this gap.
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Affiliation(s)
- Xingchao Du
- Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, National Centre for Cardiovascular Disease, Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, PUMC, Beijing, China
| | - Yuan Chang
- Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, National Centre for Cardiovascular Disease, Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, PUMC, Beijing, China
| | - Jiangping Song
- Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, National Centre for Cardiovascular Disease, Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, PUMC, Beijing, China
- Sanya Institute of China Agricultural University, Sanya, China
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5
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Struckmeier AK, Gosau M, Smeets R. Cutaneous squamous cell carcinoma in solid organ transplant recipients: Current therapeutic and screening strategies. Transplant Rev (Orlando) 2024; 38:100882. [PMID: 39348772 DOI: 10.1016/j.trre.2024.100882] [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: 08/06/2024] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024]
Abstract
Solid organ transplant recipients (SOTRs) are particularly prone to developing malignancies, often manifesting multiple tumors and tumors with a heightened susceptibility to metastasis, resulting in much lower survival rates when compared to the general population. Among these, cutaneous squamous cell carcinoma (CSCC) respresent a major challenge in terms of morbidity and mortality following organ transplantation. The management of post-transplant CSCC requires expertise from various disciplines, including dermatology, maxillofacial surgery, transplant medicine, radiation oncology, and medical oncology. Furthermore, the unique behaviors and prevalence of tumors in SOTRs necessitate tailored pathways for screening and treatment, distinct from those designed for immunocompetent patients. Despite the proven efficacy of immune checkpoint inhibitors (ICIs) in several cancers, SOTRs have often been systematically excluded from clinical trials due to concerns about potential allograft rejection and loss. Consequently, most data on the safety and efficacy of ICIs in SOTRs are derived from case series and reports. Given the significant risks involved, alternative therapeutic options should be thoroughly discussed with patients before considering ICI therapy. This literature review aims to provide an overview of CSCC in SOTRs, with a specific emphasis on therapeutic and screening strategies, particularly highlighting immunotherapy.
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Affiliation(s)
- Ann-Kristin Struckmeier
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
| | - Martin Gosau
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
| | - Ralf Smeets
- Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Department of Oral and Maxillofacial Surgery, Division of Regenerative Orofacial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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6
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Hesen N, Anany M, Freidel A, Baker M, Siegmund D, Zaitseva O, Wajant H, Lang I. Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism. Bioengineered 2024; 15:2302246. [PMID: 38214443 PMCID: PMC10793706 DOI: 10.1080/21655979.2024.2302246] [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: 06/07/2023] [Accepted: 12/08/2023] [Indexed: 01/13/2024] Open
Abstract
Most anti-CD40 antibodies show robust agonism only upon binding to FcγR+ cells, such as B cells, macrophages, or DCs, but a few anti-CD40 antibodies display also strong intrinsic agonism dependent on the recognized epitope and/or isotype. It is worth mentioning, however, that also the anti-CD40 antibodies with intrinsic agonism can show a further increase in agonistic activity when bound by FcγR-expressing cells. Thus, conventional antibodies appear not to be sufficient to trigger the maximum possible CD40 activation independent from FcγR-binding. We proved here the hypothesis that oligomeric and oligovalent anti-CD40 antibody variants generated by genetic engineering display high intrinsic, thus FcγR-independent, agonistic activity. We generated tetra-, hexa- and dodecavalent variants of six anti-CD40 antibodies and a CD40-specific nanobody. All these oligovalent variants, even when derived of bivalent antagonistic anti-CD40 antibodies, showed strongly enhanced CD40 agonism compared to their conventional counterparts. In most cases, the CD40 agonism reached the maximum response induced by FcγR-bound anti-CD40 antibodies or membrane CD40L, the natural engager of CD40. In sum, our data show that increasing the valency of anti-CD40 antibody constructs by genetic engineering regularly results in molecules with high intrinsic agonism and level out the specific limitations of the parental antibodies.
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Affiliation(s)
- Nienke Hesen
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Mohamed Anany
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
- Department of Microbial Biotechnology, Institute of Biotechnology, National Research Center, Giza, Egypt
| | - Andre Freidel
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Mediya Baker
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Daniela Siegmund
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Olena Zaitseva
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Harald Wajant
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Isabell Lang
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
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7
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Akbarzadeh S, Coşkun Ö, Günçer B. Studying protein-protein interactions: Latest and most popular approaches. J Struct Biol 2024; 216:108118. [PMID: 39214321 DOI: 10.1016/j.jsb.2024.108118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/20/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
PPIs, or protein-protein interactions, are essential for many biological processes. According to the findings, abnormal PPIs have been linked to several diseases, such as cancer and infectious and neurological disorders. Consequently, focusing on PPIs is a path toward disease treatment and a crucial tool for producing novel medications. Many methods exist to investigate PPIs, including low- and high-throughput studies. Since many PPIs have been discovered using in vitro and in vivo experimental approaches, the use of computational methods to predict PPIs has grown due to the expanding scale of PPI data and the intrinsic complexity of interacting mechanisms. Recognizing PPI networks offers a systematic means of predicting protein functions, and pathways that are included. These investigations can help uncover the underlying molecular mechanisms of complex phenotypes and clarify the biological processes related to health and diseases. Therefore, our goal in this study is to provide an overview of the latest and most popular approaches for investigating PPIs. We also overview some important clinical approaches based on the PPIs and how these interactions can be targeted.
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Affiliation(s)
- Sama Akbarzadeh
- Department of Biophysics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye; Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Türkiye
| | - Özlem Coşkun
- Department of Biophysics, Faculty of Medicine, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye
| | - Başak Günçer
- Department of Biophysics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
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8
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Croft M, Salek-Ardakani S, Ware CF. Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer. Nat Rev Drug Discov 2024; 23:939-961. [PMID: 39448880 DOI: 10.1038/s41573-024-01053-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2024] [Indexed: 10/26/2024]
Abstract
The first anti-tumour necrosis factor (TNF) monoclonal antibody, infliximab (Remicade), celebrated its 25th anniversary of FDA approval in 2023. Inhibitors of TNF have since proved clinically efficacious at reducing inflammation associated with several autoimmune diseases, including rheumatoid arthritis, psoriasis and Crohn's disease. The success of TNF inhibitors raised unrealistic expectations for targeting other members of the TNF superfamily (TNFSF) of ligands and their receptors, with difficulties in part related to their more limited, variable expression and potential redundancy. However, there has been a resurgence of interest and investment, with many of these cytokines or their cognate receptors now under clinical investigation as targets for modulation of autoimmune and inflammatory diseases, as well as cancer. This Review assesses TNFSF-targeted biologics currently in clinical development for immune system-related diseases, highlighting ongoing challenges and future directions.
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Affiliation(s)
- Michael Croft
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, USA.
| | | | - Carl F Ware
- Laboratory of Molecular Immunology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
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9
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Iesari S, Nava FL, Zais IE, Coubeau L, Ferraresso M, Favi E, Lerut J. Advancing immunosuppression in liver transplantation: A narrative review. Hepatobiliary Pancreat Dis Int 2024; 23:441-448. [PMID: 38523030 DOI: 10.1016/j.hbpd.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 03/14/2024] [Indexed: 03/26/2024]
Abstract
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
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Affiliation(s)
- Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Francesca Laura Nava
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Ilaria Elena Zais
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Laurent Coubeau
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium; Service de Chirurgie et Transplantation Abdominale, Cliniques Universitaires Saint-Luc, 55 Avenue Hippocrate, 1200 Brussels, Belgium
| | - Mariano Ferraresso
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy
| | - Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy.
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium
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10
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Hou S, Yang B, Chen Q, Xu Y, Li H. Potential biomarkers of recurrent FSGS: a review. BMC Nephrol 2024; 25:258. [PMID: 39134955 PMCID: PMC11318291 DOI: 10.1186/s12882-024-03695-8] [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] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS), a clinicopathological condition characterized by nephrotic-range proteinuria, has a high risk of progression to end-stage renal disease (ESRD). Meanwhile, the recurrence of FSGS after renal transplantation is one of the main causes of graft loss. The diagnosis of recurrent FSGS is mainly based on renal puncture biopsy transplants, an approach not widely consented by patients with early mild disease. Therefore, there is an urgent need to find definitive diagnostic markers that can act as a target for early diagnosis and intervention in the treatment of patients. In this review, we summarize the domestic and international studies on the pathophysiology, pathogenesis and earliest screening methods of FSGS and describe the functions and roles of specific circulating factors in the progression of early FSGS, in order to provide a new theoretical basis for early diagnosis of FSGS recurrence, as well as aid the exploration of therapeutic targets.
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Affiliation(s)
- Shuang Hou
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Bo Yang
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Qian Chen
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Yuan Xu
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
| | - Haiyang Li
- Hepatological surgery department, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
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11
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Shoji J, Goggins WC, Wellen JR, Cunningham PN, Johnston O, Chang SS, Solez K, Santos V, Larson TJ, Takeuchi M, Wang X. Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study. Transplantation 2024; 108:1782-1792. [PMID: 39042770 PMCID: PMC11262731 DOI: 10.1097/tp.0000000000004985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 01/08/2024] [Accepted: 01/29/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. CONCLUSIONS In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.
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MESH Headings
- Humans
- Kidney Transplantation/adverse effects
- Glomerulosclerosis, Focal Segmental/drug therapy
- Glomerulosclerosis, Focal Segmental/immunology
- Male
- Female
- Middle Aged
- Adult
- Immunosuppressive Agents/therapeutic use
- Immunosuppressive Agents/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Treatment Outcome
- Recurrence
- Tacrolimus/therapeutic use
- Tacrolimus/adverse effects
- Graft Survival/drug effects
- Drug Therapy, Combination
- Adrenal Cortex Hormones/therapeutic use
- Secondary Prevention/methods
- Kidney Failure, Chronic/surgery
- Kidney Failure, Chronic/prevention & control
- Kidney Failure, Chronic/etiology
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Affiliation(s)
- Jun Shoji
- Division of Transplant Nephrology, University of California San Francisco, San Francisco, CA
| | - William C. Goggins
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Jason R. Wellen
- Division of Transplantation, Department of Surgery, Washington University in St Louis, St Louis, MO
| | | | - Olwyn Johnston
- Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Shirley S. Chang
- Division of Nephrology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Erie County Medical Center, Buffalo, NY
| | - Kim Solez
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Vicki Santos
- Astellas Pharma Global Development Inc, Northbrook, IL
| | | | | | - Xuegong Wang
- Astellas Pharma Global Development Inc, Northbrook, IL
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12
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Adams AB, Faber D, Lovasik BP, Matar AJ, Kim SC, Burlak C, Tector M, Tector AJ. Iscalimab Combined With Transient Tesidolumab Prolongs Survival in Pig-to-Rhesus Monkey Renal Xenografts. Xenotransplantation 2024; 31:e12880. [PMID: 39185772 DOI: 10.1111/xen.12880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 07/29/2024] [Accepted: 08/07/2024] [Indexed: 08/27/2024]
Abstract
OBJECTIVE To evaluate the clinically relevant anti-CD40 antibody iscalimab for baseline immunosuppression in a preclinical pig-to-rhesus renal xenograft model. SUMMARY BACKGROUND DATA CD40/CD40L co-stimulation blockade-based immunosuppression has been more successful than calcineurin-based protocols in prolonging xenograft survival in preclinical models. METHODS GGTA1 knockout/CD55 transgenic pig kidneys were transplanted into rhesus monkeys (n = 6) receiving an iscalimab-based immunosuppressive regimen. RESULTS Two grafts were lost early (22 and 26 days) because of ectatic donor ureters with otherwise normal histology. The other recipients survived 171, 315, 422, and 439 days with good renal function throughout the posttransplant course. None of the recipients experienced serious infectious morbidity. CONCLUSIONS It may be reasonable to evaluate an iscalimab-based immunosuppressive regimen in clinical renal xenotransplantation.
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Affiliation(s)
- Andrew B Adams
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
| | - David Faber
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
| | - Brendan P Lovasik
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Abraham J Matar
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
| | - Steven C Kim
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Christopher Burlak
- Department of Surgery, University of Miami School of Medicine, Miami, Florida, USA
| | | | - Alfred J Tector
- Department of Surgery, University of Miami School of Medicine, Miami, Florida, USA
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13
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Asano R, Nakakido M, Pérez JF, Ise T, Caaveiro JMM, Nagata S, Tsumoto K. Crystal structures of human CD40 in complex with monoclonal antibodies dacetuzumab and bleselumab. Biochem Biophys Res Commun 2024; 714:149969. [PMID: 38657446 DOI: 10.1016/j.bbrc.2024.149969] [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: 04/17/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024]
Abstract
CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the CD40 ligand (CD40L) plays an essential function in signaling, and the CD40/CD40L complex works as an immune checkpoint molecule. CD40 has become a therapeutic target, and a variety of agonistic/antagonistic anti-CD40 monoclonal antibodies (mAbs) have been developed. To better understand the mode of action of anti-CD40 mAbs, we determined the X-ray crystal structures of dacetuzumab (agonist) and bleselumab (antagonist) in complex with the extracellular domain of human CD40, respectively. The structure reveals that dacetuzumab binds to CD40 on the top of cysteine-rich domain 1 (CRD1), which is the domain most distant from the cell surface, and it does not compete with CD40L binding. The binding interface of bleselumab spread between CRD2 and CRD1, overlapping with the binding surface of the ligand. Our results offer important insights for future structural and functional studies of CD40 and provide clues to understanding the mechanism of biological response. These data can be applied to developing new strategies for designing antibodies with more therapeutic efficacy.
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Affiliation(s)
- Risa Asano
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Makoto Nakakido
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan; Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan.
| | - Jorge Fernández Pérez
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Tomoko Ise
- Laboratory of Antibody Design, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Jose M M Caaveiro
- Department of Protein Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoshi Nagata
- Laboratory of Antibody Design, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Kouhei Tsumoto
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan; Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan; Medical Device Development and Regulation Research Center, School of Engineering, The University of Tokyo, Tokyo, Japan; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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14
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Shah K, Leandro M, Cragg M, Kollert F, Schuler F, Klein C, Reddy V. Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy? Clin Exp Immunol 2024; 217:15-30. [PMID: 38642912 PMCID: PMC11188544 DOI: 10.1093/cei/uxae031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 02/07/2024] [Accepted: 04/18/2024] [Indexed: 04/22/2024] Open
Abstract
B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.
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Affiliation(s)
| | - Maria Leandro
- Centre for Rheumatology, UCLH, London,UK
- Department of Rheumatology, University College London Hospital, London, UK
| | - Mark Cragg
- University of Southampton Faculty of Medicine, Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton, Southampton, UK
| | - Florian Kollert
- Roche Innovation Center Basel, Early Development Immunology, Infectious Diseases & Ophthalmology, Basel, Switzerland
| | - Franz Schuler
- Roche Innovation Center Basel, Roche Pharma Research and Early Development, Schlieren, Switzerland
| | - Christian Klein
- Roche Innovation Center Zurich, Cancer Immunotherapy Discovery, Oncology Discovery & Translational Area, Schlieren, Switzerland
| | - Venkat Reddy
- Centre for Rheumatology, UCLH, London,UK
- Department of Rheumatology, University College London Hospital, London, UK
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15
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Datrino LN, Boccuzzi ML, Silva RM, Castilho PHBT, Riva WJ, Rocha JS, Tustumi F. Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies. Transplant Proc 2024; 56:1066-1076. [PMID: 38853029 DOI: 10.1016/j.transproceed.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 06/11/2024]
Abstract
INTRODUCTION This study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. METHODS A systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. RESULTS Thirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). CONCLUSION Gastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections.
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Affiliation(s)
| | - Matheus Lopes Boccuzzi
- Department of Evidenced-based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil
| | - Rafael Matosinho Silva
- Department of Evidenced-based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil
| | | | - Wagner José Riva
- Department of Evidenced-based Medicine, Centro Universitário Lusíada, Santos, SP, Brazil
| | - Jéssica Silva Rocha
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Francisco Tustumi
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; Department of Gastroenterology, Universidade de São Paulo, São Paulo, SP, Brazil.
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16
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Grosu-Bularda A, Hodea FV, Zamfirescu D, Stoian A, Teodoreanu RN, Lascăr I, Hariga CS. Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation? J Pers Med 2024; 14:322. [PMID: 38541064 PMCID: PMC10971463 DOI: 10.3390/jpm14030322] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 11/12/2024] Open
Abstract
The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.
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Affiliation(s)
- Andreea Grosu-Bularda
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Florin-Vlad Hodea
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | | | | | - Răzvan Nicolae Teodoreanu
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Ioan Lascăr
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Cristian Sorin Hariga
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
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17
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Fitzsimmons WE, Naesens M. Acute Rejection After Kidney Transplant-An Endpoint Not Predictive of Treatment Effect on Graft Survival. Transplantation 2024; 108:593-597. [PMID: 37322579 DOI: 10.1097/tp.0000000000004696] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Affiliation(s)
- William E Fitzsimmons
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois, Chicago, IL
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Maarten Naesens
- Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
- Department of Nephrology, UZ Leuven, Leuven, Belgium
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18
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Lansberry TR, Stabler CL. Immunoprotection of cellular transplants for autoimmune type 1 diabetes through local drug delivery. Adv Drug Deliv Rev 2024; 206:115179. [PMID: 38286164 PMCID: PMC11140763 DOI: 10.1016/j.addr.2024.115179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/19/2023] [Accepted: 01/19/2024] [Indexed: 01/31/2024]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in the destruction of insulin-secreting β cells of the islets of Langerhans. Allogeneic islet transplantation could be a successful treatment for T1DM; however, it is limited by the need for effective, permanent immunosuppression to prevent graft rejection. Upon transplantation, islets are rejected through non-specific, alloantigen specific, and recurring autoimmune pathways. Immunosuppressive agents used for islet transplantation are generally successful in inhibiting alloantigen rejection, but they are suboptimal in hindering non-specific and autoimmune pathways. In this review, we summarize the challenges with cellular immunological rejection and therapeutics used for islet transplantation. We highlight agents that target these three immune rejection pathways and how to package them for controlled, local delivery via biomaterials. Exploring macro-, micro-, and nano-scale immunomodulatory biomaterial platforms, we summarize their advantages, challenges, and future directions. We hypothesize that understanding their key features will help identify effective platforms to prevent islet graft rejection. Outcomes can further be translated to other cellular therapies beyond T1DM.
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Affiliation(s)
- T R Lansberry
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - C L Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA; Department of Immunology and Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; University of Florida Diabetes Institute, Gainesville, FL, USA.
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19
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Samant M, Ziemniak J, Paolini JF. First-in-Human Phase 1 Randomized Trial with the Anti-CD40 Monoclonal Antibody KPL-404: Safety, Tolerability, Receptor Occupancy, and Suppression of T-Cell-Dependent Antibody Response. J Pharmacol Exp Ther 2023; 387:306-314. [PMID: 37699709 DOI: 10.1124/jpet.123.001771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/04/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
Blockade of the cluster of differentiation 40 (CD40)-CD40L interaction has potential for treating autoimmune diseases and preventing graft rejection. This first-in-human, randomized, double-blind, placebo-controlled study (NCT04497662) evaluated safety, pharmacokinetics, receptor occupancy, and pharmacodynamics of the humanized anti-CD40 monoclonal antibody KPL-404. Healthy volunteers were randomized to one of two single-ascending-dose groups: single intravenous KPL-404 dose 0.03, 0.3, 1, 3, or 10 mg/kg or single subcutaneous KPL-404 dose 1 or 5 mg/kg. There were no dose-limiting or dose-related safety findings. Nonlinear dose-dependent changes in various pharmacokinetic parameters were identified following the range of intravenous doses. At the 10 mg/kg intravenous dose level, the t1/2 was approximately 7 days, and full receptor occupancy was observed through Day 71, with complete suppression of T-cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) challenge on Day 1 and rechallenge on Day 29 through Day 57. With KPL-404 5 mg/kg subcutaneously, full receptor occupancy was observed through Day 43, with complete suppression of TDAR through at least Day 29. Antidrug antibodies to KPL-404 were suppressed for 57 days with 10 mg/kg intravenously and for 50 days with 5 mg/kg subcutaneously, further confirming prolonged target engagement and pharmacodynamics. These findings support continued investigation of KPL-404 intravenous and subcutaneous administration in a broad range of indications. SIGNIFICANCE STATEMENT: This first-in-human clinical trial of KPL-404, a fully humanized IgG4 monoclonal antibody, was designed with two independent (by route of administration) placebo-controlled single-ascending-dose-level groups, one with four intravenous single-dose cohorts and another with two subcutaneous single-dose cohorts. The pharmacokinetic profile, duration of full CD40 receptor occupancy, and magnitude and duration of memory immune response suppression observed confirm pharmacodynamic activity regardless of administration route. These data provide evidence that chronic KPL-404 dosing regimens (intravenous or subcutaneous) could be practical.
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Affiliation(s)
- Manoj Samant
- Kiniksa Pharmaceuticals, Lexington, Massachusetts
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20
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Qayyum S, Shahid K. Comparative Safety and Efficacy of Immunosuppressive Regimens Post-kidney Transplant: A Systematic Review. Cureus 2023; 15:e43903. [PMID: 37746361 PMCID: PMC10512192 DOI: 10.7759/cureus.43903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
Immunosuppressive agents are used post-organ transplant to prevent acute rejection and graft losses. Tacrolimus, the most widely used immunosuppressive agent for kidney transplant recipients, has unfavorable side effects such as new-onset diabetes after transplant, nephrotoxicity, and electrolyte imbalances. Other drug groups such as the mammalian target of rapamycin (mTOR) inhibitors, belatacept, and bleselumab have been used to either substitute calcineurin inhibitors or reduce their exposure. This systematic analysis reviews evidence from randomized controlled trials to compare the safety and efficacy of various immunosuppressive regimens for kidney transplant recipients. An in-depth methodical search was conducted across PubMed, Cochrane Library, and Mendeley. PRISMA 2020 guidelines were followed for this study. Randomized controlled trials comparing varying regimens were included in this study. While there was no difference in safety and efficacy between once-daily and twice-daily tacrolimus, mTOR inhibitors showed to be a viable option for a reduced tacrolimus exposure regimen. Calcineurin inhibitor avoidance and early steroid withdrawal regimens both showed increased rates of rejection. Based on these findings, a regimen containing once-daily tacrolimus and an mTOR inhibitor with or without corticosteroid is a viable immunosuppressive regimen post-kidney transplant. Further trials, especially ones with longer follow-up periods, are needed to explore these regimens' long-term safety and efficacy.
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Affiliation(s)
- Shahid Qayyum
- Nephrology, Diaverum Dialysis Center, Wadi Al Dawasir, SAU
| | - Kamran Shahid
- Internal Medicine/Family Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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21
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Zhu J, Fan J, Xia Y, Wang H, Li Y, Feng Z, Fu C. Potential therapeutic targets of macrophages in inhibiting immune damage and fibrotic processes in musculoskeletal diseases. Front Immunol 2023; 14:1219487. [PMID: 37545490 PMCID: PMC10400722 DOI: 10.3389/fimmu.2023.1219487] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 07/04/2023] [Indexed: 08/08/2023] Open
Abstract
Macrophages are a heterogeneous cell type with high plasticity, exhibiting unique activation characteristics that modulate the progression and resolution of diseases, serving as a key mediator in maintaining tissue homeostasis. Macrophages display a variety of activation states in response to stimuli in the local environment, with their subpopulations and biological functions being dependent on the local microenvironment. Resident tissue macrophages exhibit distinct transcriptional profiles and functions, all of which are essential for maintaining internal homeostasis. Dysfunctional macrophage subpopulations, or an imbalance in the M1/M2 subpopulation ratio, contribute to the pathogenesis of diseases. In skeletal muscle disorders, immune and inflammatory damage, as well as fibrosis induced by macrophages, are prominent pathological features. Therefore, targeting macrophages is of great significance for maintaining tissue homeostasis and treating skeletal muscle disorders. In this review, we discuss the receptor-ligand interactions regulating macrophages and identify potential targets for inhibiting collateral damage and fibrosis in skeletal muscle disorders. Furthermore, we explore strategies for modulating macrophages to maintain tissue homeostasis.
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Affiliation(s)
- Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Jiawei Fan
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yuanliang Xia
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hengyi Wang
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yuehong Li
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Zijia Feng
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Changfeng Fu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
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22
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Shi T, Burg AR, Caldwell JT, Roskin KM, Castro-Rojas CM, Chukwuma PC, Gray GI, Foote SG, Alonso JA, Cuda CM, Allman DA, Rush JS, Regnier CH, Wieczorek G, Alloway RR, Shields AR, Baker BM, Woodle ES, Hildeman DA. Single-cell transcriptomic analysis of renal allograft rejection reveals insights into intragraft TCR clonality. J Clin Invest 2023; 133:e170191. [PMID: 37227784 PMCID: PMC10348771 DOI: 10.1172/jci170191] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/23/2023] [Indexed: 05/27/2023] Open
Abstract
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.
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Affiliation(s)
- Tiffany Shi
- Division of Immunobiology and
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Medical Scientist Training Program and
| | - Ashley R. Burg
- Division of Immunobiology and
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | | | - Krishna M. Roskin
- Division of Immunobiology and
- Divison of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | | | - P. Chukwunalu Chukwuma
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - George I. Gray
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - Sara G. Foote
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - Jesus A. Alonso
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - Carla M. Cuda
- Northwestern University, Feinberg School of Medicine, Department of Medicine, Division of Rheumatology, Chicago, Illinois, USA
| | - David A. Allman
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - James S. Rush
- Novartis Institutes for Biomedical Research, Immunology Disease Area, Basel, Switzerland
| | - Catherine H. Regnier
- Novartis Institutes for Biomedical Research, Immunology Disease Area, Basel, Switzerland
| | - Grazyna Wieczorek
- Novartis Institutes for Biomedical Research, Immunology Disease Area, Basel, Switzerland
| | - Rita R. Alloway
- Division of Nephrology and Hypertension, Department of Internal Medicine, and
| | - Adele R. Shields
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Brian M. Baker
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - E. Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - David A. Hildeman
- Division of Immunobiology and
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Medical Scientist Training Program and
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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23
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Singh AK, Goerlich CE, Zhang T, Lewis BG, Hershfeld A, Mohiuddin MM. CD40-CD40L Blockade: Update on Novel Investigational Therapeutics for Transplantation. Transplantation 2023; 107:1472-1481. [PMID: 36584382 PMCID: PMC10287837 DOI: 10.1097/tp.0000000000004469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Effective immune responses require antigen presentation by major histocompatibility complexes with cognate T-cell receptor and antigen-independent costimulatory signaling for T-cell activation, proliferation, and differentiation. Among several costimulatory signals, CD40-CD40L is of special interest to the transplantation community because it plays a vital role in controlling or regulating humoral and cellular immunity. Blockade of this pathway has demonstrated inhibition of donor-reactive T-cell responses and prolonged the survival of transplanted organs. Several anti-CD154 and anti-CD40 antibodies have been used in the transplantation model and demonstrated the potential of extending allograft and xenograft rejection-free survival. The wide use of anti-CD154 antibodies was hampered because of thromboembolic complications in transplant recipients. These antibodies have been modified to overcome the thromboembolic complications by altering the antibody binding fragment (Fab) and Fc (fragment, crystallizable) receptor region for therapeutic purposes. Here, we review recent preclinical advances to target the CD40-CD40L pair in transplantation.
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Affiliation(s)
| | | | - Tianshu Zhang
- University of Maryland School of Medicine, Baltimore, MD
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Shi T, Burg AR, Caldwell JT, Roskin K, Castro-Rojas CM, Chukwuma PC, Gray GI, Foote SG, Alonso J, Cuda CM, Allman DA, Rush JS, Regnier CH, Wieczorek G, Alloway RR, Shields AR, Baker BM, Woodle ES, Hildeman DA. Single cell transcriptomic analysis of renal allograft rejection reveals novel insights into intragraft TCR clonality. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.08.524808. [PMID: 36798151 PMCID: PMC9934650 DOI: 10.1101/2023.02.08.524808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding. We performed combined single cell RNA transcriptomic and TCRα/β sequencing on rBx from patients with ACR under differing immunosuppression (IS): tacrolimus, iscalimab, and belatacept. TCR analysis revealed a highly restricted CD8 + T cell clonal expansion (CD8 EXP ), independent of HLA mismatch or IS type. Subcloning of TCRα/β cDNAs from CD8 EXP into Jurkat76 cells (TCR -/- ) conferred alloreactivity by mixed lymphocyte reaction. scRNAseq analysis of CD8 EXP revealed effector, memory, and exhausted phenotypes that were influenced by IS type. Successful anti-rejection treatment decreased, but did not eliminate, CD8 EXP , while CD8 EXP were maintained during treatment-refractory rejection. Finally, most rBx-derived CD8 EXP were also observed in matching urine samples. Overall, our data define the clonal CD8 + T cell response to ACR, providing novel insights to improve detection, assessment, and treatment of rejection.
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Farshbafnadi M, Razi S, Rezaei N. Transplantation. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Unger LW, Muckenhuber M, Mahr B, Schwarz C, Pilat N, Granofszky N, Regele H, Wekerle T. Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen. Front Immunol 2022; 13:1060576. [PMID: 36569922 PMCID: PMC9773869 DOI: 10.3389/fimmu.2022.1060576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 11/17/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction In de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model. Methods Naïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period. Results and Discussion Administering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.
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Affiliation(s)
- Lukas W. Unger
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Moritz Muckenhuber
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Benedikt Mahr
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Christoph Schwarz
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Nina Pilat
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Nicolas Granofszky
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Heinz Regele
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Thomas Wekerle
- Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
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Kervella D, Blancho G. New immunosuppressive agents in transplantation. Presse Med 2022; 51:104142. [PMID: 36252821 DOI: 10.1016/j.lpm.2022.104142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 09/29/2022] [Indexed: 11/24/2022] Open
Abstract
Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival. Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection. The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials. Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.
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Affiliation(s)
- Delphine Kervella
- CHU Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, ITUN, Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Gilles Blancho
- CHU Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, ITUN, Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France.
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Lang I, Zaitseva O, Wajant H. FcγRs and Their Relevance for the Activity of Anti-CD40 Antibodies. Int J Mol Sci 2022; 23:12869. [PMID: 36361658 PMCID: PMC9655775 DOI: 10.3390/ijms232112869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 03/14/2024] Open
Abstract
Inhibitory targeting of the CD40L-CD40 system is a promising therapeutic option in the field of organ transplantation and is also attractive in the treatment of autoimmune diseases. After early complex results with neutralizing CD40L antibodies, it turned out that lack of Fcγ receptor (FcγR)-binding is the crucial factor for the development of safe inhibitory antibodies targeting CD40L or CD40. Indeed, in recent years, blocking CD40 antibodies not interacting with FcγRs, has proven to be well tolerated in clinical studies and has shown initial clinical efficacy. Stimulation of CD40 is also of considerable therapeutic interest, especially in cancer immunotherapy. CD40 can be robustly activated by genetically engineered variants of soluble CD40L but also by anti-CD40 antibodies. However, the development of CD40L-based agonists is biotechnologically and pharmacokinetically challenging, and anti-CD40 antibodies typically display only strong agonism in complex with FcγRs or upon secondary crosslinking. The latter, however, typically results in poorly developable mixtures of molecule species of varying stoichiometry and FcγR-binding by anti-CD40 antibodies can elicit unwanted side effects such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of CD40 expressing immune cells. Here, we summarize and compare strategies to overcome the unwanted target cell-destroying activity of anti-CD40-FcγR complexes, especially the use of FcγR type-specific mutants and the FcγR-independent cell surface anchoring of bispecific anti-CD40 fusion proteins. Especially, we discuss the therapeutic potential of these strategies in view of the emerging evidence for the dose-limiting activities of systemic CD40 engagement.
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Affiliation(s)
| | | | - Harald Wajant
- Department of Internal Medicine II, Division of Molecular Internal Medicine, University Hospital Würzburg, Auvera Haus, Grombühlstrasse 12, 97080 Würzburg, Germany
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Updated Pathways in Cardiorenal Continuum after Kidney Transplantation. TRANSPLANTOLOGY 2022. [DOI: 10.3390/transplantology3020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Cardiovascular disease (CVD) remains one of the leading causes for increased morbidity and mortality in chronic kidney disease (CKD). Kidney transplantation is the preferred treatment option for CKD G5. Improved perioperative and postoperative care, personalized immunosuppressive regimes, and refined matching procedures of kidney transplants improves cardiovascular health in the early posttransplant period. However, the long-term burden of CVD is considerable. Previously underrecognized, the role of the complement system alongside innate immunity, inflammaging, structural changes in the glomerular filtration barrier and early vascular ageing also seem to play an important role in the posttransplant management. This review provides up-to-date knowledge on these pathways that may influence the cardiovascular and renal continuum and identifies potential targets for future therapies. Arterial destiffening strategies and the applicability of sodium-glucose cotransporter 2 inhibitors and their role in cardiovascular health after kidney transplantation are also addressed.
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30
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Aiyegbusi O, McGregor E, McManus SK, Stevens KI. Immunosuppression Therapy in Kidney Transplantation. Urol Clin North Am 2022; 49:345-360. [DOI: 10.1016/j.ucl.2021.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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CD40-CD40L in Neurological Disease. Int J Mol Sci 2022; 23:ijms23084115. [PMID: 35456932 PMCID: PMC9031401 DOI: 10.3390/ijms23084115] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Immune-inflammatory conditions in the central nervous system (CNS) rely on molecular and cellular interactions which are homeostatically maintained to protect neural tissue from harm. The CD40–CD40L interaction upregulates key proinflammatory molecules, a function best understood in the context of infection, during which B-cells are activated via CD40 signaling to produce antibodies. However, the role of CD40 in neurological disease of non-infectious etiology is unclear. We review the role of CD40–CD40L in traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis, ALS, myasthenia gravis and brain tumors. We also highlight therapeutic advancements targeting the CD40 system to either attenuate the neuroinflammatory response or leverage the downstream effects of CD40 signaling for direct tumor cell lysis.
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Perrin S, Magill M. The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. Front Immunol 2022; 13:861471. [PMID: 35464470 PMCID: PMC9022482 DOI: 10.3389/fimmu.2022.861471] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022] Open
Abstract
The prevention of allograft transplant rejection by inhibition of the CD40/CD40L costimulatory pathway has been described in several species. We searched pubmed for studies reporting the prevention of kidney transplant rejection in nonhuman primates utilizing either anti CD40 or anti CD40L (CD154) treatment. Inclusion of data required treatment with anti CD40 or anti CD154 as monotherapy treatment arms, full text available, studies conducted in nonhuman primate species, the transplant was renal transplantation, sufficient duration of treatment to assess long term rejection, and the reporting of individual graft survival or survival duration. Eleven publications were included in the study. Rejection free survival was calculated using the Kaplan-Meier (KM) life test methods to estimate the survival functions. The 95% CI for the medians was also calculated. A log-rank test was used to test the equality of the survival curves between control and treatment arms (CD40 and CD154). The hazard ratio for CD154 compared to CD40 and 95% CI was calculated using a Cox proportional-hazards model including treatment as the covariate to assess the magnitude of the treatment effect. Both anti CD40 and anti CD154 treatments prevented acute and long term graft rejection. The median (95% CI) rejection free survival was 131 days (84,169 days) in the anti CD40 treated animals and 352 days (173,710 days) in the anti CD154 treated animals. Median survival in the untreated animals was 6 days. The inhibition of transplant rejection was more durable in the anti CD154 group compared to the anti CD40 group after cessation of treatment. The median (95% CI) rejection free survival after cessation of treatment was 60 days (21,80 days) in the anti CD40 treated animals and 230 days (84,552 days) in the anti CD154 treated animals.
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Mou L, Shi G, Cooper DK, Lu Y, Chen J, Zhu S, Deng J, Huang Y, Ni Y, Zhan Y, Cai Z, Pu Z. Current Topics of Relevance to the Xenotransplantation of Free Pig Islets. Front Immunol 2022; 13:854883. [PMID: 35432379 PMCID: PMC9010617 DOI: 10.3389/fimmu.2022.854883] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Pig islet xenotransplantation is a potential treatment for patients with type 1 diabetes. Current efforts are focused on identifying the optimal pig islet source and overcoming the immunological barrier. The optimal age of the pig donors remains controversial since both adult and neonatal pig islets have advantages. Isolation of adult islets using GMP grade collagenase has significantly improved the quantity and quality of adult islets, but neonatal islets can be isolated at a much lower cost. Certain culture media and coculture with mesenchymal stromal cells facilitate neonatal islet maturation and function. Genetic modification in pigs affords a promising strategy to prevent rejection. Deletion of expression of the three known carbohydrate xenoantigens (Gal, Neu5Gc, Sda) will certainly be beneficial in pig organ transplantation in humans, but this is not yet proven in islet transplantation, though the challenge of the '4th xenoantigen' may prove problematic in nonhuman primate models. Blockade of the CD40/CD154 costimulation pathway leads to long-term islet graft survival (of up to 965 days). Anti-CD40mAbs have already been applied in phase II clinical trials of islet allotransplantation. Fc region-modified anti-CD154mAbs successfully prevent the thrombotic complications reported previously. In this review, we discuss (I) the optimal age of the islet-source pig, (ii) progress in genetic modification of pigs, (iii) the immunosuppressive regimen for pig islet xenotransplantation, and (iv) the reduction in the instant blood-mediated inflammatory reaction.
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Affiliation(s)
- Lisha Mou
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Guanghan Shi
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada
| | - David K.C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States
| | - Ying Lu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jiao Chen
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Shufang Zhu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jing Deng
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yuanyuan Huang
- Department of Life Science, Bellevue College, Bellevue, WA, United States
| | - Yong Ni
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yongqiang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Zuhui Pu
- Imaging Department, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
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Salvadori M, Tsalouchos A. Innovative immunosuppression in kidney transplantation: A challenge for unmet needs. World J Transplant 2022; 12:27-41. [PMID: 35433332 PMCID: PMC8968476 DOI: 10.5500/wjt.v12.i3.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 01/27/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Division of Nephrology, Santa Maria Annunziata Hospital, Florence 50012, Italy
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Louis K, Macedo C, Lefaucheur C, Metes D. Adaptive immune cell responses as therapeutic targets in antibody-mediated organ rejection. Trends Mol Med 2022; 28:237-250. [PMID: 35093288 PMCID: PMC8882148 DOI: 10.1016/j.molmed.2022.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 01/17/2023]
Abstract
Humoral alloimmunity of organ transplant recipient to donor can lead to antibody-mediated rejection (ABMR), causing thousands of organ transplants to fail each year worldwide. However, the mechanisms of adaptive immune cell responses at the basis of humoral alloimmunity have not been entirely understood. In this review, we discuss how recent investigations have uncovered the key contributions of T follicular helper (TFH) and B cells and their coordinated actions in driving donor-specific antibody generation and immune progression towards ABMR. We show how recognition of the role of TFH-B cell interactions may allow the elaboration of improved clinical strategies for immune monitoring and the identification of novel therapeutic targets to tackle ABMR that will ultimately improve organ transplant survival.
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Affiliation(s)
- Kevin Louis
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Human Immunology and Immunopathology, Institut National de la Santé et de la Recherche Médicale UMR 976, Université de Paris, Paris, France
| | - Camila Macedo
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Carmen Lefaucheur
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale UMR 970, Université de Paris, Paris, France
| | - Diana Metes
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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36
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Immunosuppression in the Age of Precision Medicine. Semin Nephrol 2022; 42:86-98. [DOI: 10.1016/j.semnephrol.2022.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Louis K, Macedo C, Metes D. Targeting T Follicular Helper Cells to Control Humoral Allogeneic Immunity. Transplantation 2021; 105:e168-e180. [PMID: 33909968 PMCID: PMC8484368 DOI: 10.1097/tp.0000000000003776] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Humoral allogeneic immunity driven by anti-HLA donor-specific antibodies and antibody-mediated rejection (AMR) significantly impede prolonged survival of organ allografts after transplantation. Although the importance of T follicular helper (TFH) cells in controlling antibody responses has been long established, their role in directing donor-specific antibody generation leading to AMR was only recently appreciated in the clinical setting of organ transplantation. In this review, we provide a comprehensive summary of the current knowledge on the biology of human TFH cells as well as their circulating counterparts and describe their pivotal role in driving humoral alloimmunity. In addition, we discuss the intrinsic effects of current induction therapies and maintenance immunosuppressive drugs as well as of biotherapies on TFH cells and provide future directions and novel opportunities of biotherapeutic targeting of TFH cells that have the potential of bringing the prophylactic and curative treatments of AMR toward personalized and precision medicine.
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Affiliation(s)
- Kevin Louis
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Human Immunology and Immunopathology, Inserm UMR 976, Université de Paris, Paris, France
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Camila Macedo
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Diana Metes
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Lutgens E, Joffre J, van Os B, Ait-Oufella H. Targeting cytokines and immune checkpoints in atherosclerosis with monoclonal antibodies. Atherosclerosis 2021; 335:98-109. [PMID: 34593238 DOI: 10.1016/j.atherosclerosis.2021.09.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/24/2021] [Accepted: 09/21/2021] [Indexed: 11/15/2022]
Abstract
Over the past fifteen years, treatments using monoclonal antibodies specifically targeting cytokines have been developed to treat chronic inflammatory diseases, including rheumatoid arthritis or psoriasis, both associated with increased cardiovascular risk. The cardiovascular impact of these therapies allows us to validate the clinical relevance of the knowledge acquired from experimental studies about the role of cytokines in atherosclerosis. Several clinical studies have confirmed the protective effects of anti-TNFα and anti-IL-6R monoclonal antibodies against athero-thrombotic cardiovascular risk in patients with chronic inflammatory diseases. Yet, caution is needed since anti-TNFα treatment can aggravate chronic heart failure. More recently, the CANTOS study showed for the first time that an anti-inflammatory treatment using anti-IL-1β monoclonal antibody in coronary artery disease patients significantly reduced cardiovascular events. The effects of IL-23/IL-17 axis blockade on cardiovascular risk in patients with psoriasis or arthritis remain controversial. Several monoclonal antibodies targeting costimulatory molecules have also been developed, a direct way to confirm their involvement in atherothrombotic cardiovascular diseases. Blocking the CD28-CD80/86 axis with Abatacept has been shown to reduce cardiovascular risk. In contrast, the treatment of cancer patients with antibodies blocking immune checkpoint inhibitory receptors, such as CTLA-4, PD1, or PDL1, could worsen the risk of atherothrombotic events. In the future, cardiologists will be increasingly solicited to assess the cardiovascular risk of patients suffering from chronic inflammatory diseases or cancer and participate in choosing the most appropriate treatment. At the same time, immunomodulatory approaches directly targeting cardiovascular diseases will be developed as a complement to the usual treatment strategies.
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Affiliation(s)
- Esther Lutgens
- Department of Medical Biochemistry Experimental Vascular Biology, Amsterdam, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität, Pettenkoferstraße 8a & 9, 80336, Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Pettenkoferstraße 8a & 9, 80336, Munich, Germany.
| | - Jeremie Joffre
- Service de Réanimation Médicale, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France; Université de Paris, Inserm U970, Paris Cardiovascular Research Center, Paris, France; Department of Anesthesia and Perioperative Care, UCSF School of Medicine, San Francisco, CA, USA
| | - Bram van Os
- Department of Medical Biochemistry Experimental Vascular Biology, Amsterdam, the Netherlands
| | - Hafid Ait-Oufella
- Service de Réanimation Médicale, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France; Université de Paris, Inserm U970, Paris Cardiovascular Research Center, Paris, France.
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Olaso D, Manook M, Moris D, Knechtle S, Kwun J. Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient. J Clin Med 2021; 10:3656. [PMID: 34441950 PMCID: PMC8396983 DOI: 10.3390/jcm10163656] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 01/10/2023] Open
Abstract
Patients with previous sensitization events against anti-human leukocyte antigens (HLA) often have circulating anti-HLA antibodies. Following organ transplantation, sensitized patients have higher rates of antibody-mediated rejection (AMR) compared to those who are non-sensitized. More stringent donor matching is required for these patients, which results in a reduced donor pool and increased time on the waitlist. Current approaches for sensitized patients focus on reducing preformed antibodies that preclude transplantation; however, this type of desensitization does not modulate the primed immune response in sensitized patients. Thus, an optimized maintenance immunosuppressive regimen is necessary for highly sensitized patients, which may be distinct from non-sensitized patients. In this review, we will discuss the currently available therapeutic options for induction, maintenance, and adjuvant immunosuppression for sensitized patients.
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Affiliation(s)
| | | | | | - Stuart Knechtle
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; (D.O.); (M.M.); (D.M.)
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; (D.O.); (M.M.); (D.M.)
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Koritzinsky EH, Tsuda H, Fairchild RL. Endogenous memory T cells with donor-reactivity: early post-transplant mediators of acute graft injury in unsensitized recipients. Transpl Int 2021; 34:1360-1373. [PMID: 33963616 PMCID: PMC8389524 DOI: 10.1111/tri.13900] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/15/2021] [Accepted: 05/03/2021] [Indexed: 11/29/2022]
Abstract
The pretransplant presence of endogenous donor-reactive memory T cells is an established risk factor for acute rejection and poorer transplant outcomes. A major source of these memory T cells in unsensitized recipients is heterologously generated memory T cells expressing reactivity to donor allogeneic MHC molecules. Multiple clinical studies have shown that the pretransplant presence of high numbers of circulating endogenous donor-reactive memory T cells correlates with higher incidence of acute rejection and decreased graft function during the first-year post-transplant. These findings have spurred investigation in preclinical models to better understand mechanisms underlying endogenous donor-reactive memory T-cell-mediated allograft injury in unsensitized graft recipients. These studies have led to the identification of unique mechanisms underlying the activation of these memory T cells within allografts at early times after transplant. In particular, optimal activation to mediate acute allograft injury is dependent on the intensity of ischaemia-reperfusion injury. Therapeutic strategies directed at the recruitment and activation of endogenous donor-reactive memory T cells are effective in attenuating acute injury in allografts experiencing increased ischaemia-reperfusion injury in preclinical models and should be translatable to clinical transplantation.
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Affiliation(s)
- Erik H. Koritzinsky
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
| | - Hidetoshi Tsuda
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Robert L. Fairchild
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Transplant Center, Cleveland Clinic, Cleveland, OH
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
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Bikhet M, Iwase H, Yamamoto T, Jagdale A, Foote JB, Ezzelarab M, Anderson DJ, Locke JE, Eckhoff DE, Hara H, Cooper DKC. What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation? Transplantation 2021; 105:1143-1155. [PMID: 33534529 DOI: 10.1097/tp.0000000000003622] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
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Affiliation(s)
- Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL
| | - Mohamed Ezzelarab
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Douglas J Anderson
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jayme E Locke
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Devin E Eckhoff
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
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Fida N, Tantrachoti P, Guha A, Bhimaraj A. Post-transplant Management in Heart Transplant Recipients: New Drugs and Prophylactic Strategies. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2021. [DOI: 10.1007/s11936-021-00933-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Meier RPH, Longchamp A, Mohiuddin M, Manuel O, Vrakas G, Maluf DG, Buhler LH, Muller YD, Pascual M. Recent progress and remaining hurdles toward clinical xenotransplantation. Xenotransplantation 2021; 28:e12681. [PMID: 33759229 DOI: 10.1111/xen.12681] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/12/2021] [Accepted: 02/21/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Xenotransplantation has made tremendous progress over the last decade. METHODS We discuss kidney and heart xenotransplantation, which are nearing initial clinical trials. RESULTS Life sustaining genetically modified kidney xenografts can now last for approximately 500 days and orthotopic heart xenografts for 200 days in non-human primates. Anti-swine specific antibody screening, preemptive desensitization protocols, complement inhibition and targeted immunosuppression are currently being adapted to xenotransplantation with the hope to achieve better control of antibody-mediated rejection (AMR) and improve xenograft longevity. These newest advances could probably facilitate future clinical trials, a significant step for the medical community, given that dialysis remains difficult for many patients and can have prohibitive costs. Performing a successful pig-to-human clinical kidney xenograft, that could last for more than a year after transplant, seems feasible but it still has significant potential hurdles to overcome. The risk/benefit balance is progressively reaching an acceptable equilibrium for future human recipients, e.g. those with a life expectancy inferior to two years. The ultimate question at this stage would be to determine if a "proof of concept" in humans is desirable, or whether further experimental/pre-clinical advances are still needed to demonstrate longer xenograft survival in non-human primates. CONCLUSION In this review, we discuss the most recent advances in kidney and heart xenotransplantation, with a focus on the prevention and treatment of AMR and on the recipient's selection, two aspects that will likely be the major points of discussion in the first pig organ xenotransplantation clinical trials.
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Affiliation(s)
- Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alban Longchamp
- Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Muhammad Mohiuddin
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Oriol Manuel
- Transplantation Center, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Georgios Vrakas
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Daniel G Maluf
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Leo H Buhler
- Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Yannick D Muller
- Division of Immunology and Allergy, University Hospital of Lausanne, Lausanne, Switzerland
| | - Manuel Pascual
- Transplantation Center, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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Yoon CH, Choi HJ, Kim MK. Corneal xenotransplantation: Where are we standing? Prog Retin Eye Res 2021; 80:100876. [PMID: 32755676 PMCID: PMC7396149 DOI: 10.1016/j.preteyeres.2020.100876] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/23/2020] [Accepted: 06/04/2020] [Indexed: 02/08/2023]
Abstract
The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed, current progress in genetically engineered (GE) pigs, the introduction of gene-editing technology by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, and advanced immunosuppressants have made xenotransplantation a possible option for a human trial. Porcine corneal xenotransplantation is considered applicable because the eye is regarded as an immune-privileged site. Furthermore, recent non-human primate studies have shown long-term survival of porcine xenotransplants in keratoplasty. Herein, corneal immune privilege is briefly introduced, and xenogeneic reactions are compared with allogeneic reactions in corneal transplantation. This review describes the current knowledge on special issues of xenotransplantation, xenogeneic rejection mechanisms, current immunosuppressive regimens of corneal xenotransplantation, preclinical efficacy and safety data of corneal xenotransplantation, and updates of the regulatory framework to conduct a clinical trial on corneal xenotransplantation. We also discuss barriers that might prevent xenotransplantation from becoming common practice, such as ethical dilemmas, public concerns on xenotransplantation, and the possible risk of xenozoonosis. Given that the legal definition of decellularized porcine cornea (DPC) lies somewhere between a medical device and a xenotransplant, the preclinical efficacy and clinical trial data using DPC are included. The review finally provides perspectives on the current standpoint of corneal xenotransplantation in the fields of regenerative medicine.
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Affiliation(s)
- Chang Ho Yoon
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea
| | - Hyuk Jin Choi
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea; Department of Ophthalmology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Mee Kum Kim
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea.
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CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease. J Clin Med 2020; 9:jcm9113653. [PMID: 33202988 PMCID: PMC7697100 DOI: 10.3390/jcm9113653] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
The cluster of differentiation 40 (CD40) is activated by the CD40 ligand (CD40L) in a variety of diverse cells types and regulates important processes associated with kidney disease. The CD40/CD40L signaling cascade has been comprehensively studied for its roles in immune functions, whereas the signaling axis involved in local kidney injury has only drawn attention in recent years. Clinical studies have revealed that circulating levels of soluble CD40L (sCD40L) are associated with renal function in the setting of kidney disease. Levels of the circulating CD40 receptor (sCD40), sCD40L, and local CD40 expression are tightly related to renal injury in different types of kidney disease. Additionally, various kidney cell types have been identified as non-professional antigen-presenting cells (APCs) that express CD40 on the cell membrane, which contributes to the interactions between immune cells and local kidney cells during the development of kidney injury. Although the potential for adverse CD40 signaling in kidney cells has been reported in several studies, a summary of those studies focusing on the role of CD40 signaling in the development of kidney disease is lacking. In this review, we describe the outcomes of recent studies and summarize the potential therapeutic methods for kidney disease which target CD40.
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Tang T, Cheng X, Truong B, Sun L, Yang X, Wang H. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther 2020; 219:107709. [PMID: 33091428 DOI: 10.1016/j.pharmthera.2020.107709] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/15/2020] [Indexed: 12/22/2022]
Abstract
The CD40 receptor and its ligand CD40L is one of the most critical molecular pairs of the stimulatory immune checkpoints. Both CD40 and CD40L have a membrane form and a soluble form generated by proteolytic cleavage or alternative splicing. CD40 and CD40L are widely expressed in various types of cells, among which B cells and myeloid cells constitutively express high levels of CD40, and T cells and platelets express high levels of CD40L upon activation. CD40L self-assembles into functional trimers which induce CD40 trimerization and downstream signaling. The canonical CD40/CD40L signaling is mediated by recruitment of TRAFs and NF-κB activation, which is supplemented by signal pathways such as PI3K/AKT, MAPKs and JAK3/STATs. CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells via two-way signaling. CD40/CD40L interaction also participates in regulating thrombosis, tissue inflammation, hematopoiesis and tumor cell fate. Because of its essential role in immune activation, CD40/CD40L interaction has been regarded as an attractive immunotherapy target. In recent years, significant advance has been made in CD40/CD40L-targeted therapy. Various types of agents, including agonistic/antagonistic monoclonal antibodies, cellular vaccines, adenoviral vectors and protein antagonist, have been developed and evaluated in early-stage clinical trials for treating malignancies, autoimmune diseases and allograft rejection. In general, these agents have demonstrated favorable safety and some of them show promising clinical efficacy. The mechanisms of benefits include immune cell activation and tumor cell lysis/apoptosis in malignancies, or immune cell inactivation in autoimmune diseases and allograft rejection. This review provides a comprehensive overview of the structure, processing, cellular expression pattern, signaling and effector function of CD40/CD40L checkpoint molecules. In addition, we summarize the progress, targeted diseases and outcomes of current ongoing and completed clinical trials of CD40/CD40L-targeted therapy.
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Affiliation(s)
- TingTing Tang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Billy Truong
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - LiZhe Sun
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Cardiovascular Medicine, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - XiaoFeng Yang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
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Abstract
Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.
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Abstract
Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.
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Yu X, Chan HTC, Fisher H, Penfold CA, Kim J, Inzhelevskaya T, Mockridge CI, French RR, Duriez PJ, Douglas LR, English V, Verbeek JS, White AL, Tews I, Glennie MJ, Cragg MS. Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity. Cancer Cell 2020; 37:850-866.e7. [PMID: 32442402 PMCID: PMC7280789 DOI: 10.1016/j.ccell.2020.04.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/28/2020] [Accepted: 04/21/2020] [Indexed: 12/28/2022]
Abstract
Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcγR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.
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Affiliation(s)
- Xiaojie Yu
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK.
| | - H T Claude Chan
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Hayden Fisher
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK; Biological Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK
| | - Christine A Penfold
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Jinny Kim
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Tatyana Inzhelevskaya
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - C Ian Mockridge
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Ruth R French
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Patrick J Duriez
- CRUK Protein Core Facility, University of Southampton Faculty of Medicine, Southampton, UK
| | - Leon R Douglas
- CRUK Protein Core Facility, University of Southampton Faculty of Medicine, Southampton, UK
| | - Vikki English
- Pre-clinical Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - J Sjef Verbeek
- Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Ann L White
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Ivo Tews
- Institute for Life Sciences, University of Southampton, Southampton, UK; Biological Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK
| | - Martin J Glennie
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Mark S Cragg
- Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK.
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