Jochen Seissler, Constanca Figueiredo, Elisabeth Kemter, Nikolai Klymiuk, Eckhard Wolf, Lelia Wolf-van Buerck
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引用次数: 0
Abstract
Background: In previous studies, we showed that beta cell-specific overexpression of high-affinity variant of human CTLA-4 (LEA29Y), a high-affinity variant of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-immunoglobulin, prevented porcine islet rejection in humanized mouse models. We here investigate whether long-term xenograft function and survival is maintained after neutralization of LEA29Y-mediated co-stimulation blockade.
Methods: Diabetic humanized NOD-SCID IL2rγ-/- mice were transplanted with transgenic neonatal porcine islet-like clusters expressing LEA29Y under control of the porcine insulin promoter. After development of normal glucose tolerance, mice were treated with blocking anti-CTLA-4 antibody (Ab) or isotype control Ab. Reoccurrence of diabetes, plasma cytokines/chemokines and graft histology were analyzed.
Results: Systemic treatment with an inhibitory anti-humanized CTLA-4 Ab led to a significant increase of pro-inflammatory plasma cytokine production (interferon gamma, monokine induced by interferon gamma; P < 0.05) at day 14 and reoccurrence of diabetes in 100% of the animals within 40 d after Ab application (P = 0.01). Strong infiltration with human CD45+ cells consisting mainly of CD4+ and CD8+ T cells and some B lymphocytes and few destructed remaining beta cells were observed in the treatment group indicating rapid and severe graft rejection.
Conclusions: The present data demonstrate that long-lasting acceptance of LEA29Y transgenic porcine islet grafts is dependent on CTLA-4/LEA29Y signaling even several months after transplantation. This finding has important implications on safety of pig islet xenotransplantation in patients with type 1 diabetes because it provides a potent tool for graft elimination in case of medical indication.
期刊介绍：
The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year.
Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal.
Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed.
The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.
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