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Scientific article
English

Caspase inhibitor therapy synergizes with costimulation blockade to promote indefinite islet allograft survival

Published inDiabetes, vol. 59, no. 6, p. 1469-1477
Publication date2010
Abstract

OBJECTIVE: Costimulation blockade has emerged as a selective nontoxic maintenance therapy in transplantation. However, these drugs must be combined with other immunomodulatory agents to ensure long-term graft survival. RESEARCH DESIGN AND METHODS: Recent work has demonstrated that caspase inhibitor therapy (EP1013) prevents engraftment phase islet loss and markedly reduces the islet mass required to reverse diabetes. The "danger" hypothesis suggests that reduction in graft apoptosis should reduce the threshold for immunosuppression and increase the possibility for tolerance induction. Thus, the impact of combination of EP1013 treatment with costimulation blockade (CTLA4-Ig) was investigated in this study. RESULTS: Islet allografts were completed in fully major histocompatibility complex (MHC)-mismatched mice (Balb/C to B6). When animals received vehicle or EP1013, there was no difference in graft survival. CTLA4-Ig resulted in prolonged graft survival in 40% of the animals, whereas EP1013+CLTA4-Ig resulted in a significant increase in graft survival (91% >180 days; P = 0.01). Ex vivo analysis revealed that animals receiving EP1013 or EP1013+CTLA4-Ig had a reduced frequency of alloreactive interferon (IFN)-gamma-secreting T-cells and an increased frequency of intragraft Foxp3(+) Treg cells. Alloantibody assays indicated that treatment with EP1013 or CTLA4-Ig prevented allosensitization. CONCLUSIONS: This study suggests that addition of caspase inhibitor therapy to costimulation blockade will improve clinical transplantation by minimizing immune stimulation and thus reduce the requirement for long-term immunosuppressive therapy. The approach also prevents allosensitization, which may be an important component of chronic graft loss in clinical transplantation.

Keywords
  • Amino Acid Chloromethyl Ketones/therapeutic use
  • Animals
  • Caspases/ antagonists & inhibitors
  • Enzyme Inhibitors/ therapeutic use
  • Graft Survival/drug effects
  • Immunoconjugates/therapeutic use
  • Immunosuppressive Agents/therapeutic use
  • Islets of Langerhans Transplantation/methods/ physiology
  • Isoantibodies/blood
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Transplantation, Homologous/ physiology
Citation (ISO format)
EMAMAULLEE, Juliet A. et al. Caspase inhibitor therapy synergizes with costimulation blockade to promote indefinite islet allograft survival. In: Diabetes, 2010, vol. 59, n° 6, p. 1469–1477. doi: 10.2337/db09-0502
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ISSN of the journal0012-1797
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