CTLA4Ig Prevents Alloantibody Formation Following Nonhuman Primate Islet Transplantation Using the CD40-specific Antibody 3A8

• Type of Material: Article
• Authors: Idelberto R. Badell, Emory University; Maria C. Russell, Emory University; Ken Cardona, Emory University; Virginia Oliva Shaffer, Emory University; AP Turner, Emory University; Jose G Avila, Emory University; JA Cano, Emory University; FV Leopardi, Emory University; M Song, Emory University; Elizabeth Strobert, Emory University; Mandy L Ford, Emory University; Thomas C Pearson, Emory University; Allan D Kirk, Emory University; Christian P Larsen, Emory University
• Language: English
• Date: 2012-07
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 The American Society of Transplantation and the American Society of Transplant Surgeons
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2012.04029.x/abstract;jsessionid=AD9EEF9DB31E2F7EDCE9D832D74FCC04.d03t01
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 12
• Issue: 7
• Start Page: 1918
• End Page: 1923
• Grant/Funding Information: The Juvenile Diabetes Research Foundation (4-2005-1328) primarily funded this work, with additional support from the NIH (5U19-AI051731 and 5R01-AI073707) and the Yerkes National Primate Research Center Base Grant (P51RR-000165).; The NHP Reagent Resource (NIAID HHSN272200900037C) provided assistance with antibody production.
• Keywords: alloantibodies; Islet transplantation; nonhuman primate; immunosuppressive therapy
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Islet transplantation to treat type 1 diabetes has been limited in part by toxicities of current immunosuppression and recipient humoral sensitization. Blockade of the CD28/CD80/86 and CD40/CD154 pathways has shown promise to remedy both these limitations, but translation has been hampered by difficulties in translating CD154-directed therapies. Prior CD40-directed regimens have led to prolonged islet survival, but fail to prevent humoral allosensitization. We therefore evaluated the addition of CTLA4Ig to a CD40-blockade based regimen in nonhuman primate (NHP) alloislet transplantation. Diabetic rhesus macaques were transplanted allogeneic islets using the CD40-specific antibody 3A8, basiliximab induction, and sirolimus with or without CTLA4Ig maintenance therapy. Allograft survival was determined by fasting blood glucose levels and flow cytometric techniques were used to test for donor-specific antibody (DSA) formation. CTLA4Ig plus 3A8, basiliximab and sirolimus was well tolerated and induced long-term islet allograft survival. The addition of CTLA4Ig prevented DSA formation, but did not facilitate withdrawal of the 3A8-based regimen. Thus, CTLA4Ig combines with a CD40-specific regimen to prevent DSA formation in NHPs, and offers a potentially translatable calcineurin inhibitor-free protocol inclusive of a single investigational agent for use in clinical islet transplantation without relying upon CD154 blockade.