CD40-Specific Costimulation Blockade Enhances Neonatal Porcine Islet Survival in Nonhuman Primates

• Type of Material: Article
• Authors: P Thompson, Emory University; Kenneth Cardona, Emory University; Maria Russell, Emory University; Idelberto Badell, Emory University; Virginia Shaffer, Emory University; G Korbutt, University of Alberta; J Cano, Emory University; M Song, Emory University; W Jiang, Emory University; Elizabeth Strobert, Emory University; R Rajotte, University of Alberta; Thomas Pearson, Emory University; Allan Kirk, Emory University; Christian Larsen, Emory University
• Language: English
• Date: 2011-05-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2011 The Authors. Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
• Final Published Version (URL): http://dx.doi.org/10.1111/j.1600-6143.2011.03509.x
• Title of Journal or Parent Work: American Journal of Transplantation
• ISSN: 1600-6135
• Volume: 11
• Issue: 5
• Start Page: 947
• End Page: 957
• Grant/Funding Information: Juvenile Diabetes Research Foundation Grant – 4–2005-1328 and Yerkes Base Grant – P51RR-00065
• Keywords: Transplantation; islets; Costimulation blockade; Surgery; PATHWAYS; depletion; ALLOGRAFT-REJECTION; RHESUS MACAQUES; CD40; type 1 diabetes; Science & Technology; ANTI-CD40 MONOCLONAL-ANTIBODY; Life Sciences & Biomedicine; monoclonoal antibodies; PHASE-I; MONKEYS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; LONG-TERM SURVIVAL; xenotransplantation
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using CD154-specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154-specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40-specific antibodies. Herein, we evaluate the ability of a chimeric CD40-specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (∼50 000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL-2 receptor-specific antibody basiliximab, and maintenance therapy with sirolimus and the B7-specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin-independent normoglycemia (median rejection-free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40-specific antibodies in islet xenotransplantation warrants further investigation.