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Author Notes:

Corresponding author: Christian P. Larsen, Christian P. Larsen, M.D., D.Phil., Emory University Hospital, 1364 Clifton Road, NE, Suite B206, Atlanta, Georgia 30322, Ph. (404) 727-5800, Fax: (404) 727-4716, Email: clarsen@emory.edu

The authors of this manuscript would like to acknowledge the Juvenile Diabetes Research Foundation for their assistance in funding this project.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Subjects:

Research Funding:

Juvenile Diabetes Research Foundation Grant – 4–2005-1328 and Yerkes Base Grant – P51RR-00065

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Surgery
  • Transplantation
  • Costimulation blockade
  • depletion
  • islets
  • monoclonoal antibodies
  • type 1 diabetes
  • xenotransplantation
  • ANTI-CD40 MONOCLONAL-ANTIBODY
  • SYSTEMIC-LUPUS-ERYTHEMATOSUS
  • LONG-TERM SURVIVAL
  • ALLOGRAFT-REJECTION
  • PHASE-I
  • RHESUS MACAQUES
  • PATHWAYS
  • MONKEYS
  • CD40

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

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Journal Title:

American Journal of Transplantation

Volume:

Volume 11, Number 5

Publisher:

, Pages 947-957

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

©2011 The Authors. Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

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