CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates

P. Thompson, K. Cardona, M. Russell, I. R. Badell, V. Shaffer, G. Korbutt, G. R. Rayat, J. Cano, M. Song, W. Jiang, E. Strobert, R. Rajotte, T. Pearson, A. D. Kirk, C. P. Larsen

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

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.

Original languageEnglish
Pages (from-to)947-957
Number of pages11
JournalAmerican Journal of Transplantation
Volume11
Issue number5
DOIs
StatePublished - May 2011
Externally publishedYes

Keywords

  • Costimulation blockade
  • depletion
  • islets
  • monoclonoal antibodies
  • type 1 diabetes
  • xenotransplantation

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