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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Thompson, P; Cardona, K; Russell, M; Badell, IR; Shaffer, V; Korbutt, G; Rayat, GR; Cano, J; Song, M; Jiang, W; Strobert, E; Rajotte, R; Pearson, T; Kirk, AD; Larsen, CP

Published Date

  • May 2011

Published In

Volume / Issue

  • 11 / 5

Start / End Page

  • 947 - 957

PubMed ID

  • 21521467

Pubmed Central ID

  • 21521467

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

International Standard Serial Number (ISSN)

  • 1600-6135

Digital Object Identifier (DOI)

  • 10.1111/j.1600-6143.2011.03509.x

Language

  • eng