Transient B-Cell Depletion Combined With Apoptotic Donor Splenocytes Induces Xeno-Specific T- and B-Cell Tolerance to Islet Xenografts

  1. Xunrong Luo1,3,5
  1. 1Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  2. 2Department of Surgery, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, People's Republic of China
  3. 3Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois the
  4. 4Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
  5. 5Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  1. Corresponding author: Xunrong Luo, xunrongluo{at}northwestern.edu.

Abstract

Peritransplant infusion of apoptotic donor splenocytes cross-linked with ethylene carbodiimide (ECDI-SPs) has been demonstrated to effectively induce allogeneic donor-specific tolerance. The objective of the current study is to determine the effectiveness and additional requirements for tolerance induction for xenogeneic islet transplantation using donor ECDI-SPs. In a rat-to-mouse xenogeneic islet transplant model, we show that rat ECDI-SPs alone significantly prolonged islet xenograft survival but failed to induce tolerance. In contrast to allogeneic donor ECDI-SPs, xenogeneic donor ECDI-SPs induced production of xenodonor-specific antibodies partially responsible for the eventual islet xenograft rejection. Consequently, depletion of B cells prior to infusions of rat ECDI-SPs effectively prevented such antibody production and led to the indefinite survival of rat islet xenografts. In addition to controlling antibody responses, transient B-cell depletion combined with ECDI-SPs synergistically suppressed xenodonor-specific T-cell priming as well as memory T-cell generation. Reciprocally, after initial depletion, the recovered B cells in long-term tolerized mice exhibited xenodonor-specific hyporesponsiveness. We conclude that transient B-cell depletion combined with donor ECDI-SPs is a robust strategy for induction of xenodonor-specific T- and B-cell tolerance. This combinatorial therapy may be a promising strategy for tolerance induction for clinical xenogeneic islet transplantation.

Footnotes

  • Received December 2, 2012.
  • Accepted May 30, 2013.

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  1. Diabetes vol. 62 no. 9 3143-3150
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