Transient B Cell Depletion Combined with Apoptotic Donor Splenocytes Induces Xeno-specific T and B cell Tolerance to Islet Xenografts

  1. Xunrong Luo1,2,4,6
  1. 1Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States;
  2. 2Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States;
  3. 3Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States.
  4. 4Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
  5. 5Department of Surgery, People's Hospital of Tianjin, Nankai University Affiliated Hospital, Tianjin, 300121, P.R. of China.
  6. 6Co-senior authors
  1. Corresponding author: Xunrong Luo Email: 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 hypo-responsiveness. 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.

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

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