Transient B Cell Depletion Combined with Apoptotic Donor Splenocytes Induces Xeno-specific T and B cell Tolerance to Islet Xenografts
- Shusen Wang1,5,
- James Tasch2,
- Taba Kheradmand2,
- Jodie Ulaszek2,
- Sora Ely2,
- Xiaomin Zhang1,
- Bernhard J. Hering3,
- Stephen D. Miller4,6 and
- Xunrong Luo1,2,4,6⇑
- 1Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States;
- 2Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States;
- 3Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, United States.
- 4Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
- 5Department of Surgery, People's Hospital of Tianjin, Nankai University Affiliated Hospital, Tianjin, 300121, P.R. of China.
- 6Co-senior authors
- Corresponding author: Xunrong Luo Email:
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.
- © 2013 by the American Diabetes Association.
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