Transient B-Cell Depletion Combined With Apoptotic Donor Splenocytes Induces Xeno-Specific T- and B-Cell Tolerance to Islet Xenografts
- Shusen Wang1,2,
- James Tasch3,
- Taba Kheradmand3,
- Jodie Ulaszek3,
- Sora Ely3,
- Xiaomin Zhang1,
- Bernhard J. Hering4,
- Stephen D. Miller5 and
- Xunrong Luo1,3,5⇑
- 1Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- 2Department of Surgery, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, People's Republic of China
- 3Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois the
- 4Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
- 5Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
- Corresponding author: Xunrong Luo, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1678/-/DC1.
S.D.M. and X.L. are co-senior authors.
- Received December 2, 2012.
- Accepted May 30, 2013.
- © 2013 by the American Diabetes Association.
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