Transient B-cell depletion combined with apoptotic donor splenocytes induces xeno-specific T-and B-cell tolerance to islet xenografts

Shusen Wang, James Tasch, Taba Kheradmand, Jodie Ulaszek, Sora Ely, Xiaomin Zhang, Bernhard J. Hering, Stephen D. Miller, Xunrong Luo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Peritransplant infusion of apoptotic donor splenocytes crosslinked 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 ratto-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 xenodonorspecific 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.

Original languageEnglish (US)
Pages (from-to)3143-3150
Number of pages8
JournalDiabetes
Volume62
Issue number9
DOIs
StatePublished - Sep 2013

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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