Preemptive Tolerogenic Delivery of Donor Antigens for Permanent Allogeneic Islet Graft Protection

Shusen Wang, Xiaomin Zhang, Lei Zhang, Jane Bryant, Taba Kheradmand, Bernhard J. Hering, Stephen D. Miller, Xunrong Luo

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

We have previously developed a robust regimen for tolerance induction in murine models of islet cell transplantation using pre- and posttransplant infusions of donor splenocytes (SPs) treated with a chemical cross-linker ethylcarbodiimide (ECDI). However, the requirement for large numbers of fresh donor SPs for ECDI coupling impairs its clinical feasibility, and additionally, the compatibility of this tolerance regimen with commonly used immunosuppressive drugs is largely unknown. In the current study, we demonstrate that equivalent tolerance efficacy for islet cell transplantation can be successfully achieved not only with a significantly lower dose of ECDI-SPs than originally established but also with culture-expanded donor B-cells or with soluble donor antigens in the form of donor cell lysate, which is ECDI coupled to recipient SPs. We further demonstrate that tolerance induced by donor ECDI-SPs is dependent on a favorable apoptotic-to-necrotic cell ratio post-ECDI coupling and is not affected by a transient course of conventional immunosuppressive drugs including tacrolimus and mycophenolate mofetil. While splenic antigen-presenting cells of the recipient play an important role in mediating the tolerogenic effects of donor ECDI-SPs, splenectomized recipients can be readily tolerized and appear to employ liver Kupffer cells for uptaking and processing of the ECDI-SPs. We conclude that infusion of donor ECDI-SPs is a versatile tolerance strategy that has a high potential for adaptation to clinically feasible regimens for tolerance trials for human islet cell transplantation.

Original languageEnglish (US)
Pages (from-to)1155-1165
Number of pages11
JournalCell transplantation
Volume24
Issue number6
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

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    Wang, S., Zhang, X., Zhang, L., Bryant, J., Kheradmand, T., Hering, B. J., Miller, S. D., & Luo, X. (2015). Preemptive Tolerogenic Delivery of Donor Antigens for Permanent Allogeneic Islet Graft Protection. Cell transplantation, 24(6), 1155-1165. https://doi.org/10.3727/096368914X681027