title: Transient B-cell depletion combined with apoptotic donor splenocytes induces xeno-specific T- and B-cell tolerance to islet xenografts.
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 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.
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Shusen
authors.initials: S
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Tasch
authors.forename: Taba
authors.initials: T
authors.lastname: Kheradmand
authors.forename: Jodie
authors.initials: J
authors.lastname: Ulaszek
authors.forename: Sora
authors.initials: S
authors.lastname: Ely
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008297:Male; D051379:Mice; D051381:Rats; D013154:Spleen / Q000166:cytology; D014183:Transplantation, Heterologous / Q000379:methods*