2548: Tolerance induction to vascularized composite allografts by costimulation blockade

Abstract

2548: Tolerance induction to vascularized composite allografts by costimulation blockade Byoung Chol Oh, DVM, PhD, Georg Furtmuller, MD, Madeline Fryer, BS, Johanna Grahammer, Stefan Schneeberger, Damon Cooney, MD, PhD, W. P. Andrew Lee, MD, Giorgio Raimondi, PhD, and Gerald Brandacher, MD Johns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA; Dept. of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria Background Vascularized composite allotransplantation (VCA) has become a valid therapeutic option after devastating tissue loss While costimulation blockade (CoB) has shown considerable efficacy in preventing rejection, its efficacy in VCA remains poorly explored Here we investigated the immunoregulatory potential of CoB in a novel murine model of hind limb transplantation. Methods Fully MHC-mismatched allogeneic, orthotopic hind limb transplants were performed from Balb/c to C57BL/6 mice Recipient animals received combinations of total body irradiation (TBI), CTLA4-Ig, and anti-CD154 mAb (CoB) Mixed chimerism, clonal deletion of alloreactive T cells, and cytokine production were assessed by flow cytometry. Results CoB treated recipients showed increased survival compared to untreated and CTLA4-Ig only groups (Mean survival time [MST] 82 days) Adding non-myeloablative TBI to CoB enabled indefinite graft survival (MST,>210 days) Mixed chimerism induced by donorderived bone marrow (BM) was detected in the CoB treated group, and was even higher in TBICCoB treated recipients Decreased v̂I211C and v̂I25CCD4C T cells were detected in both groups treated with either CoB or TBICCoB, suggesting central thymic deletion of donor reactive T cells Donor specific tolerance was confirmed in long-term survivors (TBICCoB group) by acceptance of donor matched secondary skin grafts and rejection of third party ones In long term survivors treated with TBICCoB, decreased T cell responsiveness and increased graft-infiltrating regulatory T cells were detected on POD50. Conclusion Our results show that CoB enables the tolerogenicity of BM components carried by VCA, but requires TBI to establish durable donor-specific tolerance. CONTACT Byoung Chol Oh, DVM, PhD boh3@jhmi.edu © 2016 Byoung Chol Oh, Georg Furtmuller, Madeline Fryer, Johanna Grahammer, Stefan Schneeberger, Damon Cooney, W. P. Andrew Lee, Giorgio Raimondi, and Gerald Brandacher. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. VASCULARIZED COMPOSITE ALLOTRANSPLANTATION 2016, VOL. 3, NOS. 1–2, 9 http://dx.doi.org/10.1080/23723505.2016.1232975