2546: Non-cytoreductive immunosuppression prevents rejection of vascularized composite allografts

2546: Non-cytoreductive immunosuppression prevents rejection of vascularized composite allografts Byoung Chol Oh, DVM, PhD, Georg Furtmuller, MD, Marcos Iglesias, PhD, Madeline Fryer, BS, Giorgio Raimondi, PhD, Damon Cooney, MD, PhD, W. P. Andrew Lee, MD, and Gerald Brandacher, MD Johns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA Background Reconstructive transplantation represents a valid therapeutic option after devastating tissue loss such as an extremity or face Immunosuppression-free donorspecific immunological tolerance has been successfully achieved in the setting of solid organ transplantation through mixed chimerism Routine clinical application of this approach, however, is hampered by the toxicity of the cytoreductive recipient conditioning The current study investigated a novel non-cytoreductive immunosuppressive strategy in a 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 in the experimental groups received no treatment (Group 1); 025 mg CTLA4 Ig on postoperative days (POD) 0, 2, 4, and 6 (Group 2); 20 mg/kg anti-T cells (anti-Thy 12 mAb) on POD-1 plus CTLA4-Ig and 1 mg/kg Rapamycin (POD0-9) (Group 3) Flow cytometric analysis was performed to evaluate mixed chimerism and clonal deletion of alloreactive T cells. Results The CTLA4 Ig treated group showed increased graft survival compared to non-treated controls (mean survival time [MST] 17 d and 8 d, respectively, p < 001) Interestingly, combination of T cell depletion and CTLA4 Ig plus short-course of Rapamycin increased VCA survival significantly (MST 105 days; p < 001) Donor derived mixed chimerism was detected in recipients receiving the combined treatment protocol with 50 § 12 % of donor derived CD11bC cells on POD 55 VÎ – TCR staining profiles in recipients after combined treatment showed 16 § 04 % of Î=2Î25CCD4C T cells, while nae Ave C57BL/6 express 36 § 04 % of Î=2Î 25CCD4C T cells, suggesting central deletion of donor-reactive T cells Also, we found infiltrating Foxp3C regulatory T cells expressing donor derived marker (H-2K) at POD60 on combined treatment representing donor derived T reg cells were infiltrated. Conclusion This study shows that combination of T cell depletion and costimulation blockade and short-course of Rapamycin prevents VCA rejection and significantly prolongs graft survival Also, these data show that a clinically acceptable non-cytoreductive strategy could be applied in VCA to avoid long-term maintenance immunosuppression. CONTACT Gerald Brandacher, MD gbranda2@jhmi.edu © 2016 Byoung Chol Oh, Georg Furtmuller, Marcos Iglesias, Madeline Fryer, Giorgio Raimondi, Damon Cooney, W. P. Andrew Lee, 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, 18 http://dx.doi.org/10.1080/23723505.2016.1232969