Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Costimulation Blockade Prevents Rejection Of Vascularized Composite Allografts.
Byoungchol Oh, D.V.M., Ph.D.1, Georg J. Furtmüller, M.D.1, Madeline Fryer, B.S.1, Johanna Grahammer, M.D.2, Stefan Schneeberger, M.D.2, Damon Cooney, M.D., Ph.D.1, W.P. Andrew Lee, M.D., Ph.D.1, Giorgio Raimondi, Ph.D.1, Gerald Brandacher, M.D.1.
1Johns Hopkins University, Baltimore, MD, USA, 2Innsbruck Medical University, Innsbruck, Austria.

PURPOSE: Vascularized composite allotransplantation (VCA) is an emerging new era in transplant medicine and has become a valid therapeutic option after devastating tissue loss, such as an extremity or face. The costimulatory blocking fusion protein CTLA4 Ig has shown considerable efficacy in preventing rejection of solid organ transplants in preclinical models and clinical trials, however, its effects in VCA are still poorly understood. The current study investigated the immunosuppressive potential of CTLA4Ig 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 in the experimental groups received (1) no treatment; (2) 0.5mg CTLA4 Ig on postoperative days (POD) 0, and 0.25mg on POD 2, 4, and 6; (3) CTLA4 Ig plus 0.5mg anti-CD154 mAb on POD 0, 2, 4, and 6; or (4) 250cGy whole body irradiation with CTLA4 Ig plus anti-CD154mAb on POD 0, 2, 4, 6. Mixed chimerism and clonal deletion of alloreactive T cells were checked by analyzing PBMC profiles by flow cytometry.
RESULTS: The CTLA4 Ig treated group showed increased graft survival compared to the non-treated controls (mean survival time [MST] 15 days vs. 8 days; p<0.01). Interestingly, adding anti-CD154 mAb with CTLA4 Ig significantly increased graft survival (MST 82 days; p<0.01). Moreover, increased mixed chimerism precipitated by donor derived bone marrow components was detected in the CTLA4 Ig plus anti-CD154mAb treated group. On POD 13, the percentage of donor derived CD11b+ cells was 10.44% in the CTLA4 Ig plus anti-CD154 mAb group and level was maintained over POD60 in CTLA4 Ig plus anti-CD154mAb treated recipients. Non-myeloablative whole body irradiation (WBI) further increased survival and the level of mixed chimerism. In central deletion, decreased νβ11+ and νβ5+CD4+ T cells were detected in recipients treated with CTLA4 Ig plus anti-CD154 mAb w/o WBI while control groups failed to delete donor-reactive νβ11+ and νβ5+ CD4+ T cells (% of νβ 5+CD4+ T cells; 2.135 ± 0.3225 vs. 3.690 ± 0.4747, P<0.05, % of νβ11+CD4+ T cells; 2.450 ± 0.1723 vs. 4.803 ± 0.2456, P<0.01)

CONCLUSION: This study shows that costimulatory blockade prevents VCA rejection and significantly prolongs graft survival. Also, these data show a close correlation between rejection kinetics and mixed chimerism in VCA.


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