Date: Sunday, May 3, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
[Background] Vascularized composite allotransplantation (VCA) is an emerging new era in transplant medicine and has become a valid therapeutic option after devastating tissue loss. The costimulatory blocking has shown considerable efficacy in preventing rejection of solid organ transplants in preclinical models and clinical trial, 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. Recipients 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 (CoB); or (4) 250cGy non-myeloablative whole body irradiation (WBI) on POD -1 plus CoB. Mixed chimerism and clonal deletion of alloreactive T cells were assessed by analyzing PBMC profiles by flow cytometry. Secondary grafts were transplanted with donor matched and third party donor skin.
[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). Adding anti-CD154 mAb combined with CTLA4 Ig significantly increased graft survival (MST 82 days; p<0.01). Moreover, mixed chimerism induced by donor derived bone marrow components was detected in the CoB treated group. At POD 21, chimerism for the CTLA4 Ig plus anti-CD154 mAb group in CD11b+ cells was 10.76% vs. 0.82% in the CTLA4 Ig alone group.. Non-myeloablative WBI in combination with CoB increased graft survival significantly (MST 200 days; P<0.01) compared to CoB treated group. Also, mixed chimerism further increased and maintained over POD200. Decreased νβ11+ and νβ5+CD4+ T cells were detected in recipients treated with WBI + CoB while control groups failed to delete representing central deletion of donor reactive T cells.
[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 maintenance of stable mixed chimerism in VCA.
To cite this abstract in AMA style:Oh B, Furtmüller G, Fryer M, Grahammer J, Schneeberger S, Cooney D, Lee W, Brandacher G. Costimulation Blockade Prevents Rejection of Vascularized Composite Allografts [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/costimulation-blockade-prevents-rejection-of-vascularized-composite-allografts/. Accessed November 25, 2020.
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