[Background] 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 CTLA4 Ig in a novel murine model of hind limb transplantation.

[Methods] To investigate the immunoregulatory potential of CoB, fully MHC-mismatched allogeneic orthotopic hind limb transplants were performed from Balb/c to C57BL/6 mice, and recipients treated with CoB (CTLA4-Ig +/- anti-CD154 mAb) with or without total body irradiation (TBI). Mixed chimerism and clonal deletion of alloreactive T cells, infiltrating regulatory T cells and intracellular cytokines profiles were checked by flow cytometry.

[Results]CoB treated recipients showed increased survival compared to untreated and CTLA4-Ig only groups (MST 82 days). Adding non-myeloablative TBI to CoB enabled indefinite graft survival (MST >210 days). Mixed chimerism induced by donor derived bone marrow (BM) was detected in the CoB treated group, and was even higher in TBI+CoB treated recipients.

Staining for donor reactive vβ TCR subtypes indicated central thymic deletion of donor reactive T cells. Donor specific tolerance was confirmed in long-term survivors by acceptance of donor matched secondary skin grafts, decreased T cell responsiveness and increased graft-infiltrating regulatory T cells.

[Conclusion] Our data suggests that the combination of induction therapy, combined costimulation blockade and VCA promotes stable bone marrow engraftment leading to multi-lineage mixed chimerism and donor antigen specific immune tolerance.

CITATION INFORMATION: Oh B, Furtmüller G, Fryer M, Grahammer J, Schneeberger S, Cooney D, Raimondi G, Brandacher G. Tolerance Induction in Vascularized Composite Allotransplantation with Peri-Transplant Combined Costimulation Blockade. Am J Transplant. 2016;16 (suppl 3).

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