Positioning Vascularized Composite Allotransplantation in the Spectrum of Transplantation

We have continued our studies of the immune mechanisms contributing to rejection of vascularized composite allografts VCA in murine models, and how these may be overcome to promote long-term allograft survival. We have now firmly established orthotopic hindlimb and forelimb VCA models in our lab, and using these have shown that either of 2 protocols, namely costimulation blockade CD154 monoclonal antibody plus 4 weeks of rapamycin, RPM, or CTLA4Ig plus 4 weeks of RPM can each achieve long-term VCA survival without maintenance immunosuppression. We have now shown that the efficacy of both protocols is dependent upon a radiation-sensitive donor bone marrow BM cell type thatis of T or B cell origin and is CXCR4 positive. The latest data indicate that this is a Foxp3 positive donor Treg population resident in donor BM. In addition, we have found that Treg therapy can significantly prolong VCA survival. This work is continuing in the form of an approved 1 year no-cost extension.