Experimental research on the extremity alloeraft-Induction of immunotolerance and chimerism-

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Recent advances in the field of transplant immunology and reconstructive surgery resulted in interest in extremity allograft. Until now, more than 20 hand transplants have been performed in human. Rejection is well controlled by currently available immunosuppressive drugs. The hand transplant, however, is not a life-supporting organ transplant and these drugs are unlikely to represent the final solution for hand transplantation due to serious adverse effects. The ultimate goal of extremity allograft is the induction of donor-specific immunotolerance. The major strategies for tolerance induction are: (1) T-cell co stimulation blockade, (2) induction of mixed chimerism (3), T-cell depletion, and (4) tolerance mediated by regulatory T-cells. Amongst these, the establishment of a high-level of chimerism may be the most stable strategy for donor-specific tolerance and our laboratory has been investigating the induction of macrochimerism following extremity allotransplantation. Recently, some studies demonstrated that macrochimerism induced immunotolerance for extremity allograft in the rodent model. We made a new protocol using cyclophosphamide (CYP) and granulocyte colony-stimulation factor (G-CSF) to induce high-level chimerism following rat whole-limb allotransplantation. Limb allografting could function as a vascularized carrier for bone marrow transplantation, provide a continuous source of donor cells and contribute to a high-level of chimerism in the recipient. Pre-transplant CYP followed by G-CSF and FK506 treatment significantly prolonged the survival of limb allografts but frequently caused chronic GVHD in the recipients