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

移植免疫学和重建外科领域的最新进展引起了人们对四肢同种异体移植的兴趣。到目前为止，已经进行了20多例人体手部移植手术。目前可用的免疫抑制药物可以很好地控制排斥反应。然而，手部移植并不是维持生命的器官移植，由于严重的副作用，这些药物不太可能代表手部移植的最终解决方案。肢体同种异体移植的最终目的是诱导供体特异性免疫耐受。诱导耐受性的主要策略有：(1)t细胞共刺激阻断；(2)诱导混合嵌合；(3)t细胞耗竭；(4)调节性t细胞介导的耐受性。其中，建立高水平嵌合可能是供体特异性耐受最稳定的策略，我们的实验室一直在研究肢体异体移植后诱导巨嵌合。近年来，一些研究表明，巨嵌合在啮齿类动物模型中诱导了肢体同种异体移植物的免疫耐受。采用环磷酰胺（CYP）和粒细胞集落刺激因子（G-CSF）诱导大鼠全肢移植后的高水平嵌合。同种异体肢体移植可以作为骨髓移植的血管化载体，提供连续的供体细胞来源，并有助于受体的高水平嵌合。移植前CYP后G-CSF和FK506治疗可显著延长肢体异体移植物的存活时间，但经常引起受体慢性GVHD

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