Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras.
Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras.
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DOI：
10.1097/tp.0b013e318237d6d4
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发表时间：
2011-12-27
期刊：
影响因子：
6.2
通讯作者：
Storb R
中科院分区：
文献类型：
--
作者：
Mathes DW;Hwang B;Graves SS;Edwards J;Chang J;Storer BE;Butts-Miwongtum T;Sale GE;Nash RA;Storb R
供者-宿主混合嵌合体是通过造血细胞移植(HCT)建立的，是一种高度可重复性的诱导对固体器官的耐受的策略。在这里，我们询问建立供体-宿主混合嵌合体的非清髓性预适应方案是否会导致高抗原血供复合同种异体移植物的耐受。在狗白细胞抗原相合的骨髓移植前给予亚致死剂量(1-2GY)全身照射和短期免疫抑制后，建立了稳定的混合嵌合体。HCT后平均36个月(范围4-54个月)进行了来自骨髓供者的带血管的复合异体移植。所有骨髓移植受者均维持供者-宿主混合造血嵌合体，接受复合组织移植的时间为52~90周，而骨髓供者在18~29天内排斥来自各自骨髓受者的带血管的同种异体移植。来自混合嵌合体的带血管复合移植物的肌肉和皮肤活检显示，与来自骨髓捐赠者的带血管复合移植物的活检组织相比，渗透细胞很少。与正常组织相比，混合嵌合体血管复合移植物的皮肤和肌肉中CD3+FoxP3+T调节细胞水平升高。在混合嵌合体中，与带血管的复合移植物相比，引流的T调节细胞的数量比非引流的淋巴结多。这些数据表明，非清髓性HCT可能为未来实体器官移植的临床应用奠定基础，T调节细胞可能对维持带血管的复合同种异体移植物起作用。
Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a highly reproducible strategy for the induction of tolerance towards solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of highly antigenic vascularized composite allografts. Stable mixed chimerism was established in dogs given a sublethal dose (1–2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 (range 4-54) months after HCT. All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted composite tissue grafts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18–29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared to extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared to normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared to non-draining lymph nodes of vascularized composite allografts. These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function towards maintenance of the vascularized composite allograft.