PATHOGENESIS AND TREATMENT OF CHRONIC REJECTION

描述(改编自申请人的摘要)：本次调查 假设同种异体移植物的慢性排斥反应是由消除引起的 供体抗原提呈细胞驻留在移植物中，并通过 保留这些细胞，促进对受体S的低度刺激 免疫系统导致CR的预防。一直以来的动物模型 是为了检验这一假设而开发的。用供体骨预处理动物 骨髓或肝移植联合他克莫司。捐赠者 微嵌合体持续至少100天，然后，动物 接受异位心脏移植(CCA)。私家侦探找到了 以前接受同种异体肝移植的动物没有出现CR 而那些接受骨髓移植的人会这样做。提出的假设是 肝脏为供者造血细胞的存活提供基质元素 保护同种异体心脏移植物免受CR的干细胞。相比之下，在 动物接受供体骨髓后，有强烈的Th-1诱导 由于微嵌合体丢失而引起的类型细胞反应，导致CR。在……里面 在这个项目中，PI建议研究负责机制 淋巴细胞转运和细胞活化对持续性的影响 供者抗原提呈细胞对CR和CD的发生率和强度的影响 人肝组织中供体嵌合体是否有扩大的操作 移植患者可降低CR的严重程度。

DESCRIPTION (Adapted from the applicant's abstract): This investigation postulates that chronic rejection of allografts is caused by the elimination of donor antigen presenting cells residing in the graft, and that through retention of these cells, promotes low grade stimulation of the recipient s immune system leading to prevention of CR. An animal model as been developed to test this hypothesis. Animals are pretreated with donor bone marrow or a hepatic allograft in concert with Tacrolimus. Donor microchimerism persists for at least 100 days, and then, the animals are challenged with a heterotopic cardiac allograft (CCA). The PI has found that animals previously receiving a liver allograft do not experience CR while those that receive bone marrow do. The hypothesis is advanced that the liver provides the stromal elements for survival of donor hematopoietic stem cells which protect cardiac allografts from CR. In contrast, with animals receiving donor bone marrow, there is induction of a strong Th-1 type cell response due to a loss of microchimerism, which leads to CR. In this project, the PI proposes to study the mechanisms responsible for lymphocyte trafficking and cellular activation, the influence of persistent donor antigen presenting cells on the incidence and intensity of CR and whether maneuvers for augmentation of donor chimerism in human liver transplant patients lowers the severity of CR.