PATHOGENESIS AND TREATMENT OF CHRONIC REJECTION

描述（改编自申请人摘要）：本研究 假定同种异体移植物的慢性排斥反应是由于 供体抗原呈递细胞驻留在移植物中， 这些细胞的保留促进了对受体的低级刺激， 免疫系统导致预防CR。 一种动物模型 来测试这个假设。 用供体骨对动物进行预处理 骨髓或肝移植与他克莫司联合治疗 捐助 微嵌合体持续至少100天，然后， 异位心脏移植（CCA）。 私家侦探发现 先前接受肝脏同种异体移植的动物没有经历CR 而接受骨髓移植的人则可以。 假设是先进的， 肝脏为供体造血细胞的存活提供基质成分 保护心脏移植物免受CR的干细胞。 相比之下， 动物接受供体骨髓后，存在较强的Th-1诱导 由于微嵌合体的丧失，导致CR。 在 在这个项目中，PI建议研究负责 淋巴细胞运输和细胞活化，持续的影响， 供体抗原呈递细胞对CR发生率和强度的影响， 是否有增强人肝供体嵌合体的策略 移植患者降低了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.