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于消除 驻留在移植物中的供体抗原呈递细胞，并且通过 这些细胞的保留，促进了接受者的低度刺激 immune system leading to prevention of CR. 动物模型 developed to test this hypothesis. Animals are pretreated with donor bone 骨髓或同种异体肝移植物与他克莫司配合使用。 捐赠者 微嵌合现象持续至少 100 天，然后，动物 面临异位同种异体心脏移植（CCA）的挑战。 PI 发现 之前接受同种异体肝脏移植的动物不会经历 CR while those that receive bone marrow do. The hypothesis is advanced that 肝脏为供体造血细胞的存活提供基质元素 保护心脏同种异体移植物免受 CR 的干细胞。 相比之下，与 接受供体骨髓的动物，会诱导强烈的 Th-1 由于微嵌合体丧失而引起的细胞反应，从而导致 CR。 在 在该项目中，PI 建议研究负责的机制 淋巴细胞运输和细胞激活，持续的影响 供体抗原呈递细胞对 CR 的发生率和强度的影响 是否可以进行增强人肝脏供体嵌合的操作 transplant patients lowers the severity of CR.

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.