Effect of Virus Infections on the Maintenance of Transplantation Tolerance

病毒感染对接受异基因移植的患者构成威胁，因为 用于预防移植物排斥反应的免疫抑制药物方案。出于这个原因，已经开发了涉及诱导免疫耐受的替代方案，作为选择性但不是全局耐受患者的替代策略。我们使用抗体(抗CDI54)方法在小鼠身上开发了外周和中枢耐受方案，成功地建立了对异基因移植物的长期耐受性。这些小鼠可以维持移植物，并最终有效地控制病毒感染。然而，在耐受后的最初几周，这些小鼠及其移植物很容易受到感染，我们提出了以下具体目标，以了解在这一脆弱时期，几种实验病毒，包括淋巴细胞性脉络膜脑膜炎病毒(LCMV)、Pichinde病毒(PV)、牛痘病毒(W)、小鼠巨细胞病毒(MCMV)和甲型流感病毒(LAV)的感染如何破坏移植耐受的维持。在项目1中，我们还开发了额外的CDI 54 RNA击倒方法来耐受小鼠。本项目2支持或驳斥的总体假设是，异源交叉反应免疫，而不是旁观者激活，负责病毒诱导的外周耐受的消除和维持，T调节细胞可能调节这一过程，以及病毒对集中耐受的宿主及其移植物的维持构成威胁。

Viral infections pose a threat to patients receiving allogeneic transplants because of the immunosuppressive drug regimens used to prevent graft rejection. For this reason alternative schemes involving the induction of immunological tolerance have been developed as an alternative strategy to selectively but not globally tolerize a patient. We have developed both peripheral and central tolerization regimens in mice using antibody (anti-CDI 54) approaches that are successful in establishing long term tolerance to allogeneic grafts. These mice can maintain their grafts and eventually effectively control virus infections. However, in the first few weeks after tolerization, these mice and their grafts are vulnerable to infection, and we propose the following specific aims to understand how infections with several experimental viruses, including lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), vaccinia virus (W), murine cytomegalovirus (MCMV), and influenza A virus (lAV), can disrupt the maintenance of transplantation tolerance during this vulnerable period. With Project 1 we are also developing additional CDI 54 RNA knock down approaches to tolerize mice. The overall hypotheses to be supported or refuted in this Project 2 are that heterologous cross-reactive immunity, as opposed to bystander activation, is responsible forthe virus-induced abrogation ofthe maintenance of peripheral tolerance, that T regulatory cells may modulate this process, and that viruses are threats to centrally tolerized hosts and the maintenance of their grafts.