XENOGENEIC IMMUNE RECONSTITUTION IN SIV INFECTION

CD4+T淋巴细胞的耗尽是其基本特征之一 由艾滋病毒感染引起的免疫缺陷。现有的治疗方法 艾滋病毒感染者在扭转这一中心方面的长期影响很小 艾滋病的特征，甚至治疗导致小幅增加 CD4+T淋巴细胞似乎不能恢复幼稚T细胞的产生 淋巴细胞。艾滋病毒感染胸腺显著损害新生 产生新的T细胞，而这种缺陷可能会阻碍 通过抗病毒治疗或干细胞基因治疗重建免疫。 因此，艾滋病毒感染者的免疫功能恢复是可能的 需要恢复胸腺功能。梅根博士最近提供的证据 赛克斯的实验室已经证明了猪胎儿胸腺的能力 移植以重建正常的小鼠T细胞群 胸腺切除，T细胞耗尽的免疫活性小鼠。然而，如果这些 这些发现为艾滋病毒感染的治疗提供了一种新的方法， 确定猪胸腺移植物是否可以 在感染SIV的灵长类动物中也执行这一功能。因此，总体上， 这项建议的目标是使用SIV/猕猴模型来确定 实现T细胞和宿主T细胞植入所需的条件 猪胸腺和造血干细胞在SIV感染中的重建 主持人。具体地说，我们将：1.使用AS体外模型来评估 猪胸腺组织支持灵长类T细胞分化的能力 CD34+造血祖细胞，2.检测猪胸腺的能力 移植以重建SIV感染恒河猴的T细胞 接受抗逆转录病毒治疗并确定对宿主的要求 在疾病的不同阶段进行调节，以及3.使用猪 造血干细胞与猪胸腺移植物的联合应用 重建感染SIV的猕猴的免疫功能。如果成功， 这些研究应该为异种生物的使用建立框架。 胸腺和造血细胞对HIV感染者T细胞免疫的恢复作用 人民。

Depletion of CD4+ T lymphocytes is one of the fundamental characteristics of the immunodeficiency induced by HIV infection. Existing therapies for HIV-infected people have little long-term impact on reversing this central feature of AIDS, and even treatments that result in modest increases in CD4+ T lymphocytes do not appear to restore production of naive T lymphocytes. Infection of the thymus by HIV significantly impairs de novo production of new T cells, and this deficit is likely to thwart efforts to reconstitute immunity by antiviral therapy or stem cell gene therapy. Restoration of immune function in HIV-infected people is therefore likely to require restoration of thymic function. Recent evidence from Dr. Megan Sykes' laboratory has demonstrated the capacity of porcine fetal thymus transplants to reconstitute normal murine T cell populations in thymectomized, T cell-depleted immunocompetent mice. However, if these findings are to provide a new approach to the treatment of HIV infection, it will be essential to determine whether or not porcine thymic grafts can also perform this function in SIV-infected primates. Thus, the overall goal of this proposal is to use the SIV/macaque model to determine the conditions required to achieve engraftment of, and host T cell reconstitution by, pig thymus and hematopoietic stem cells in SIV-infected hosts. Specifically, we will: 1. Use as in vitro model to evaluate the ability of pig thymic tissue to support T cell differentiation of primate CD34+ hematopoietic progenitor cells, 2. Examine the ability of pig thymus transplants to reconstitute T cells in SIV=infected rhesus monkeys receiving antiretroviral therapy and determine the requirement for host conditioning at different stages of disease, and 3. Employ porcine hematopoietic stem cells in combination with swine thymic grafts to reconstitute immune function in SIV-infected macaques. If successful, these studies should establish the framework for the use of xenogeneic thymic and hematopoietic cells to restore T cell immunity in HIV-infected people.