XENOGENEIC IMMUNE RECONSTITUTION IN SIV INFECTION

SIV 感染的异种免疫重建

• 批准号: 5206008
• 负责人: R JOHNSON
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5206008
• 关键词: Macaca mulatta; T cell receptor; T lymphocyte; antigen presentation; antiviral agents; cell differentiation; cell transplantation; combination chemotherapy; cytokine; flow cytometry; hematopoietic stem cells; human subject; human tissue; humoral immunity; immune tolerance /unresponsiveness; immunopathology chemotherapy; leukopoiesis; lymphocyte proliferation; miniature swine; newborn animals; nonhuman therapy evaluation; simian AIDSs; thymus transplantation; transplantation immunology; xenotransplantation

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.

CD 4 + T淋巴细胞的耗竭是其基本特征之一， 艾滋病病毒感染引起的免疫缺陷。 现有疗法 艾滋病毒感染者对扭转这一中心趋势几乎没有长期影响。 艾滋病的特点，甚至治疗，导致适度增加， CD 4 + T淋巴细胞似乎不能恢复幼稚T细胞的产生， 淋巴细胞 HIV感染胸腺会显著损害新生 产生新的T细胞，这种赤字可能会阻碍 通过抗病毒治疗或干细胞基因治疗重建免疫力。 因此，艾滋病毒感染者的免疫功能有可能恢复 需要恢复胸腺功能 梅根博士最近的证据 Sykes的实验室已经证明了猪胎儿胸腺 移植以重建正常鼠T细胞群， 胸腺切除、T细胞耗尽的免疫活性小鼠。 但如果这些 这一发现为治疗艾滋病提供了一种新的方法， 必须确定猪胸腺移植物是否 在SIV感染的灵长类动物中也有这种功能。 因此， 该提案的目标是使用SIV/猕猴模型来确定 实现宿主T细胞植入所需的条件 猪胸腺和造血干细胞重建SIV感染的 hosts. 具体来说，我们将：1。 用作体外模型以评价 猪胸腺组织支持灵长类T细胞分化的能力 CD 34+造血祖细胞，2. 检测猪胸腺的能力 在SIV=感染的恒河猴中移植以重建T细胞 接受抗逆转录病毒治疗，并确定宿主的需求 在疾病的不同阶段进行调理，以及3. 雇用猪 造血干细胞与猪胸腺移植物的组合， 在SIV感染的猕猴中重建免疫功能。 如果成功， 这些研究应建立使用异种 胸腺和造血细胞恢复HIV感染者的T细胞免疫 人