Blood Stem Cell Transplantation as Immunotherapy

描述（由申请人提供）： 该项目的一个中心主题是使用异基因造血祖细胞移植来诱导患者和实验室动物在嵌合体形成后的宿主对供体和供体对宿主免疫耐受，而不会发生移植物抗宿主病（GVHD）。 将研究调节性T细胞在抗GVHD保护中的作用以及受保护宿主的免疫能力。 我们将检验一种新的预处理方案实现的持续嵌合体将诱导肾移植患者的免疫耐受，从而可以撤回所有免疫抑制药物的假设。 我们还将测试的假设，这些患者的血液中的调节性自然杀伤T细胞将抑制免疫反应的供体和宿主同种异体抗原。我们将使用预处理方案诱导危及生命的系统性红斑狼疮患者的完全嵌合体，这些患者将通过调节性T细胞免受GVHD的影响。 我们将检验持续的嵌合状态将诱导自身免疫性疾病的完全缓解，从而允许免疫抑制药物停药的假设。我们将检验调节性T细胞（CD 4 + CD 25+或NK 1.1 + T细胞）可以通过阻断不同的免疫效应子途径将小鼠中的移植物抗肿瘤/淋巴瘤（GVL）活性与GVHD分离的假设，使得在不存在GVHD的情况下发生有效的GVL活性。 我们将测试的假设，供体朗格汉斯细胞替代宿主朗格汉斯细胞在同种异体骨髓移植后的皮肤是依赖于供体T细胞的功能，促进更换，即使在没有临床或显微镜GVHD。 我们还将研究嵌合肾移植和自身免疫性疾病患者的朗格汉斯细胞替代，以及用调节性T细胞保护小鼠免受GVHD的朗格汉斯细胞替代。行政和生物统计核心将满足所有项目的需要，免疫测定和流式细胞术核心也将服务于所有项目。

DESCRIPTION (provided by applicant): A central theme of the program project is the use of allogeneic blood progenitor cell transplantation to induce host versus donor and donor versus host immune tolerance in patients and laboratory animals after the development of chimerism without the development of graft versus host disease (GVHD). The role of regulatory T cells in the protection against GVHD will be studied as well as the immune competence of the protected hosts. We will test the hypothesis that sustained chimerism achieved with a novel conditioning regimen will induce immune tolerance in patients given kidney transplants such that all immune suppressive drugs can be withdrawn. We will also test the hypothesis that regulatory natural killer T cells in the blood of these patients will suppress immune responses to donor and host alloantigens. We will use a conditioning regimen to induce full chimerism in patients with life threatening systemic lupus erythematosus who will be protected against GVHD by regulatory T cells. We will test the hypothesis that sustained chimerism will induce a complete remission in the autoimmune disease allowing for immunosuppressive drug withdrawal. We will test the hypothesis that regulatory T cells (CD4+CD25+or NK1.1+ T cells) can separate GVHD from graft versus tumor/lymphoma (GVL) activity in mice by blocking different immune effector pathways such that potent GVL activity occurs in the absence of GVHD. We will test the hypothesis that donor Langerhans cell replacement of host Langerhans cells in the skin after allogeneic bone marrow transplantation is dependent on the function of donor T cells that facilitate replacement even in the absence of clinical or microscopic GVHD. We will also study Langerhans cell replacement in chimeric kidney transplant and autoimmune disease patients, and Langerhans cell replacement in mice protected from GVHD with regulatory T cells. The administrative and biostatistical core will serve the needs of all projects, and the immune assay and flow cytometry core will service all projects as well.