Non-Myeloablative Host Conditioning that Protects Against GVHD

预防 GVHD 的非清髓性宿主调理

• 批准号: 8260363
• 负责人: SAMUEL STROBER
• 金额: $ 31.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260363
• 关键词: Acute Graft Versus Host Disease; Antithymoglobulin; Attenuated; BCL1 Oncogene; Bioluminescence; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Transplantation; Cell Transplants; Cell secretion; Cells; Cytolysis; Cytotoxic T-Lymphocytes; Development; Disease remission; Flow Cytometry; Goals; Human; IL2RA gene; Image; In Vitro; Inbred BALB C Mice; Inflammatory; Injection of therapeutic agent; Interferons; Interleukin-10; Interleukin-4; Intestines; Killer Cells; Lymphatic Irradiation; Lymphoid Tissue; Lymphoma; Measures; Mediating; Mixed Lymphocyte Culture Test; Mouse Strains; Mus; Natural Increases; Pattern; Process; Production; Regimen; Rodent; Serum; Spleen; T cell regulation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Transgenic Organisms; base; cell killing; conditioning; cytokine; graft vs host disease; injured; irradiation; killer T cell; killings; leukemia/lymphoma; mouse model; neoplastic cell; prevent; tumor; tumor progression

The goal oftheresearch plan is touse host regulatory natural killer (NK) I cells toprevent graft versus host disease (GVHD) and retain graft anti-lymphoma activity after MHC-mismatched bone marrow transplantation in mice. In particular, we will test the hypothesis that regulatory NK T cells, the predominant T cell subset after conditioning hosts with total lymphoid irradiation (TLI) and anti-thymoctye serum (ATS), prevents GVHD by secreting IL-4, and polarizing donor T cells to a Th2 cytokine profile. The Th2 polarization is theorized to attenuate GVHD, but not interfere with BCLi tumor cell killing by donor CD8* T cells that mediate direct cell contact cytolysis via perform cytolytic molecules. We will test the hypothesisby determining whether protection against GVHD that is observed in TLI and ATS conditioned wild-type hosts is lost in NK T cell deficient CD1d''" and Ja281''" hosts, and can be restored by the injection of purified NK T cells from wild-type but not IL-4~/~ host strain mice. We will also determine whether donor CD4+ T cells that secrete IL-4 are required for protection against GVHD and for the Th2 polarization process. We will test whether the polarization process markedly reduces the early rapid expansion of donor T cells in the host tissues as measured by flow cytometry and bioluminescence imaging, and the early secretion of pro- inflammatory Th1 cytokines that injure host tissues. NK T cells will be studied for their capacity to block donor T cell expansion and Th1 cytokine secretion in vitro in the mixed leukocyte reaction (MLR), while permiting the differentiation of CDS* cytolytic T cell precursors into effector killer cells that can kill tumor cells. Finally, we will determine whether p53"7"and Bcl-2 transgenic hosts that fail to show an increase in the NK T cell subset among all T cells after irradiation, also fail to be protected against GVHD after conditioning with TLI and ATS.

研究计划的目标是使用宿主调节性自然杀伤(NK)I细胞来保护移植物 抗宿主病(GVHD)并保留MHC不相合骨髓后移植物抗淋巴瘤活性 在小鼠体内移植。特别是，我们将检验这一假设，即调节性NK T细胞，占主导地位 用全淋巴照射(TLI)和抗胸腺细胞血清(ATS)处理宿主后T细胞亚群， 通过分泌IL-4和使供者T细胞极化到Th2细胞因子谱来预防GVHD。Th2 极化理论上可以减弱移植物抗宿主病，但不会干扰供体CD8*T对BCLi肿瘤细胞的杀伤 通过执行细胞溶解分子来介导直接细胞接触细胞溶解的细胞。我们将通过以下方式检验假设 确定在TLI和ATS条件下的野生型宿主中观察到的对GVHD的保护是否 在NK T细胞缺陷的CD1d‘’和Ja281‘’宿主中丢失，并可通过注射纯化的NK T来恢复 野生型小鼠的细胞，而不是IL-4~/~宿主小鼠。我们还将确定捐赠者的CD4+T细胞是否 分泌IL-4是预防移植物抗宿主病和Th2极化过程所必需的。我们将测试 极化过程是否显著降低了供体T细胞在宿主体内的早期快速扩增 用流式细胞仪和生物发光成像检测组织，以及早期分泌的前-羟色胺。 损伤宿主组织的炎性Th1细胞因子。将研究NK T细胞的阻断能力 供者T细胞体外扩增和Th1细胞因子分泌的混合白细胞反应(MLR)，而 允许将CDS*细胞杀伤T细胞前体分化为能够杀死肿瘤细胞的效应杀伤细胞。 最后，我们将确定P537和Bcl2转基因宿主是否没有表现出NK T的增加 照射后所有T细胞中的细胞亚群也不能被GVHD保护 TLI和ATS。