Biology of the Immune Response

免疫反应生物学

• 批准号: 6756199
• 负责人: DAVID NELSON
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 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/6756199
• 关键词: AIDS; B lymphocyte; Wiskott Aldrich syndrome; acquired immunodeficiency; gene expression; gene therapy; genetic disorder; human subject; human therapy evaluation; hypogammaglobulinemia; immunodeficiency; immunopathology therapy; immunoregulation; inborn immunodeficiency; lymphocyte proliferation; megakaryocytes; microarray technology; molecular pathology; monocyte; neoplasm /cancer immunology; patient oriented research; platelets; receptor expression; sex chromosomes; yeast two hybrid system

Studies were performed to examine the human immune response in normal individuals and in patients with congenital and acquired immunodeficiency states associated with a high frequency of cancer. We have focused our current studies on patients with X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD), X-linked hyper-IgM syndrome (XLM), X-linked lymphoproliferative syndrome (XLP), common variable immunodeficiency disease (CVID), the Wiskott-Aldrich syndrome (WAS) and selective IgA deficiency. X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) shares many features with the more common X-linked agammaglobulinemia (XLA) or Bruton's disease caused by mutations in Bruton's tyrosine kinase (Btk). We have shown XLA/GHD to be distinct from XLA since the former patients have no abnormalities in Btk expression including normal catalytic activity. We are currently examining additional X-chromosome genes as the cause of XLA/GHD as they become available as part of the Human Genome Project. We have shown that patients with XLM have markedly reduced cytokine production in response to T-cell activation and that this could be restored with the addition of recombinant CD40L trimer (CD154). These studies suggest the therapeutic possibility of CD154 administration for XLM. These observations are the scientific basis for a new clinical protocol and patients with XHM are currently being treated with recombinant CD154 in the Clinical Center. Recently two other groups cloned the gene responsible for XLP. This gene, termed SH2D1A, has no clearly defined function. We are currently examining the function of this gene. Several studies have suggested a genetic basis for CVID. To gain possible insight into aberrant gene expression, we are using cDNA microarrays to analyze differential gene expression in stimulated CVID and normal B-cells. A recently identified member of the tumor necrosis factor family, termed BLyS, drives B-cell proliferation and immunoglobulin secretion in vitro and in vivo. We have recently shown that a subset of patients with CVID can be stimulated with BLyS in vitro to proliferate and secrete antibodies. We have initiated a clinical trial NCI 02-C-0009 treating IgA deficient patients in vivo with BLyS. We continue to study the function of the Wiskott-Aldrich syndrome protein (WASp). These studies include demonstration of the expression of WASp in primary human megakaryocytes, platelets and monocytes. Moreover, we have identified two additional WASp-interacting proteins using the yeast two-hybrid system. Finally, using retroviral mediated gene therapy we have corrected the phenotypic abnormalities in Wiskott Aldrich syndrome patients' cells. Recently we have identified three patients with spontaneous genetic "reversions" where the reverted cells appear to have a selective growth advantage in vivo. These results suggest that gene therapy might be used for the treatment of the Wiskott-Aldrich syndrome.

进行的研究旨在检查正常个体以及患有与高发癌症相关的先天性和获得性免疫缺陷状态的患者的人体免疫反应。我们目前的研究重点是 X 连锁无丙种球蛋白血症和孤立性生长激素缺乏症 (XLA/GHD)、X 连锁高 IgM 综合征 (XLM)、X 连锁淋巴细胞增殖综合征 (XLP)、常见变异型免疫缺陷病 (CVID)、Wiskott-Aldrich 综合征 (WAS) 和选择性 IgA 缺乏症患者。 X 连锁无丙种球蛋白血症和孤立性生长激素缺乏症 (XLA/GHD) 与更常见的 X 连锁无丙种球蛋白血症 (XLA) 或由布鲁顿酪氨酸激酶 (Btk) 突变引起的布鲁顿病具有许多特征。我们已经证明 XLA/GHD 与 XLA 不同，因为前者的 Btk 表达没有异常，包括正常的催化活性。我们目前正在研究导致 XLA/GHD 的其他 X 染色体基因，因为它们已成为人类基因组计划的一部分。我们已经证明，XLM 患者响应 T 细胞激活而显着减少细胞因子的产生，并且可以通过添加重组 CD40L 三聚体 (CD154) 来恢复这种情况。这些研究表明 CD154 给药对于 XLM 的治疗可能性。这些观察结果是新临床方案的科学基础，XHM 患者目前正在临床中心接受重组 CD154 治疗。最近，另外两个小组克隆了负责 XLP 的基因。该基因称为 SH2D1A，没有明确定义的功能。我们目前正在研究该基因的功能。多项研究表明 CVID 存在遗传基础。为了尽可能深入了解异常基因表达，我们使用 cDNA 微阵列来分析受刺激的 CVID 和正常 B 细胞中的差异基因表达。最近发现的肿瘤坏死因子家族成员，称为 BLyS，在体外和体内驱动 B 细胞增殖和免疫球蛋白分泌。我们最近表明，可以在体外用 BLyS 刺激一部分 CVID 患者增殖和分泌抗体。我们已经启动了一项临床试验 NCI 02-C-0009，用 BLyS 体内治疗 IgA 缺陷患者。我们继续研究 Wiskott-Aldrich 综合征蛋白 (WASp) 的功能。这些研究包括证明 WASp 在原代人巨核细胞、血小板和单核细胞中的表达。此外，我们还利用酵母双杂交系统鉴定了另外两种 WASp 相互作用蛋白。最后，利用逆转录病毒介导的基因治疗，我们纠正了威斯科特·奥尔德里奇综合征患者细胞的表型异常。最近，我们发现了三名患有自发遗传“逆转”的患者，其中逆转的细胞似乎在体内具有选择性生长优势。这些结果表明基因疗法可能用于治疗 Wiskott-Aldrich 综合征。