Biology of the Immune Response

免疫反应生物学

• 批准号: 6433338
• 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/6433338
• 关键词: AIDS; B lymphocyte; Wiskott Aldrich syndrome; clinical research; cytokine receptors; gene therapy; genetic disorder; human subject; hypogammaglobulinemia; immunodeficiency; immunopathology therapy; immunoregulation; inborn immunodeficiency; interleukin 15; interleukin 2; lymphocyte proliferation; molecular pathology; monoclonal antibody; neoplasm /cancer immunology; protein tyrosine kinase; receptor expression; tissue /cell culture

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. Two clinical protocols have been submitted to treat patients with CVID or IgA deficiency with BLyS in vivo. 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.

进行研究以检查正常个体和患有与高频率癌症相关的先天性和获得性免疫缺陷状态的患者中的人体免疫应答。 我们目前的研究集中在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连锁淋巴组织增生综合征（XLP）、常见变异性免疫缺陷病（CVID）、Wiskott-Aldrich综合征（WAS）和选择性伊加缺乏症、X连锁无丙种球蛋白血症和单纯性生长激素缺乏症（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有许多共同特征。 我们已经证明XLA/GHD与XLA不同，因为前者患者Btk表达没有异常，包括正常的催化活性。 我们目前正在研究其他X染色体基因作为XLA/GHD的原因，因为它们成为人类基因组计划的一部分。 我们已经表明，XLM患者在T细胞活化时细胞因子的产生明显减少，并且通过加入重组CD 40 L三聚体（CD 154）可以恢复。 这些研究表明CD 154给药治疗XLM的可能性。 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CD 154治疗。 最近，另外两个研究小组克隆了负责XLP的基因。 这个基因被称为SH 2D 1A，没有明确的功能。 目前，我们正在研究这个基因的功能。 一些研究表明CVID的遗传基础。 为了获得可能的洞察异常基因表达，我们正在使用cDNA微阵列分析差异基因表达刺激CVID和正常B细胞。 最近鉴定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。 我们最近已经表明，CVID患者的一个子集可以在体外用BLyS刺激增殖和分泌抗体。 已经提交了两个临床方案，用于在体内用BLyS治疗CVID或伊加缺乏症患者。 我们继续研究Wiskott-Aldrich综合征蛋白（WASp）的功能。 这些研究包括证实WASp在原代人巨核细胞、血小板和单核细胞中的表达。 此外，我们已经确定了两个额外的WASP相互作用的蛋白质使用酵母双杂交系统。 最后，使用逆转录病毒介导的基因治疗，我们已经纠正了Wiskott-Aldrich综合征患者细胞中的表型异常。