Biology of the Immune Response

免疫反应生物学

• 批准号: 6558252
• 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/6558252
• 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. 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.

研究人员检查了正常人和与癌症高发相关的先天性和获得性免疫缺陷状态患者的人体免疫反应。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连锁淋巴组织增殖性综合征(XLP)、常见变量免疫缺陷病(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Bruton酪氨酸激酶(BTK)突变引起的Bruton病有许多相似之处。我们已经证明XLA/GHD不同于XLA，因为以前的患者在BTK表达方面没有异常，包括正常的催化活性。我们目前正在检查额外的X染色体基因，作为XLA/GHD的原因，因为它们是人类基因组计划的一部分。我们已经证明，XLM患者对T细胞激活的反应明显减少了细胞因子的产生，这可以通过添加重组CD40L三聚体(CD154)来恢复。这些研究提示CD154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CD154治疗。最近，另外两个研究小组克隆了与XLP有关的基因。这个名为SH2D1A的基因没有明确的功能。我们目前正在研究这种基因的功能。几项研究表明，CVID的遗传基础。为了对异常基因表达有可能的了解，我们正在使用基因芯片分析刺激的CVID和正常B细胞的差异基因表达。肿瘤坏死因子家族的一个新成员，称为BLyS，在体外和体内推动B细胞的增殖和免疫球蛋白的分泌。我们最近已经证明，在体外，BLyS可以刺激CVID患者的一部分患者增殖和分泌抗体。已经提出了两种临床方案来治疗CVID或IgA缺乏症患者体内的BLyS。我们继续研究Wiskott-Aldrich综合征蛋白(WASP)的功能。这些研究包括证明黄蜂在原代人类巨核细胞、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个与黄蜂相互作用的蛋白。最后，利用逆转录病毒介导的基因治疗，我们纠正了Wiskott Aldrich综合征患者细胞的表型异常。