BIOLOGY OF THE IMMUNE RESPONSE

研究是为了检查正常人和患有与癌症高频率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连锁无球蛋白血症和分离性生长激素缺乏症（XLA/GHD）、X连锁高igm综合征（XLM）、X连锁淋巴细胞增殖性综合征（XLP）、常见可变免疫缺陷病（CVID）和Wiskott- Aldrich综合征（WAS）患者。x -连锁无球蛋白血症和分离性生长激素缺乏症（XLA/GHD）与更常见的x -连锁无球蛋白血症（XLA）或布鲁顿病(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，因为前者患者没有Btk表达异常，包括正常的催化活性。作为人类基因组计划的一部分，我们目前正在研究导致XLA/GHD的其他x染色体基因。我们已经证明，XLM患者对t细胞活化的反应显著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。这些研究提示给药CD154治疗XLM的可能性。这些观察结果为新的临床方案提供了科学依据。最近，另外两个研究小组克隆了导致XLP的基因。这个被称为SH2D1A的基因没有明确定义的功能。我们目前正在研究这个基因的功能。一些研究表明CVID有遗传基础。为了进一步了解异常基因的表达，我们使用cDNA微阵列分析受刺激的CVID细胞和正常b细胞的差异基因表达。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。我们目前正在协商合作，以检测BLyS和BLyS受体在CVID中的表达以及CVID b细胞对BLyS的反应性。如果CVID b细胞对BLyS有反应，将为新的临床试验提供科学依据。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在人原代巨核细胞、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wasp相互作用的蛋白。最后，利用逆转录病毒介导的基因疗法，我们纠正了Wiskott Aldrich综合征患者细胞中的表型异常。-免疫缺陷，基因治疗，基因克隆，-人类受试者和人类受试者：18岁以下未成年人和人体组织，液体，细胞等。

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) and the Wiskott- Aldrich syndrome (WAS).X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) shares many features with the more common X-linked agammaglobulinemia (XLA) or Brutons disease caused by mutations in Brutons 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. 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 are currently negotiating collaboration to examine BLyS and BLyS receptor expression in CVID and the responsiveness of CVID B-cells to BLyS. If CVID B-cells respond to BLyS, it would provide the scientific basis for a new clinical trial. 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. - Immunodeficiency, gene therapy, gene cloning, - Human Subjects & Human Subjects: Minor under 18 Years Old & Human Tissues, Fluids, Cells, etc.