MODE OF ACTION OF H-LINKED IMMUNE RESPONSE (IR) GENES

H连锁免疫反应（IR）基因的作用模式

• 批准号: 3125595
• 负责人: JUDITH A KAPP
• 金额: $ 19.9万
• 依托单位: JEWISH HOSPITAL OF SAINT LOUIS
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-04-01 至 1990-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3125595
• 关键词: B lymphocyte; alanine; antibody formation; autoimmune thyroiditis; cellular immunity; gene expression; glutamates; helper T lymphocyte; histocompatibility antigens; immune response genes; immunoregulation; insulin; insulin dependent diabetes mellitus; laboratory mouse; laboratory rabbit; macrophage; proinsulin; suppressor T lymphocyte; tyrosine

The long term objectives of this project are to determine the mechanisms by which H-2-linked immune response (Ir) genes regulate immune responses to T cell dependent antigens. Although the hypothesis that the Ia antigens are the Ir gene products is widely accepted, it does not explain how Ia antigens mediate the highly specific Ir gene functions. Our previous studies support the postulate that Ir gene control is the net result of the stimulation of various regulatory helper and suppressor T cell subsets. Thus, the specific aims of this proposal focus on the detailed characterization of differences in regulatory T cell subsets between responder and nonresponder mice. Development of antibody responses by inbred strains of mice to the synthetic polypeptides: L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) and L-glutamic acid50-L-tyrosine (GT) and a panel of proteins comprised of several insulin variants obtained from different species serve as model systems. Development of specific helper T cell clones and suppressor T cell hybridomas as sources of homogeneous regulatory T cells will be continued. The mechanisms by which suppressor T cells inhibit responses will be analyzed using soluble, antigen-specific suppressor factors and suppressor-inducer factors. The clinical importance of understanding precisely how Ir genes function is supported by evidence that Ir genes also regulate immune responses in humans. Several organ-specific autoimmune diseases are associated with certain haplotypes of the D/DR region of the HLA-complex suggesting that this locus is analogous to the murine I region. Thus, the role of Ir genes in development of experimental autoimmune diseases in mice will be investigated as a model system. Once the biology of suppressor T cells is well understood, it should be possible to produce suppressor factors to modulate indesirable immune responses specifically. Because it would not be feasible to design a new factor for every disease and every individual, we will determine whether specific factors can be targeted to neoantigenic determinants via an antigen bridge. If numerous responses can be suppressed with a single factor, the therapeutic potential of suppressor factors would be very promising. Ultimately these studies might provide the basis to prevent induction of anti-insulin antibodies in insulin-dependent diabetics and to reverse autoimmune diseases with specific suppressor T cell factors.

该项目的长期目标是通过以下方式确定机制： 哪些 H-2 相关免疫反应 (Ir) 基因调节对 T 的免疫反应 细胞依赖性抗原。 尽管 Ia 抗原的假设 Ir基因产物被广泛接受，它并没有解释Ia如何 抗原介导高度特异性的 Ir 基因功能。 我们之前的 研究支持这样的假设：Ir 基因控制是 刺激各种调节性辅助和抑制性 T 细胞亚群。 因此，本提案的具体目标侧重于详细的 调节性 T 细胞亚群差异的表征 反应小鼠和非反应小鼠。 近交系小鼠对抗体反应的发展 合成多肽：L-谷氨酸60-L-丙氨酸30-L-酪氨酸10 (GAT) 和 L-谷氨酸50-L-酪氨酸 (GT) 以及一组蛋白质，包括 从不同物种获得的几种胰岛素变体作为模型 系统。 特异性辅助 T 细胞克隆和抑制 T 细胞的开发 细胞杂交瘤作为同质调节性 T 细胞的来源 持续。 抑制性 T 细胞抑制反应的机制 将使用可溶性抗原特异性抑制因子进行分析， 抑制-诱导因素。 准确理解 Ir 基因功能的临床重要性 有证据表明 Ir 基因还调节免疫反应 人类。 多种器官特异性自身免疫性疾病与 HLA 复合体 D/DR 区域的某些单倍型表明 该位点类似于小鼠 I 区域。 因此，Ir 基因的作用 在小鼠实验性自身免疫性疾病的发展中 作为模型系统进行研究。 一旦抑制性 T 细胞的生物学特性被充分了解，就应该 可能产生抑制因子来调节不良免疫 具体回应。 因为设计一个新的方案是不可行的 对于每种疾病和每个人的因素，我们将确定是否 特定因素可以通过以下方式针对新抗原决定簇： 抗原桥。 如果可以用一个单一的方法来抑制大量的反应 因子，抑制因子的治疗潜力将非常大 有希望的。 最终这些研究可能为预防提供基础 诱导胰岛素依赖型糖尿病患者产生抗胰岛素抗体 使用特定的抑制性 T 细胞因子逆转自身免疫性疾病。