MACROPHAGE MEDIATED IMMUNOREGULATION VIA TRYPTOPHAN

巨噬细胞通过色氨酸介导的免疫调节

• 批准号: 6139287
• 负责人: David H. Munn
• 金额: $ 25.37万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6139287
• 关键词: CD40 molecule; T lymphocyte; aminoacid transport; autoantigens; autoimmunity; colony stimulating factor; enzyme activity; enzyme induction /repression; enzyme inhibitors; gene expression; genetically modified animals; human tissue; immunoregulation; indoleamine; interferon gamma; laboratory mouse; leukocyte activation /transformation; macrophage; pregnancy; tryptophan; tryptophan 2,3 dioxygenase

DESCRIPTION: (Adapted from the applicant's abstract) Macrophages phagocytose microorganisms and present antigens to T cells. Paradoxically, however, macrophages are also professional scavengers which normally phagocytose and present antigens derive from self proteins. The long-term goal of this project is to identify the mechanism by which macrophages inhibit autoimmune responses to these self antigens. The applications have identified a novel mechanism whereby macrophages may present antigens in an immunosuppressive, rather than immunostimulatory fashion. They show that macrophages that have differentiated under the influence of macrophage colony-stimulating factor (MCSF) inhibit attempted T cell activation. The mechanism of this inhibition is massive induction of the enzyme indoleamine 2, 3- dioxygenase (IDO), which selectively degrades the essential amino acid tryptophan. Simultaneously, MCSF-derived macrophages markedly increase trypthphan uptake via induction of a novel high-affinity, tryptophan- selective transport pathway. The applicants hypothesize that the combination of these two mechanisms allows macrophages to rapidly deplete tryptophan from the local microenvironment, thus aborting normal T cell activation. Consistent with the proposed role of IDO in suppresssing T cells, the applicants show that pharmacologic inhibition of IDO in vivo results in enhanced activation of autoreactive T cells, and that inhibition of IDO activity in placenta results in rapid, uniform, T cell-mediated rejection of all allogeneic fetuses. The aims of the current proposal are to: (1) test the hypothesis that a synergistic combination of IFNgamma and CD40-ligand expression by T cells triggers IDO expression in macrophages, and characterize the effect of the resulting tryptophan depletion on T cell activation; (2) use a transgenic mouse model to test the hypothesis that IDO-expressing macrophages inhibit autoreactive T cell activation in vivo; and (3) define the functional characteristics and regulation of the high- affinity tryptophan transport system. These studies will define a fundamental and previously unsuspected mechanism of T cell regulation imposed by cells of the innate immune system.

描述：（改编自申请人的摘要） 巨噬细胞吞噬微生物并向 T 细胞呈递抗原。 然而，矛盾的是，巨噬细胞也是专业的清道夫 通常吞噬并呈现来自自身的抗原 蛋白质。该项目的长期目标是确定 巨噬细胞抑制自身免疫反应的机制 自身抗原。这些应用程序已经确定了一种新颖的机制 由此巨噬细胞可以以免疫抑制的方式呈递抗原，而不是 比免疫刺激时尚。他们表明巨噬细胞具有 在巨噬细胞集落刺激的影响下分化 因子 (MCSF) 抑制尝试的 T 细胞激活。这个的机制 抑制是吲哚胺 2, 3- 酶的大量诱导 双加氧酶 (IDO)，选择性降解必需氨基酸 色氨酸。同时，MCSF 衍生的巨噬细胞显着增加 通过诱导新型高亲和力色氨酸吸收色氨酸 选择性转运途径。申请人假设 这两种机制的结合使巨噬细胞能够快速 从局部微环境中耗尽色氨酸，从而中止正常 T 细胞激活。与 IDO 的拟议作用一致 抑制 T 细胞，申请人表明药理学抑制 体内 IDO 会增强自身反应性 T 细胞的激活， 抑制胎盘中的 IDO 活性会导致快速、 对所有同种异体胎儿均一的 T 细胞介导的排斥反应。目标 当前提案的目的是：（1）检验假设 T 的 IFNγ 和 CD40 配体表达的协同组合 细胞触发巨噬细胞中的 IDO 表达，并表征 由此产生的色氨酸消耗对 T 细胞激活的影响； (2) 使用转基因小鼠模型来检验表达 IDO 的假设 巨噬细胞抑制体内自身反应性 T 细胞活化；和（3） 定义高的功能特性和调节 亲和色氨酸转运系统。这些研究将定义一个 T 细胞调节的基本且先前未被怀疑的机制 由先天免疫系统细胞强加的。