REGULATION OF IL 12 PRODUCTION

IL 12 生产的监管

• 批准号: 6431689
• 负责人: BRIAN KELSALL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/6431689
• 关键词: cellular immunity; clinical research; complement receptor; human subject; integrins; interferon gamma; interleukin 12; laboratory mouse; microorganism immunology; monocyte; neutrophil; protein biosynthesis; tissue /cell culture

The broad purpose of this work is to further understand how microorganisms and vaccine adjuvants via their interaction with antigen presenting cells, such as macrophages and dendritic cells, affect the generation of T cell mediated immune responses via their ability to regulate the production of critical cytokines, such as IL-12 and IL-10. We initially determined that signaling via complement receptor 3 (CR3, CD11b/CD18), which serves as a receptor for a number of infectious organisms and endogenous molecules, such as the complement fragment opsonin iC3b, suppresses the ability of human monocytes to make IL-12 in response to known IL-12 stimuli. These studies suggest that organisms that bind to CR3 in either a complement-dependent or independent fashion have evolved to take advantage of this pathway to avoid the induction of IL-12 dependent T helper 1 (Th1) immune responses that are important for host defenses. Since these initial findings, we have focused our work on this part of this project on the following areas: (1) Understanding the intracellular mechanism of CR3-mediated suppression of IL-12 production. (2) Determining IL-12 production from cells of patients with a genetic defect in b2-integrin expression (leukocyte adhesion deficiency) (3) Examining the role of CR3 activation on IL-12 production in vitro and in vivo, and (4) Determining the ability of antibodies to CR3, as well as CR4, to affect the outcome of ongoing Th1-mediated autoimmune diseases in a mouse model of inflammatory bowel disease. The second aspect of this project examines the regulation of IL-12 production by G-protein signaling. We showed that a primary mechanism by which the family of vaccine adjuvants known as ADP-rybosylating toxins, which include cholera toxin and pertussis toxin work is by regulating IL-12 production and the subsequent induction of Th1 responses via interaction with G-protein coupled surface receptors. CT acts to potently suppress IL-12 by activating Gs-protein coupled receptors, while PT acts to enhance IL-12 production by inhibiting endogenous suppressive Gi-protein coupled receptor signals. In addition, we have demonstrated that certain chemokines and chemoattractans, which act via Gi-protein pathways, can potently suppress the production of IL-12 from monocytes. We are currently exploring (1) the intracellular mechanisms by which chemokines and ADP-rybosylating adjuvants effect IL-12 production, (2) the significance of these novel mechanisms of immunoregulation in vivo, and (3) possibile ways to exploit these findings for the development of new immunotherapies.

这项工作的广泛目的是进一步了解微生物和疫苗佐剂如何通过它们与抗原提呈细胞(如巨噬细胞和树突状细胞)的相互作用，通过它们调节关键细胞因子(如IL-12和IL-10)的产生来影响T细胞介导的免疫反应的产生。我们最初确定，通过补体受体3(CR3，CD11b/CD18)发出的信号可以抑制人单核细胞对已知IL-12刺激的产生IL-12的能力。补体受体3(CR3，CD11b/CD18)是许多感染性生物和内源性分子(如补体片段Opsonin iC3b)的受体。这些研究表明，以补体依赖或独立的方式与CR3结合的生物已经进化到利用这一途径来避免诱导对宿主防御至关重要的IL-12依赖的T辅助细胞1(Th1)免疫反应。由于这些初步的发现，我们在这个项目的这部分工作集中在以下几个方面：(1)了解CR3介导的抑制IL-12产生的细胞内机制。(2)检测b2整合素基因表达缺陷(白细胞黏附缺陷)患者细胞中IL-12的产生；(3)检测CR3激活在体外和体内对IL-12产生的作用；以及(4)在炎症性肠病小鼠模型中，确定CR3和CR4抗体影响Th1介导的自身免疫性疾病结局的能力。这个项目的第二个方面研究了G蛋白信号对IL-12产生的调节。我们发现，包括霍乱毒素和百日咳毒素在内的一系列疫苗佐剂，包括霍乱毒素和百日咳毒素，其作用的主要机制是通过调节IL-12的产生，以及随后通过与G蛋白偶联表面受体的相互作用来诱导Th1反应。CT通过激活Gs蛋白偶联受体有效地抑制IL-12，PT通过抑制内源性抑制性Gi蛋白偶联受体信号而增强IL-12的产生。此外，我们还证明了某些通过胃肠道蛋白途径发挥作用的趋化因子和趋化因子可以有效地抑制单核细胞产生IL-12。我们目前正在探索(1)趋化因子和ADP-核糖化佐剂影响IL-12产生的细胞内机制，(2)这些新的免疫调节机制在体内的意义，以及(3)利用这些发现开发新的免疫疗法的可能途径。