ROLE OF CYTOKINES IN THE PATHOGENESIS AND TREATMENT OF AUTOIMMUNE DISEASE

细胞因子在自身免疫性疾病发病机制和治疗中的作用

• 批准号: 6431612
• 负责人: ETHAN M. SHEVACH
• 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/6431612
• 关键词: autoantibody; autoimmune disorder; autoimmunity; cytokine; cytokine receptors; experimental allergic encephalomyelitis; helper T lymphocyte; immunopathology; immunoregulation; immunotherapy; interferon gamma; interleukin 12; laboratory mouse; leukocyte activation /transformation

Studies in infectious disease and autoimmunity models have shown that immune responses to both self and foreign antigens are frequently dominated by induction of a particular Th1/Th2 subset with profound consequences for clinical outcome. Although the inflammatory effector function of Th1 cells is essential for the clearance of intracellular pathogens, it is also responsible for the tissue damage typical of organ-specific autoimmunity. Th2 cells which play an important role in the clearance of many helminthic infections function as suppressor cells or ineffectual bystanders in organ-specific autoimmune diseases. We have selected Experimental Allergic Encephalomyelitis (EAE) as our major model for the study of the role of the Th1/Th2 balance in the regulation of organ-specific autoimmunity. EAE is a demyelinating disease of the central nervous system (CNS) induced either by active immunization with myelin proteins or by the adoptive transfer of myelin protein reactive T cells. EAE is mediated by CD4+ T cells and the T cells responsible for disease induction produce Th1 type cytokines; myelin protein reactive Th2 T cells are non-encephalitogenic and in rare cases may be protective. As IL-12 produced by monocytes/dendritic cells has been shown to the most critical factor in the regulation of the development and differentiation of Th1 cells, we have focused our efforts on (1) the role of the IL-12/IL-12Rbeta2 pathway in the generation of autoreactive effector T cells which mediate EAE, (2) the potential contribution of IL-2 and IL-18 as costimulatory factors in the regulation of the IL-12/IL-12Rbeta2 pathway, (3) the downregulatory role of Th2 cytokines on this pathway, and (4) the role of the IL-12/IL-12Rbeta2 pathway in unmasking latent autoimmune effector T cells. We have demonstrated that the primary effect of IL-18 on Th1 differentiation is mediated by its capacity to directly upregulate IL-12 receptor expression which thereby enhances IL-12 mediated signaling. The enhancement of IL-12 receptor expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development. We also demonstrated that IL-10 plays a critical role in the regulation of the IL-12/IL-12Rbeta2 pathway. Addition of IL-10 to cultures of primed T cells strongly inhibited upregulation of the IL-12Rbeta2 subunit. Presumably, IL-10 acted on the antigen presenting cell in these cultures to inhibit IL-12 production, but a direct effect of IL-10 on the responding T cell has not been excluded. The other major factors which we have identified as important in regulation of IL-12 receptor expression are costimulatory signals delivered to the antigen-specific T cells by interactions of the CD80/CD86 molecules on antigen presenting cells with CD28 on the T cell. We have demonstrated that costimulation is required for production of both IL-2 and IL-12 and that both of these cytokines are critical for the ability of T cells to express IL-12 receptors and to differentiate into pathogenic autoreactive T cells. We developed a novel system for induction of EAE by substituting CpG oligonucleotides for Freund's complete adjuvant. CpG oligos were potent adjuvants, but the results of these studies also suggested that they could potentially trigger autoimmune disease in susceptible individuals.

在传染病和自身免疫模型中的研究表明，对自我和外国抗原的免疫反应经常通过诱导特定的TH1/TH2子集而主导，对临床结果产生了深远的影响。 尽管Th1细胞的炎症效应功能对于清除细胞内病原体至关重要，但它也负责典型的器官特异性自身免疫性的组织损伤。在清除许多蠕虫感染中起着重要作用的Th2细胞在器官特异性自身免疫性疾病中充当抑制细胞或无效旁观者。我们选择了实验性过敏性脑脊髓炎（EAE）作为研究TH1/TH2平衡在调节器官特异性自身免疫性调节中的作用的主要模型。 EAE是通过用髓磷脂蛋白或通过髓磷脂蛋白反应性T细胞的过继转移引起的中枢神经系统（CNS）的脱髓鞘疾病。 EAE由CD4+ T细胞介导，负责疾病诱导的T细胞会产生Th1型细胞因子。髓磷脂蛋白反应性Th2 T细胞是非脑脑化的，在极少数情况下可能具有保护性。 由于单核细胞/树突细胞产生的IL-12已显示为调节Th1细胞的发展和分化的最关键因素，我们将精力集中在（1）IL-12/IL-12/IL-12RBETA2途径的作用上IL-12/IL-12RBETA2途径，（3）Th2细胞因子在该途径上的下调作用，以及（4）IL-12/IL-12/IL-12RBETA2途径在揭示潜在的潜在自身免疫性效应T细胞中的作用。 我们已经证明，IL-18对Th1分化的主要作用是由于其直接上调IL-12受体表达的能力而介导的，从而增强了IL-12介导的信号传导。当微环境中IL-12的刺激性浓度略低于TH1发育所需的阈值时，IL-18对IL-12受体表达的增强对于分化外抗原或自身抗原特异性Th1细胞可能尤其重要。我们还证明，IL-10在IL-12/IL-12RBETA2途径的调节中起着至关重要的作用。将IL-10添加到引发T细胞的培养物中，强烈抑制了IL-12RBETA2亚基的上调。 据推测，IL-10作用于这些培养物中抗原呈现的细胞以抑制IL-12的产生，但尚未排除IL-10对响应T细胞的直接影响。 我们确定在调节IL-12受体表达中很重要的其他主要因素是通过在抗原特异性T细胞中传递给抗原特异性T细胞的共同信号，这是通过在T细胞上与CD28的CD80/CD86分子相互作用。我们已经证明，生产IL-2和IL-12所必需的，并且这两种细胞因子对于T细胞表达IL-12受体并分化为致病性自动反应性T细胞的能力至关重要。我们通过将CpG寡核苷酸代替弗洛德的完整辅助物来开发出一种新型的诱导EAE系统。 CpG寡核酸是有效的佐剂，但是这些研究的结果还表明，它们可能会触发易感个体的自身免疫性疾病。