The role of costimulatory molecules in uveitis

共刺激分子在葡萄膜炎中的作用

• 批准号: 7752504
• 负责人: HUI SHAO
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752504
• 关键词: Acute; Animals; Anti-Inflammatory Agents; Antibodies; Autoimmune Diseases; Autoimmune Process; CTLA4-Ig; Cells; Chronic; Clinical Treatment; Combined Modality Therapy; Complex; Data; Development; Disease; Disease Progression; Disease model; Disease remission; Dose; Environmental Risk Factor; Eye; Generations; Genetic; Goals; Grant; Guanine Nucleotide Dissociation Inhibitors; Human; Immune response; Immunotherapy; Inflammation; Inflammatory; LTB4R gene; Laboratories; Leukotriene B4; Ligation; Lymphoid; MHC antigen; Mediating; Modeling; Molecular; Mus; Nature; Onset of illness; Pathogenesis; Pathway interactions; Patients; Pattern; Phase; Rattus; Reaction; Recruitment Activity; Recurrence; Regimen; Regulation; Regulatory T-Lymphocyte; Relapse; Research Personnel; Resistance; Rodent; Role; Signal Transduction; Study models; T memory cell; T-Cell Activation; T-Lymphocyte; Therapeutic; Therapeutic Effect; Time; Treatment Protocols; Uveitis; Visit; Work; autoimmune uveitis; autoreactive T cell; cell motility; chemokine; cytokine; disorder control; human disease; insight; novel strategies; prevent; programs; protective effect; receptor; response; treatment effect; tumor

The identification of costimulatory molecules has provided important insights into molecular mechanisms for the regulation of the immune response, and,more importantly, into several novel approaches for autoimmune or tumor immunotherapy. The growing number of known T cell costimulatory pathways, together with the dynamic nature of the immune response, suggests that there may be a functional hierarchy of costimulatory molecules regulating responses of naive, effector, and memory T cells. With the support of the current grant, my laboratory has made significant progress in understanding the role of costimulatory molecules in autoimmune uveitis. However, our studies have also raised two important questions: (1) why are effector uveitogenic T cells more resistant than naive T cells to treatment by costimulatory molecule blockers? (2) Do pathogenic and regulatory T cells rely on different costimulation, so that a specific treatment regimen can be identified to maximally suppress the pathogenic response with a minimal inhibitory effect on regulatory T cell activation? For human disease, immunotherapies that can interfere with an ongoing autoimmune disease are more important than those preventing the development of disease, since disease has already started by the time the patient visits the doctor. Thus, the long-term goal of this proposal is to explore therapeutic approaches inhibiting already activated autoreactive effector T cells. We will therefore determine whether CD28/B7 costimulatory molecules are crucial for the pathogenic effect of uveitogenic T cells, specifically: (1) whether effector and regulatory T cells use CD28/B7 differently in terms of time and quantity and whether blockade of a combination of costimulatory molecules favors the treatment of ongoing autoimmune disease; (2) whether we can identify therapeutic regimens that have a limited impact on regulatory T cell activity, while inhibiting pathogenic activity; and (3) whether a combined treatment acting on costimulation of autoreactive T cell and ocular inflammation can provide better control of ongoing disease. To provide a working model that will allow better understanding of the pathogenesis of recurrent uveitis, we have established chronic, recurrent models in the rat and mouse. These studies should provide insights into the pathogenic mechanism leading to disease progression and help in the development of supplementary therapies for this devastating disease.

共刺激分子的鉴定为了解其分子机制提供了重要的见解。 免疫反应的调节，更重要的是，几种针对自身免疫的新方法 或肿瘤免疫治疗。已知 T 细胞共刺激途径的数量不断增加，以及 免疫反应的动态性质表明，可能存在共刺激的功能层次 调节初始 T 细胞、效应 T 细胞和记忆 T 细胞反应的分子。在当前拨款的支持下， 我的实验室在理解共刺激分子的作用方面取得了重大进展 自身免疫性葡萄膜炎。然而，我们的研究也提出了两个重要的问题：（1）为什么效应子 致葡萄膜的 T 细胞比初始 T 细胞对共刺激分子阻断剂的治疗具有更强的抵抗力？ (2) 做 致病性T细胞和调节性T细胞依赖于不同的共刺激，因此可以制定特定的治疗方案 经鉴定可最大程度地抑制致病反应，同时对调节性 T 细胞的抑制作用最小 激活？ 对于人类疾病，可以干扰正在进行的自身免疫性疾病的免疫疗法更有效 比预防疾病发展更重要，因为疾病在出现时就已经开始了 病人去看医生。因此，该提案的长期目标是探索治疗方法 抑制已经激活的自身反应性效应 T 细胞。因此，我们将确定 CD28/B7 是否 共刺激分子对于葡萄膜T细胞的致病作用至关重要，具体来说：（1）是否 效应T细胞和调节性T细胞使用CD28/B7的时间和数量以及是否阻断CD28/B7都不同。 共刺激分子的组合有利于治疗正在进行的自身免疫性疾病； (2) 我们是否 可以确定对调节性 T 细胞活性影响有限的治疗方案，同时抑制 致病活性； (3)是否联合治疗作用于自身反应性T细胞的共刺激和 眼部炎症可以更好地控制正在进行的疾病。提供一个工作模型，允许 为了更好地了解复发性葡萄膜炎的发病机制，我们建立了慢性、复发性模型 大鼠和小鼠。这些研究应该提供对导致疾病的致病机制的见解 进展并帮助开发针对这种破坏性疾病的补充疗法。