The role of costimulatory molecules in uveitis

描述：共刺激分子的鉴定为调节免疫反应的分子机制提供了重要的见解，更重要的是，为自身免疫或肿瘤免疫治疗的几种新方法提供了重要的见解。越来越多的已知T细胞共刺激途径，加上免疫反应的动态性质，表明可能存在调节幼稚T细胞、效应T细胞和记忆T细胞反应的共刺激分子的功能层次。在目前拨款的支持下，我的实验室在了解共刺激分子在自身免疫性葡萄膜炎中的作用方面取得了重大进展。然而，我们的研究也提出了两个重要的问题：(1)为什么效应性葡萄膜炎T细胞比初始T细胞对共刺激分子阻滞剂的治疗更具抵抗力？(2)致病T细胞和调节性T细胞是否依赖不同的共刺激作用，从而可以确定一种特定的治疗方案来最大限度地抑制致病反应，同时对调节性T细胞激活的抑制作用最小？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比防止疾病发展的免疫疗法更重要，因为在患者去看医生的时候疾病已经开始了。因此，这项建议的长期目标是探索抑制已经激活的自身反应效应器T细胞的治疗方法。因此，我们将确定CD28/B7共刺激分子是否对葡萄膜原性T细胞的致病作用起关键作用，特别是：(1)效应T细胞和调节性T细胞在时间和数量上是否使用CD28/B7不同，以及阻断联合共刺激分子是否有利于正在进行的自身免疫性疾病的治疗；(2)我们是否能够找到对调节性T细胞活性影响有限的治疗方案，同时抑制致病活性；以及(3)对自身反应性T细胞的共刺激作用和眼部炎症的联合治疗是否可以更好地控制正在发生的疾病。为了提供一个能够更好地理解复发性葡萄膜炎发病机制的工作模型，我们在大鼠和小鼠上建立了慢性复发性葡萄膜炎模型。这些研究应该提供对导致疾病进展的致病机制的洞察，并有助于开发针对这种毁灭性疾病的补充疗法。

DESCRIPTION: 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.