The role of costimulatory molecules in uveitis

共刺激分子的鉴定为研究共刺激的分子机制提供了重要的见解。 免疫反应的调节，更重要的是，进入几种新的方法， 或肿瘤免疫疗法。越来越多的已知T细胞共刺激途径，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细胞应答的分子。在现有赠款的支持下， 我的实验室在理解共刺激分子在 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 葡萄膜原性T细胞比幼稚T细胞对共刺激分子阻断剂的治疗更具抗性？(2)做 致病性和调节性T细胞依赖于不同的共刺激，因此可以 被鉴定为最大限度地抑制致病性应答，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多 这比预防疾病的发展更重要，因为疾病已经开始的时候， 病人去看医生。因此，本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CD 28/B7是否 共刺激分子对于葡萄膜原性T细胞的致病作用是至关重要的，具体地说：（1）是否 效应性和调节性T细胞在时间和数量上使用CD 28/B7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， 致病活性;和（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， 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葡萄膜炎模型， 老鼠和老鼠这些研究应能提供有关导致疾病的致病机制的见解 并帮助开发这种毁灭性疾病的补充疗法。

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.