SYNTHETIC CROSSLINKERS OF RECEPTORS ON T CELLS

描述(改编自调查者摘要)：不想要的免疫 反应会导致许多疾病。缺乏有益的反应可能是 被指责为其他许多人的责任。尽管在解开这个问题上取得了巨大进展 免疫系统起作用，我们在很大程度上依赖广谱免疫抑制剂来 治疗不想要的反应和疫苗，以获得有益的反应。新代理商 为了抑制有害的反应，增强有益的反应是必要的。 最近阐明的抗原识别和T细胞的机制 激活表明，能够使特定受体交联的试剂 在T细胞上有很大的潜力来操纵免疫 回应。研究人员之前已经发展出高度亲和力 CD26的抑制剂，CD26是一种存在于CD4+细胞上的共刺激分子。这 应用程序建议利用这些抑制剂的高亲和力来 构建能够交联T细胞表面特异性受体的多价体 细胞，并测试它们对T细胞功能的影响。具体目标是： 1.构建和鉴定能够使CD26和CD26相互作用的化学试剂。 测试它们对T细胞功能的影响。这包括确定 对交联、共刺激和内化的最低要求。 它还包括确定化学交联剂是否可以协同刺激 幼稚T细胞以及它们是否可以替代CD28的B7共刺激。 2.构建和鉴定能够将CD26与 T细胞受体(TCR)，以测试它们对T细胞功能的影响，并 研究它们的作用机制。 能够共刺激T细胞，特别是幼稚T细胞的化学试剂有 在疫苗开发中用作合成佐剂的潜力，并可能 提高新疫苗的安全性、有效性和速度 发展起来的。它们也可能被证明对提高人的免疫功能很有用 免疫缺陷疾病。AIM 2可以提供一种通用的方法 增强或抑制特定的免疫反应，因此具有非常 与健康相关的广泛意义。这可能会带来更好的代理 治疗自身免疫因此对多发性硬化具有潜在的意义 硬化症、关节炎和其他自身免疫性疾病，以及预防 移植器官的排斥反应。目标2可以带来更好的方法来 引发特定的免疫反应，因此有潜在的应用 缺乏有效疫苗的疾病，如结核病， 疟疾和艾滋病。

DESCRIPTION (Adapted from Investigator's abstract): Unwanted immune responses cause many diseases. The lack of beneficial responses can be blamed for many others. Despite enormous progress in unraveling how the immune system works, we rely largely on broad-spectrum immunosuppressants to treat unwanted responses and vaccines to elicit beneficial ones. New agents for suppressing harmful, and for enhancing beneficial responses are needed. The recently elucidated mechanisms of antigen recognition and T-cell activation have suggested that agents able to crosslink specific receptors on the T-cell have substantial potential for manipulating the immune response. The investigator has previously developed high affinity inhibitors of CD26, a costimulatory molecule found on CD4+ cells. This application proposes to exploit the high affinity of these inhibitors to construct multivalent agents able to crosslink specific receptors on T cells, and to test their effects on T-cell function. The specific aims are: 1. To construct and characterize chemical agents able to crosslink CD26 and to test their effect on T-cell function. This includes determining the minimal requirements for crosslinking, costimulation, and internalization. It also includes determining if the chemical crosslinkers can costimulate naive T cells and if they can substitute for B7 costimulation of CD28. 2. To construct and characterize agents able to crosslink CD26 with the T-cell receptor (TCR), to test their effects on T-cell function, and to investigate their mechanism of action. Chemical agents able to costimulate T cells, especially naive T-cells, have potential for use in vaccine development as synthetic adjuvants, and may improve the safety, efficacy, and speed with which new vaccines can be developed. They may also prove useful for boosting immune function in immunodeficiency diseases. Aim 2 may provide a general method for enhancing, or suppressing specific immune responses and therefore have very broad health related significance. It could lead to better agents for treating autoimmunity and thus has potential significance for multiple sclerosis, arthritis, and other autoimmune diseases, and for preventing rejection of transplanted organs. Aim 2 could lead to better methods for eliciting specific immune responses and thus has potential application to diseases for which effective vaccines are lacking such as tuberculosis, malaria and AIDS.