SYNTHETIC CROSSLINKERS OF RECEPTORS ON T CELLS

描述（改编自研究者摘要）：不良免疫 反应导致许多疾病。 缺乏有益的反应可能是 为许多其他人负责。 尽管在揭示 免疫系统的工作，我们在很大程度上依赖于广谱免疫抑制剂， 治疗不需要的反应和疫苗，以引发有益的反应。 新药剂 抑制有害的反应和增强有益的反应。 抗原识别与T细胞免疫应答机制的研究进展 激活表明能够交联特定受体的试剂 在T细胞上有很大的潜力来操纵免疫 反应 研究人员此前曾开发出高亲和力 CD26抑制剂，一种在CD4+细胞上发现的共刺激分子。 这 该申请提出利用这些抑制剂的高亲和力， 构建能够交联T细胞上特异性受体的多价试剂， 细胞，并测试其对T细胞功能的影响。 具体目标是： 1. 构建和表征能够交联CD 26和CD 26的化学试剂 来测试它们对T细胞功能的影响 这包括确定 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共刺激 幼稚T细胞以及它们是否可以替代B7对CD28的共刺激。 2. 为了构建和表征能够使CD26与 T细胞受体（TCR），以测试它们对T细胞功能的作用，以及 研究其作用机制。 能够共刺激T细胞，特别是幼稚T细胞的化学试剂， 作为合成佐剂用于疫苗开发的潜力， 提高新疫苗的安全性、有效性和速度， 开发 它们也可能被证明有助于增强免疫功能， 免疫缺陷疾病。 目标2可能提供一种通用方法， 增强或抑制特异性免疫反应，因此具有非常 广泛的健康意义。 这可能会导致更好的代理人， 治疗自身免疫性，因此对多种免疫性疾病具有潜在意义。 硬化症、关节炎和其他自身免疫性疾病，以及用于预防 移植器官的排斥反应 Aim 2可能会带来更好的方法， 从而具有潜在的应用， 缺乏有效疫苗的疾病，如肺结核， 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.