MECHANISMS FOR PERIPHERAL INDUCTION OF T CELL TOLERANCE

T淋巴细胞必须通过快速增殖对特异性抗原作出反应 和分化以产生有效的免疫应答。 是 关键的是，这只发生在对外来抗原的反应中，因此， 抗原不诱导自身免疫应答。 T细胞自身耐受性 抗原是通过胸腺中的阴性选择获得的， 识别自身抗原的克隆。 此外，还建立了机制， 使外周中的成熟T细胞对抗原耐受。 这 该计划旨在解决胸腺细胞中这些机制的性质 和成熟的T细胞在分子和细胞水平上， 体外和体内模型。 CD4 + T细胞的外周耐受性是 在第一个项目和第二个项目中， 第三个项目正在检查I类限制性胸腺细胞 CD8 + T细胞的外周耐受性正在研究中。 第四个项目。 因此，该方案的四个项目审查了两个 主要类型的T细胞，CD4+细胞和CD8+细胞。 的 计划中的工作涉及各组织之间的广泛协作互动， 每个项目的调查员。 预计调查结果 在计划的研究中获得的将有助于更好的基础 了解如何避免自身免疫。 此外，本发明还提供了一种方法， 了解这些机制，因此能够操纵 他们，有可能有助于改善 移植和疾病治疗。 诱导机制 对自身抗原的耐受性也可诱导对外来抗原的耐受性 包括存在于肿瘤或病毒感染的细胞上的那些，导致 免疫系统无法产生保护性反应 最后， 使用确定的肽抗原诱导 保护性或治疗性免疫力，用于多种疾病， 目前的许多努力都集中在这方面。 然而，它正在成为 越来越清楚的是，必须非常谨慎地使用这些措施，因为它们 也可以诱导耐受性，这可能导致保护作用减弱， 可治愈的疾病 因此，更好地了解 机制，可以导致T细胞耐受性，如本研究所提出的， 它的影响远远超出了自身免疫性疾病。

T lymphocytes must respond to specific antigen by rapid proliferation and differentiation to mount an effective immune response. It is critical that this occur only in response to foreign antigen, so that self antigens do not induce autoimmune responses. T cell tolerance to self antigen is achieved by negative selection in the thymus to eliminate clones that recognize self antigen. In addition, mechanisms exist for rendering mature T cells in the periphery tolerant to antigens. This Program is addressing the nature of these mechanisms in thymocytes and mature T cells at the molecular and cellular levels using both in vitro and in vivo models. Peripheral tolerance in CD4 plus T cells is being studied in the first Project and second Project, negative selection of class I restricted thymocytes is being examined in the third Project and peripheral tolerance of CD8 plus T cells is being examined in the fourth Project. Thus, the four projects of the Program examine two major types of T cells, CD4 plus cells and CD8 plus cells. The planned work involves extensive collaborative interactions among the investigators of each project. It is anticipated that the findings obtained in the planned studies will contribute to a better fundamental understanding of how autoimmunity is avoided. In addition, understand of these mechanisms, and hence the ability to manipulate them, has the potential to contribute to improvements in transplantation and disease therapy. Mechanisms that induce tolerance to self antigens may also induce tolerance to foreign antigens including those present on tumors or virus-infected cells, resulting in the immune system failing to mount a protective response. Finally, there is great potential for using defined peptide antigens to induce protective or therapeutic immunity for a broad range of disease and much current effort is focusing on this. However, it is becoming increasingly clear that these must be used with great caution since they can also induce tolerance which may lead to lessened protection or excaccerbated disease. Thus, developing a better understanding of the mechanisms that can lead to T cell tolerance, as proposed in this Program, has implications well beyond autoimmune diseases.