Mechanisms for peripheral induction of T cell tolerance

外周诱导 T 细胞耐受的机制

• 批准号: 6763080
• 负责人: MATTHEW Franklin MESCHER
• 金额: $ 75.86万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763080
• 关键词: T lymphocyte; immune tolerance /unresponsiveness

T lymphocytes must respond to specific antigens 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 in part by negative selection in the thymus to eliminate clones that recognize self-antigen. This is not complete, however, and some self-reactive T cells escape into the periphery. Mechanisms exist for rendering these mature T cells tolerant to self antigens, but they are poorly understood. This Program is addressing the nature of these mechanisms in mature T cells at the molecular and cellular levels using both in vitro and in vivo models. 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, understanding 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 diseases 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 that may lead to lessened protection or exacerbated 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.

T淋巴细胞必须通过快速增殖和分化对特异性抗原作出反应，以产生有效的免疫应答。关键的是，这只发生在对外来抗原的反应中，这样自身抗原就不会诱导自身免疫反应。T细胞对自身抗原的耐受性部分是通过胸腺中的阴性选择来消除识别自身抗原的克隆而实现的。然而，这并不完全，一些自身反应性T细胞逃逸到外周。存在使这些成熟T细胞耐受自身抗原的机制，但对它们知之甚少。该计划正在使用体外和体内模型在分子和细胞水平上解决成熟T细胞中这些机制的性质。预计在计划的研究中获得的结果将有助于更好地了解如何避免自身免疫。此外，了解这些机制，并因此能够操纵它们，有可能有助于改善移植和疾病治疗。诱导对自身抗原的耐受性的机制也可以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抗原，导致免疫系统不能产生保护性应答。最后，使用确定的肽抗原诱导针对广泛疾病的保护性或治疗性免疫具有巨大潜力，目前的许多努力都集中在这方面。然而，越来越清楚的是，必须非常谨慎地使用这些药物，因为它们也可能引起耐受性，从而可能导致保护作用减弱或疾病加重。因此，如本计划中所提出的，更好地理解可能导致T细胞耐受的机制，其意义远远超出了自身免疫性疾病。