Mechanisms of Peripheral Tolerance Induction

描述(由申请人提供)：免疫耐受的诱导对于预防自身反应性和随后的自身免疫性疾病至关重要。尽管过去已经开发了几种系统来评估外周耐受性，但其发生机制在很大程度上仍不清楚。本提案中描述的研究的目标是了解耐受诱导的基本机制。最初，将评估诱导外周耐受所需的抗原持续时间。这将使用一种令人兴奋的可诱导表达的新系统进行分析，在该系统中，模型抗原鸡卵清蛋白(OVA)可以直接控制，该系统包含I类H-2b限制性表位Ova257-264(SIINFEKL)。因此，一旦建立耐受，就有可能在时间上调节OVA的表达，并确定耐受诱导的抗原表达持续时间和耐受的寿命。此外，我们将通过产生额外的转基因动物来扩展这个模型，这些转基因动物表达改变的Ova257-264多肽配体，但刺激T细胞的能力降低。这将使我们能够评估信号的强度将如何影响外周耐受的类型和程度。总之，这些研究将促进更好地了解外周耐受、对发育和组织特异性抗原的诱导以及自身免疫的发展。

DESCRIPTION (provided by applicant): The induction of immune tolerance is critical for the prevention of autoreactivity and subsequent autoimmune disease. Although several systems have been developed in the past to evaluate peripheral tolerance, the mechanisms by which this occurs remain largely undefined. The goal of the studies described in this proposal aim to understand the basic mechanisms of tolerance induction. Initially, the duration of antigen required to induce peripheral tolerance will be evaluated. This will be analyzed using an exciting new system of inducible expression, in which the model antigen, chicken ovalbumin (Ova), which contains the class I H- 2b restricted epitope, Ova257-264 (SIINFEKL), can be directly controlled. Thus it will be possible to temporally regulate Ova expression and determine the duration of antigen expression for tolerance induction as well as the longevity of tolerance once established. Further, we will expand on this model by generating additional transgenic animals that express altered peptide ligands of Ova257-264 with reduced abilities to stimulate T cells. This will allow us to evaluate how the strength of signal will influence the type and extent of peripheral tolerance. Together these studies will promote a better understanding of peripheral tolerance induction to developmentally and tissue specific antigens and the development of autoimmunity.