Mechanisms of Peripheral Tolerance Induction

描述（由申请人提供）：诱导免疫耐受对于预防自身反应性和随后的自身免疫性疾病至关重要。虽然过去已经开发了几个系统来评估外周耐受性，但发生这种情况的机制在很大程度上仍然不明确。本研究的目的是了解耐受性诱导的基本机制。首先，将评估诱导外周耐受所需抗原的持续时间。这将使用一个令人兴奋的诱导表达新系统进行分析，在该系统中，模型抗原，鸡卵白蛋白（Ova），包含I类H- 2b限制性表位，Ova257-264 (SIINFEKL)，可以直接控制。因此，有可能暂时调节卵子的表达，并确定抗原表达诱导耐受的持续时间，以及一旦建立耐受的寿命。此外，我们将通过产生额外的转基因动物来扩展该模型，这些转基因动物表达改变的Ova257-264肽配体，降低了刺激T细胞的能力。这将使我们能够评估信号强度如何影响外围容差的类型和程度。总之，这些研究将促进更好地理解外周耐受诱导对发育和组织特异性抗原和自身免疫的发展。

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.