Mechanisms of Peripheral Tolerance Induction

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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.