Acquired thymic tolerance appears to play a key role in the suppression of autoreactive and alloreactive T cells through the export of immunoregulatory thymocytes (THYreg) to the periphery. We have recently demonstrated that acquired thymic tolerance mediated by NKT cells can be induced by intracameral (i.c.) injection of foreign or autoantigens into the anterior chamber of the eye. We have also demonstrated that the afferent limb of this immunoregulatory loop is mediated by F4/80+ regulatory APCs that appear in the blood shortly after i.c.-injection of antigen. We therefore postulate that APCreg (presumably immature dendritic cells induce anterior chamber-associated immune deviation (ACAID) by transporting antigen to the thymus and inducing the formation and export of THYreg. As APCreg can also be generated ex vivo in the presence of antigen and TGF_or other cytokines, we further postulate that it should be possible to induce auto- or alloantigen-specific acquired thymic tolerance on demand by i.v. infusion of APCreg generated ex vivo from autologous (or syngeneic) APCs in blood or bone marrow. To test these hypotheses, the F4/80+ APCs from blood of i.c.-injected mice will be characterized phenotypically, their ability to migrate to thymus will be determined after labeling with fluorescent tracers, and a series of protocols for generating similar APCreg ex vivo will be tested and optimized. In addition, the ability of acquired thymic tolerance to prevent or ameliorate murine EAE, IDDM and skin allograft rejection will be confirmed by i.t. and i.c. injection of autoantigens or alloantigens. The role of APCreg in this process will then be tested by i.v. transfer of in vivo-generated APCreg from blood of i.c.-injected donors; and by i.v. transfer of ex vivo-generated APCreg from blood, BM or peritoneal exudate of naive donors. Success in these experiments would not only document the ability of APCreg to induce acquired thymic tolerance, but would demonstrate potential clinical utility of ex vivo-generated APCreg in autoimmunity and allotransplantation.
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