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Intrathymic (IT) administration of antigen when combined with peripheral T-cell depletion has been shown to induce operational tolerance in a wide range of experimental protocols. IT injection of pancreatic islets has been demonstrated not only to induce tolerance to alloantigen but also to prevent the development of autoimmune β-cell destruction in models of type I diabetes. However, little is known about the mechanisms involved in tolerance induction after IT islet injection.A protocol for the induction of tolerance to fully allogeneic (C57BL/10; H2b) peripheral islet allografts was developed in CBA/Ca (H2k) recipients by the IT injection of allogeneic islets combined with depletion of peripheral CD4+ T cells. This protocol was based upon our own data and those of others showing that CD4+ T cells play a critical role in islet allograft rejection. Using this regimen, donor-type peripheral islet allografts survived indefinitely whereas third-party grafts were rejected. To determine the fate of alloreactive thymocytes that recognize donor major histocompatibility complex antigens via the direct pathway, T-cell receptor transgenic mice specific for the major histocompatibility complex class I molecule Kb (BM3 and DES) were used as recipients. IT injection of islets expressing the specific alloantigen Kb resulted in clonal deletion of alloreactive thymocytes in T-cell receptor transgenic recipients. No evidence of clonal inactivation in the residual peripheral alloreactive population was observed in this system.IT injection of allogeneic islets and concomitant CD4+ T-cell depletion is able to induce donor-specific unresponsiveness. One mechanism responsible for this unresponsiveness is the clonal deletion of thymocytes that recognize alloantigen via the direct pathway.