T cells play an important role in triggering the immune rejection of transplanted tissues. Significant efforts have been made to explore the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for life-long immunosuppressive therapy. Non-human primates are ideal animal models to test the immune-target tolerance for successful allotransplantation. Recent work done in Dr. Judy Thomas' laboratory has shown that the treatment of rhesus monkeys with anti-CD3-Immunotoxin (IT) resulted in profound T cell depletion, and induced stable tolerance without chronic allograft rejection for up to 3 years. While IT protocol clearly facilitates inducing the tolerance of allografts in macaques, important questions remain to be explored regarding fundamental T cell immunology and future application of the IT strategy to cadaveric transplant tolerance induction in humans. Based on the result demonstrating the ability of macaque repertoires in the macaques depleted of T cells can be restored to various degrees through the thymic-dependent and/or-independent pathways. We also hypothesize that alloantigens may drive the dominant T cell response that is relevant to allograft rejection or tolerance. To test these hypothesis, we will: I. Determine restoration of macaque TCR repertoires following T cell depletion. A. Determine restoration of TCR repertoires in juvenile macaques following T cell depletion. B. Determine restoration of TCR repertoires in old macaques following T cell depletion. II. Assess TCR-based thymic output in young and old macaques after T cell depletion. III. Determine the TCR repertoire in rejected kidney allografts of macaque recipients.
Showing the most recent 10 out of 26 publications
