Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8+ memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2highCD8+ effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2 high cells including CD8+ TEM while sparing naïve CD8+ T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2high T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach. The authors show that alefacept significantly delays the expansion of CD2high memory T cells and promotes mixed chimerism and immunosuppression-free renal allograft survival in a primate model of delayed tolerance induction.
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