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Taken together, these results reveal that stimulation of recipient NKT cells with alpha-gal prevents BM engraftment and tolerance induction in nonmyeloablative BMT regimens employing either CB or in vivo TCD. Mechanisms responsible for the induction of tolerance early after CB-based BMT differ substantially from those for the maintenance of tolerance late after BMT [12]. We thus investigated the effect of alpha-gal when administered several months after BMT and CB (3?Gy TBI) to mice with stable levels of mixed chimerism and viable donor skin grafts. Administration of two doses of alpha-gal (5?��g i.p. at days +70 and +77 after BMT) to established chimeras (n?=?6) did not cause a detectable decline in chimerism levels (Fig.?3e) and had no effect on skin graft survival (Table?2). Thus, http://www.selleckchem.com/products/Y-27632.html activation of NKT cells at a late time point �C when established tolerance is maintained primarily through central deletion in this model [12] �C does not break tolerance. Deletion of donor-reactive T cells was shown to be a critical mechanism during the early period of tolerance induction immediately after nonmyeloablative BMT with CB [8,12,16]. We therefore evaluated the deletion of donor-reactive T cells by following V��11+ and V��5+ CD4+ cells that recognize endogenous superantigens presented by donor but not recipient MHC and that serve as a surrogate http://www.selleckchem.com/products/chir-99021-ct99021-hcl.html population of donor-reactive T cells [8,16]. Deletion correlated with chimerism, as observed previously [8,16]. Deletion of donor-reactive T cells was also observed in NKT KO recipients (KOKO, 3?Gy TBI, CB) (e.g. 2.67% V��11+ CD4 vs. 3.93% for na?ve B6, P? http://www.selleck.cn/products/BKM-120.html time of BMT occurs also in the absence of recipient T cells, and thus rule out T cells as the critical cell population mediating BM rejection. To investigate whether stimulation of NKT cells prevents chimerism and tolerance via activation of NK cells, we administered alpha-gal to recipients depleted of NK cells and T cells (TCD?+?anti-asialo GM1 on days 0, 4, 8, 12, 3?Gy TBI). Anti-asialo GM1 has been shown to deplete NK but not NKT cells [47,48]. As a control, alpha-gal was given to recipients depleted of both NK and NKT cells (CB?+?anti-NK1.1 mAb, 3?Gy).