Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model
PG490-88 is a semisyntheüc derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium Wilfordii Hook F). Host specific tolerance in vivo was demonstrated in PG490-88-treated BALB/c recipients (H2d, Mls-21, Mls-3") of bone marrow and spleen cells from B10.D2 mice (H2d, Mls-2", Mls-3") by transplantation of recipient or third party neonatal hearts into the pinna of the ears of recipients. The mechanisms of tolerance were studied further in this model. Since all Vβ3 T cells, which recognize the superantigens Mls-2 and Mls-3 and are present in donor B l O.D2 mice but not in recipient BALB/c mice, are activated and cause GVHD in BALB/c recipients, all Vβ3+ T cells are considered host reactive T cells in this model. Therefore, the roles of clonal deletion/anergy can be studied by following the fate of Vβ3 T cells. As shown in the figure, significant numbers of host reactive Vβ3 CD4+ T cells (3.56+1.66 %), which were significant higher than those in normal BALB/c mice (0.27±0.12, P<0.0001) and were comparable with those in normal B l O.D2 mice (6.18±0.51, P>0.05), were present in PG490-88-treated mice. Simulât results were obtained on CD8 T cells. t r(Figure Presented) 6 NomulBALWc 5 OT-d«plet»d bone marrow T 4 OPG49M8 I I 3 ONwrnil BIO D2 BH These results suggest that clonal deletion was not responsible for the observed tolerance induced by PG490-88, In contrast, Vβ3- T cells were completely deleted in the control Tdepleted bone marrow recipients. Vβ3 T cells obtained from PG490-88-treated recipients which were demonstrated to be tolerant to host antigens proliferated normally in response to T cell receptor crosslinking mediated by anti-CD3 antibody. Neither antigen specific nor antigen nonspecific suppressor cells were found in PG490-88-treated mice. Taken together, the host specific tolerance induced by PG490-88 in a murine BMT model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 appears to lead to allotolerance through the induction of a state of antigen specific anergy of the responding T cells.
Chen, BJ; Cui, X; Fidler, JM; Chao, NJ
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