Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model

Background. PG490-88, a semisynthetic derivative of a novel compound PG490 (triptolide) purified from a Chinese herb (Tripterygium wilfordii Hook F), is effective in prevention of murine graft-versus-host disease (GVHD). Methods. PG490-88 was administrated into recipients in a model (B10.D2 [H2(d), Mls-2(b), Mls-3(b)] --> BALB/c [H2(d), Mls-2(a), Mls-3(a)]) of lethal GVHD. Tolerance was evaluated by transplantation of neonatal hearts. The mechanisms of tolerance were studied. Results. Host-specific tolerance was established in PG490-88-treated BALB/c recipients. Significant numbers of host reactive Vbeta3(+) T cells (3.56 +/- 1.66% among CD4, 4.06 +/- 1.62% among CD8, P<0.0001 vs. normal BALB/c mice, P>0.05 vs. normal B10.D2 mice) were present in PG490-88-treated mice, suggesting that clonal deletion was not responsible for the observed tolerance. Spleen cells from PG490-88-treated mice could not respond to the host antigens measured by a popliteal lymph node weight gain assay. The unresponsiveness was unable to be overcome by supplementation of exogenous interleukin (IL)-2. Tolerant Vbeta3(+) T cells obtained from PG490-88-treated mice proliferated normally to nonantigen-specific T cell receptor cross-linking. Neither antigen-specific nor nonantigen-specific suppressor cells were found in PG490-88-treated mice. The tolerant mice produced IL-4 rather than IL-2 and interferon (IFN)-gamma. Conclusions. Host-specific tolerance induced by PG490-88 in a murine bone marrow transplantation model is not due to deletion of alloreactive cells. Moreover, suppressor cells are not involved in the maintenance of tolerance. Rather, PG490-88 seems to lead to allogeneic tolerance either through the induction of a state of antigen-specific anergy of the responding T cells or through the induction of T-helper cell, type II (TH2) responses.