Prevention of graft-versus-host disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion

Background. PG490-88 is a water soluble, semisynthetic derivative of a novel compound PG490 (triptolide): purified from the Chinese herb Tripterygium Wilfordii Hook F. Methods. PG490-88 was administrated into recipient mice in a model (B10.D2-->BALB/c) of lethal graft-versus-host disease (GVHD) to study the effects of PG490-88 on GVHD and on the various steps involved in the pathological course of GVHD. Results. Injection of PG490-88 i.p. at a dose of 0.535 mg/kg/day for the first 3 weeks after transplantation protected all the recipients from developing GVHD up to 100 days after transplantation. PG490-88 inhibited in vivo both CD4(+)V beta3(+) and CD8(+)V beta3(+) T cell (alloreactive T cells in this model) expansion in the spleen by 64.09 and 34.02%, respectively, at the time when V beta3(+) cell expansion was in the logarithmic phase (day 3 after transplantation). Intracellular cytokine staining without further in vitro activation demonstrated 47.42% inhibition of IL-2 production among CD4(+) spleen cells in PG490-88-treated mice as compared to GVHD control on day 3 after transplantation. In contrast, CD25 (alpha chain of interleukin-2 receptor) expression did not differ. Conclusions. PG490-88 is highly effective in prevention of murine GVHD. The immunosuppressive effect of PG490-88 is mediated by inhibition of alloreactive T cell expansion through interleukin-2 production.