omtriptolide and Graft-vs-Host-Disease

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).. PG490-88 was administrated into recipients in a model (B10.D2 [H2d, Mls-2b, Mls-3b]-->BALB/c [H2d, Mls-2a, Mls-3a]) of lethal GVHD. Tolerance was evaluated by transplantation of neonatal hearts. The mechanisms of tolerance were studied.. 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.. 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.

Topics: Animals; Animals, Newborn; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Diterpenes; Female; Graft Survival; Graft vs Host Disease; Heart Transplantation; Immunosuppression Therapy; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Models, Animal; Organ Size; Phytotherapy; T-Lymphocyte Subsets; Time Factors; Transplantation, Homologous

PG490-88 is a water soluble, semisynthetic derivative of a novel compound PG490 (triptolide) purified from the Chinese herb Tripterygium Wilfordii Hook F.. 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.. 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+Vbeta3+ and CD8+Vbeta3+ T cell (alloreactive T cells in this model) expansion in the spleen by 64.09 and 34.02%, respectively, at the time when Vbeta3+ 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.. 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.

Topics: Animals; Diterpenes; Graft vs Host Disease; Immunosuppressive Agents; Isoantibodies; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Prodrugs; T-Lymphocytes