Hydrophobic extracts of a Chinese herb (CMX-13) exhibit potent immunosuppressive properties and prevent acute rejection in a highly histoincompatiblemodel of rat lung transplantation

Background The potential of higher plants as sources for new immunosuppress ive medications is well recognized. In our experiments we investigated the immunosuppressive effect of a highly refined and potent extract of a Chines e herbal preparation, CMX-13, on inhibiting acute allograft rejection (AR) in a highly histoincompatible rat lung transplant model, BN-->LEW, and on l ymphocyte activation and cytokine gene expression in vitro. Methods. Left lung transplants: the control group (group 1) received only d imethylsulfoxide (DMSO) which is the solvent for CMX-13, Group 2 received i ntramuscular cyclosporin A (CsA, 25 mg/kg) on day 2 posttransplant. Group 3 and 4 received i.p. CMX-13 (0.5 mg/day, low dose and 5 mg/day, high dose, respectively) on day 1, 2, and 3 posttransplant, All animals were killed on day 6 posttransplant, Several pathological categories of inflammation were examined. In vitro experiments: rat spleen cells were incubated with Con A or irradiated stimulator cells with/without serial dilutions of CMX-13 or CsA Cell proliferation was measured by H-3-thymidine incorporation. mRNA ex pression of interleukin-2 and interferon-gamma was examined by reverse tran scriptase-polymerase chain reaction. Results. The severity of AR in animals receiving high dose CMX-13 was signi ficantly reduced (stage II, P<0.05) compared with controls (stage IV). Sign ificant differences were also seen when more specific parameters of inflamm ation were examined (necrosis, 3 vs. 1.7+/-1.0, P<0.05; interalveolar hemor rhage, 6 vs. 3.0+/-0.9, P<0.05), The responses seen in the animals treated with high dose CMX-13 were similar to those in the CsA group, CMX-13 inhibi ted T cell proliferative responses induced by Con A and alloantigen stimula tion in a dose-dependent manner that were similar to CsA Interleukin-8, and interferon-<gamma> mRNA expression in Con A-stimulated spleen cells was no t inhibited by CMX-13 although CsA showed significant inhibition. Conclusions. 1) CMX-13 significantly reduces the stage of AR and parameters of inflammation in a highly histoincompatible rat lung transplant model. 2 ) CMX-13 has equal potency to CsA in the inhibition of Con A and alloantige n stimulated rat spleen cell proliferation. 3) CMX-13 showed no inhibitory effects on IL-2 and gamma -IFN mRNA expression, suggesting that its mechani sm of action is different from CsA 4) CMX-13 or derivatives may have potent ial utility as an immunosuppressive agent(s) in modulation of AR and manage ment of other inflammatory and immunological disorders.