title: Hydrophobic extracts of a Chinese herb (CMX-13) exhibit potent immunosuppressive properties and prevent acute rejection in a highly histoincompatible model of rat lung transplantation.
abstract: BACKGROUND
  The potential of higher plants as sources for new immunosuppressive medications is well recognized. In our experiments we investigated the immunosuppressive effect of a highly refined and potent extract of a Chinese herbal preparation, CMX-13, on inhibiting acute allograft rejection (AR) in a highly histoincompatible rat lung transplant model, BN-->LEW, and on lymphocyte activation and cytokine gene expression in vitro.
  
  
  METHODS
  Left lung transplants: the control group (group 1) received only dimethylsulfoxide (DMSO) which is the solvent for CMX-13. Group 2 received intramuscular 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 3H-thymidine incorporation. mRNA expression of interleukin-2 and interferon-gamma was examined by reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  The severity of AR in animals receiving high dose CMX-13 was significantly reduced (stage II, P<0.05) compared with controls (stage IV). Significant differences were also seen when more specific parameters of inflammation were examined (necrosis, 0 vs. 1.7+/-1.0, P<0.05; interalveolar hemorrhage, 0 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 inhibited T cell proliferative responses induced by Con A and alloantigen stimulation in a dose-dependent manner that were similar to CsA. Interleukin-2, and interferon-gamma mRNA expression in Con A-stimulated spleen cells was not 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 alloantigen stimulated rat spleen cell proliferation. 3) CMX-13 showed no inhibitory effects on IL-2 and gamma-IFN mRNA expression, suggesting that its mechanism of action is different from CsA. 4) CMX-13 or derivatives may have potential utility as an immunosuppressive agent(s) in modulation of AR and management of other inflammatory and immunological disorders.
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA 90048, USA.
authors.forename: X J
authors.initials: XJ
authors.lastname: Zuo
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Toyoda
authors.forename: H K
authors.initials: HK
authors.lastname: Yap
authors.forename: A
authors.initials: A
authors.lastname: Marchevsky
authors.forename: J M
authors.initials: JM
authors.lastname: Matloff
authors.forename: S C
authors.initials: SC
authors.lastname: Jordan
mesh_terms: D000208:Acute Disease; D000818:Animals; D002455:Cell Division; D016572:Cyclosporine / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control*; D006648:Histocompatibility; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013223:Statistics as Topic; D014184:Transplantation, Homologous / Q000473:pathology
chemical_list: C112842:CMX 13; D004365:Drugs, Chinese Herbal; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012313:RNA; D007371:Interferon-gamma; D016572:Cyclosporine