title: The phytoestrogen biochaninA weakens acute cardiac allograft rejection without affecting the reproductive system.
abstract: BACKGROUND
  Since the two estrogen receptor isoforms ERalpha and ERbeta have been discovered it is unclear by which receptor immunomodulating or feminizing effects are mediated. In this study, the effects of the two selective ERalpha- and ERbeta-agonists ethinylestradiol and biochaninA, respectively, on acute cardiac allograft rejection, uterus growth, vascular adhesion molecule and MHC-II expression were investigated and verified using in vitro cell culture.
  
  
  METHODS
  Heterotopic Lewis to ovarectomized F344 cardiac transplantations were performed. The study groups received supplemental biochaninA or ethinylestradiol, the control group received no treatment. Grafts and uteri were harvested on the fifth postoperative day and blood was taken for hormone plasma level quantifications. Purified Lewis aortic endothelial cell cultures were pre-treated with biochaninA or ethinylestradiol and stimulated with TNF-alpha or IFN-gamma for quantification of ICAM-1/VCAM-1 and MHC-II expression. Endothelium-lymphocyte adhesion assays were performed using purified F344 lymphocytes.
  
  
  RESULTS
  Both biochaninA and ethinylestradiol treatment significantly reduced graft mononuclear infiltration of CD8(+) and ED1(+) cells and markedly reduced ISHLT grading compared to untreated controls. Either agent significantly inhibited lymphocyte adhesion, endothelial VCAM-1 upregulation during graft rejection and during TNF-alpha-stimulation in vitro, whereas no effect was observed for ICAM-1 upregulation. BiochaninA but not ethinylestradiol significantly reduced endothelial MHC-II upregulation in vivo and in vitro. Only ethinylestradiol treatment strongly affected uterus growth in ovarectomized recipients.
  
  
  CONCLUSIONS
  Only the treatment with the phytoestrogen biochaninA reduced endothelial MHC-II expression in vivo and in vitro and weakened allograft rejection without affecting the reproductive system. Supplemental phytoestrogens may therefore provide further benefits in the clinical setting.
authors.affiliation: Department of Cardiovascular Surgery, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. sschrepfer@uke.uni-hamburg.de
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schäfer
authors.forename: Friedrich
authors.initials: F
authors.lastname: Koch-Nolte
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Braendle
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
mesh_terms: D000208:Acute Disease; D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D009929:Organ Size / Q000187:drug effects; D048789:Phytoestrogens / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D011960:Receptors, Estrogen / Q000819:agonists / Q000032:analysis; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D000949:Histocompatibility Antigens Class II; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D019833:Genistein; C004541:biochanin A