title: Human T cell responses to human and porcine endothelial cells are highly sensitive to cyclosporin A and FK506 in vitro.
abstract: BACKGROUND
  Human T cells proliferate in response to both human umbilical vein endothelial cells (HUVEC) and porcine aortic endothelial cells (PAEC) via the second signals LFA-3/CD2 and B7-2 (CD86), respectively. Previous studies have shown that stimulation of T cells via CD28 or phorbol myristate acetate (PMA) activation is highly resistant to inhibition by cyclosporine A (CsA) and tacrolimus (FK506), as is the response of T cells to phytohemmaglutinin in the presence of endothelial cells. We have investigated the inhibitory effects of CsA and FK506 on the direct response of human CD4+ T cells to HUVEC and PAEC and the effect of adding B7-1 transfectants.
  
  
  METHODS
  T cell proliferation, interleukin-2 release bioassays and a multiple cytokine bioassay employing the TF-1 cell line were used as indicators of T cell responses to HUVEC and PAEC either in the presence or absence of CsA and FK506. In some experiments, B7-1 transfectants were also added.
  
  
  RESULTS
  Proliferative responses and interleukin-2 release were highly sensitive to CsA, the ID50 being significantly less for HUVEC (6.5 ng/ml) than PAEC (15 ng/ml). The ID50 of CsA for the mixed lymphocyte response (MLR) was similar to PAEC (18.6 ng/ml), all these values being significantly less than the T cell activation by phytohemmaglutinin (PHA) (227 ng/ml). Addition of B7-1 transfectants significantly increased interleukin-2 production by T cells/HUVEC and resistance to CsA was greatly increased to an ID50 of > 1000 ng/ml. In contrast, addition of B7-1 transfectants to T cells/PAEC had no effect either on T cell proliferation, IL-2 production, or CsA resistance. Similar results were obtained with FK506. Using the TF-1 cell line, it was determined that cytokines other than IL-2 are released during CD4+ T cell/EC interactions, with similar sensitivity to CsA and FK506.
  
  
  CONCLUSIONS
  It is concluded that both allogeneic and xenogeneic T cell/endothelial responses should be inhibited by therapeutic levels of CsA in vivo, assuming the absence of trans-stimulation by B7 molecules.
authors.affiliation: Division of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of School of Medicine at Harefield Hospital, Middlesex, UK.
authors.forename: P
authors.initials: P
authors.lastname: Batten
authors.forename: A M
authors.initials: AM
authors.lastname: McCormack
authors.forename: C S
authors.initials: CS
authors.lastname: Page
authors.forename: M H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: M L
authors.initials: ML
authors.lastname: Rose
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001011:Aorta; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D013552:Swine; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology*; D014162:Transfection; D014471:Umbilical Veins
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D016572:Cyclosporine; D016559:Tacrolimus