title: Temporal reduction in acute rejection after heart transplantation is not associated with a reduction in cell-mediated responses to donor-specific vascular endothelium.
abstract: BACKGROUND
  Over the first 6 months after clinical transplantation, the incidence of rejection falls despite typically substantial decreases in maintenance immunosuppression. Despite this, chronic vascular rejection, manifested by an accelerated form of coronary artery disease is usually evident by the first annual angiogram and continues to progress over subsequent years.
  
  
  METHODS
  To investigate this phenomenon further, peripheral blood mononuclear cells were prepared from blood samples obtained from 42 cardiac allograft recipients at 1 week, 3 months, and 6 months after transplantation and co-cultured with endothelial cells isolated and cultured from the aortas of their specific cardiac allograft donors. Donor-specific alloreactivity was assessed by (1) peripheral blood mononuclear cell proliferation (3H-thymidine incorporation) and (2) up-regulation of endothelial cell major histocompatibility complex class I and class II antigens and ICAM-1 expression (flow cytometry) at all three time points.
  
  
  RESULTS
  Over this 6-month period, rejection incidence fell from 0.68 rejections/patient to 0.12 rejection/patient. Cyclosporine dose was reduced from 5.6 +/- 0.3 mg/kg (mean +/- standard error of the mean) to 4.5 +/- 0.2 mg/kg, prednisone dose was reduced from 0.58 +/- 0.08 mg/kg to 0.17 +/- 0.02 mg/kg, and azathioprine remained constant at approximately 2 mg/kg over the 6-month period. Despite this reduction in rejection and immunosuppression, no measure of in vitro donor-specific cell-mediated response to endothelial cells decreased over the 6-month time period. Peripheral blood mononuclear cell proliferation in response to donor-specific endothelial cells was unchanged between 1 week (916 +/- 139 counts/min [cpm]) and 3 months (896 +/- 135 cpm) and increased at 6 months (1738 +/- 243 cpm, p < 0.01). The increase in endothelial cell major histocompatibility complex class II expression in response to recipient peripheral blood mononuclear cells likewise was unchanged between 1 week (42.5 +/- 7.8 mean channel shift [mcs]) and 3 months (34.7 +/- 6.6 mcs) and increased substantially at 6 months (95.4 +/- 17.2 mcs, p < 0.02). The magnitude of the increase in endothelial cell major histocompatibility complex class I antigen and ICAM-1 expression in response to co-culture with recipient peripheral blood mononuclear cells did not change over the 6-month period.
  
  
  CONCLUSIONS
  These data suggest an important dichotomy between cell-mediated responses to allograft parenchyma versus those to allograft vasculature and may provide an explanation for progressive vascular disease despite the absence of acute rejection.
authors.affiliation: Immunobiology Research Laboratory, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Hosenpud
authors.forename: G D
authors.initials: GD
authors.lastname: Shipley
authors.forename: K A
authors.initials: KA
authors.lastname: Mauck
authors.forename: T E
authors.initials: TE
authors.lastname: Morris
authors.forename: C R
authors.initials: CR
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003327:Coronary Disease / Q000209:etiology; D004730:Endothelium, Vascular / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D014019:Tissue Donors
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1