International Immunology, Vol. 12, No. 4, 563-571,
April 2000
© 2000 Japanese Society for Immunology
Activation of NF-
B in human endothelial cells induced by monoclonal and allospecific HLA antibodies
National Heart & Lung Institute, Imperial College School of Medicine, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK
Correspondence to: M. L. Rose
Chronic graft rejection, characterized by a gradual occlusion of grafted vessels, is the most serious complication following heart and kidney transplantation. Although often associated with chronic production of anti-HLA and anti-endothelial antibodies, the precise role of antibodies in chronic rejection remains uncertain. Here we have investigated whether HLA-specific antibodies, either monoclonal or derived from patients, cause endothelial cell activation. Thus we investigated tyrosine phosphorlyation, NF-
B activation and cell proliferation in human umbilical vein endothelial cells (HUVEC) or microvascular endothelial cells from adult human heart (CMEC). Ligation of monomorphic determinants of MHC class I molecules (using the mAb W6/32) on the surface of HUVEC caused an increase in tyrosine phosphorylation of proteins of mol. wt ~75–80 kDa. Similarly, ligation of monomorphic determinants on both CMEC and HUVEC resulted in increased NF-B binding compared to controls (by 74.4 and 52.5%, P = 0.001) and this was enhanced by addition of secondary antibody. Two HLA-specific mAb resulted in a 277 and 170% increase in NF-B-binding activity compared to controls. Four patient samples containing HLA antibodies were used against HLA-specific HUVEC and four samples were incubated with HUVEC bearing irrelevant antigens. Patient sera alone enhanced NF-B binding by 27–186%, but only when added to HUVEC bearing relevant antigens. W6/32 and allospecific antibodies from patients significantly enhanced HUVEC proliferation, measured by uptake of [3H]thymidine. In conclusion, activation of NF-B by human anti-HLA antibodies demonstrates their potential role in pathogenesis of chronic vascular occlusive disease following transplantation.
Keywords: chronic rejection, endothelial cells, HLA antibodies, NF-B, transplantation
Transmitting editor: D. T. Fearon
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