Alloantibody-mediated class I signal transduction in endothelial cells and smooth muscle cells: enhancement by IFN-gamma and TNF-alpha.
Chronic rejection is the major limiting factor to long term survival of solid organ allografts. The hallmark of chronic rejection is transplant atherosclerosis, which is characterized by the intimal proliferation of smooth muscle cells, endothelial cells, and fibroblasts, leading to vessel obstruction, fibrosis, and eventual graft loss. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA Ab-mediated injury to the endothelium and smooth muscle of the graft. In this study we have investigated whether anti-HLA Abs, developed by transplant recipients following transplantation, are capable of transducing signals via HLA class I molecules, which stimulate cell proliferation. In this report we show that ligation of class I molecules with Abs to distinct HLA-A locus and HLA-B locus molecules results in increased tyrosine phosphorylation of intracellular proteins and induction of fibroblast growth factor receptor expression on endothelial and smooth muscle cells. Treatment of cells with IFN-gamma and TNF-alpha up-regulated MHC class I expression and potentiated anti-HLA Ab-induced fibroblast growth factor receptor expression. Engagement of class I molecules also stimulated enhanced proliferative responses to basic fibroblast growth factor, which augmented endothelial cell proliferation. These findings support a role for anti-HLA Abs and cytokines in the transduction of proliferative signals, which stimulate the development of myointimal hyperplasia associated with chronic rejection of human allografts.
Bian
H
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Department of Pathology, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
Reed
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EF
D000276:Adjuvants, Immunologic / Q000502:physiology; D001011:Aorta; D002455:Cell Division / Q000276:immunology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D007518:Isoantibodies / Q000502:physiology*; D008024:Ligands; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000276:immunology*; D010766:Phosphorylation; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D000276:Adjuvants, Immunologic; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; D008024:Ligands; D017468:Receptors, Fibroblast Growth Factor; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D007371:Interferon-gamma