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and TNF-
1
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032
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-
and TNF-
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.
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