#48-OR
INDUCTION OF FIBROBLAST GROWTH FACTOR RECEPTOR EXPRESSION IN HUMAN ENDOTHELIAL CELLS BY ANTI-HLA CLASS I ANTIBODIES IS LOCUS DEPENDENT.
Ke Wei Gong, Ph.D. and Elaine F. Reed, Ph.D.. Los Angeles CA, USA, David Geffen School of Medicine at UCLA, 90095, Pathology
Laboratory Medicine.
Numerous studies have shown that the humoral response to the graft plays an important role in chronic rejection as patients developing anti-donor HLA antibodies (Abs) are at higher risk of transplant arteriosclerosis (TA). Ligation of class I molecules on the surface of endothelial cells (EC) triggers fibroblast growth factor receptor (FGFR) translocation, increased FGF binding and EC proliferation. We postulate that antibodies against distinct HLA loci may differ in their capacity to elicit signaling in ECs. To explore this possibility, a panel of EC were treated with varying concentrations of monoclonal and polyclonal anti-class I Ab recognizing distinct A, B and C locus antigens (n=25) and FGFR translocation was measured by flow cytometry. Ab directed against A locus antigens were potent stimulators of class I mediated induction of FGFR on EC. In contrast, EC treated with anti-B locus or C locus Ab showed little to no increase in expression of FGFR. Analysis of the levels of HLA-A, B and C locus antigen expression on EC showed high levels of expression of A locus antigens but not B or C antigens. Exposure of EC to INF-gamma induced a 20-fold increase in B and C locus antigen expression. Increased B and C locus antigen expression was accompanied by the ability to transduce activation signals in EC and induce FGFR expression. The data indicate that the intracellular signaling events initiated by Ab ligation are influenced by the HLA locus and the degree of HLA molecular aggregation. These results may substantiate different outcomes in patients producing anti-donor HLA Ab to different HLA specificities.