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CLASS I MEDIATED SIGNAL TRANSDUCTION IN SMOOTH MUSCLE CELLS.
Ke Wei Gong MD; PhD , Yi-Ping Jin MD , Eric J. Lepin, PhD , Hsiao-Wen Chen , Hane Lee and Elaine F. Reed, PhD . Los Angeles CA, USA, David Geffen School of Medicine, University of California Los Angeles, 90095, Pathology & Laboratory Medicine .

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The common pathological feature of chronic rejection is transplant arteriosclerosis (TA) that consists of myointimal proliferation of smooth muscle cells (SMC). 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 (Ab) are at higher risk of TA. To explain the association between anti-HLA Ab and TA, we postulate that anti-HLA class I Ab are pathogenic in chronic rejection because they bind to mismatched donor class I molecules and elicit SMC activation and proliferation. To explore this possibility, SMC were treated with different concentrations of the anti-HLA class I Ab for various time points and proteins from cell lysates were immunoprecipitated and immunoblotted with Ab detecting phosphorylated proteins. Treatment of SMC with anti-HLA class I Ab stimulated a time dependent increase in tyrosine phosphorylation of Src family members, c-Src, Fyn and Yes. Signaling through class I molecules also induced fibroblast growth factor receptor (FGFR) translocation to the plasma membrane mediating increased cell proliferation. Treatment of SMC with latranculin A or cytochalasin D at concentrations established to disrupt the actin cytoskeleton abrogated class I mediated phosphorylation of FAK and inhibited FGFR expression indicating that actin-dependent clustering of HLA molecules and assembly of focal adhesions is required to trigger class I signals. Our results indicate that anti-HLA class I Ab may play an important role in the development of TA by initiating protein tyrosine phosphorylation events that stimulate FGFR translocation and subsequent SMC proliferation.