Antigraft antibody-mediated expression of metalloproteinases on endothelial cells - Differential expression of TIMP-1 and ADAM-10 depends on antibodyspecificity and isotype

Endothelial cell (EC) interaction with antigraft antibodies (Abs) mediates EC injury and activation involved in vascular graft rejection. The aim of t his study was to identify EC genes regulated in response to antigraft Ab bi nding that contribute to the endothelium alterations implicated in graft re jection or survival. By means of RNA differential display, 13 cDNA fragment s corresponding to genes differentially expressed in ECs incubated with ant igraft Abs were identified. Among these cDNAs were found the tissue inhibit or of metalloproteinase-1 (TIMP-1) and a desintegrin and metalloproteinase (ADAM-10). We demonstrated that TIMP-1 and ADAM-10 mRNA and protein express ion was rapidly upregulated in ECs in response to antigraft Ab binding. Our data showed that TIMP-1 was upregulated in response to human IgG but not I gM and anti-galactosyl (Gal) alpha1-3Gal human xenogeneic Abs, In contrast, upregulation of ADAM-10 in ECs was shown to be mostly mediated by anti-Gal alpha1-3Gal IgM Abs. Specific effects of human IgG and IgM xenogeneic Abs on endothelial transcripts indicate that different isotypes and specificiti es of Abs may mediate different EC changes. Our results suggest that intera ction of ECs with antigraft Abs, according to their specificity, selectivel y induces synthesis and release of metalloproteinases and inhibitors, contr olling proteolytic processes and immunological events that respectively con tribute to graft rejection or survival.