Antigraft antibody-mediated expression of metalloproteinases on endothelial cells. Differential expression of TIMP-1 and ADAM-10 depends on antibody specificity and isotype.
Endothelial cell (EC) interaction with antigraft antibodies (Abs) mediates EC injury and activation involved in vascular graft rejection. The aim of this study was to identify EC genes regulated in response to antigraft Ab binding that contribute to the endothelium alterations implicated in graft rejection or survival. By means of RNA differential display, 13 cDNA fragments corresponding to genes differentially expressed in ECs incubated with antigraft Abs were identified. Among these cDNAs were found the tissue inhibitor of metalloproteinase-1 (TIMP-1) and a desintegrin and metalloproteinase (ADAM-10). We demonstrated that TIMP-1 and ADAM-10 mRNA and protein expression 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 IgM 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-Galalpha1-3Gal IgM Abs. Specific effects of human IgG and IgM xenogeneic Abs on endothelial transcripts indicate that different isotypes and specificities of Abs may mediate different EC changes. Our results suggest that interaction of ECs with antigraft Abs, according to their specificity, selectively induces synthesis and release of metalloproteinases and inhibitors, controlling proteolytic processes and immunological events that respectively contribute to graft rejection or survival.
INSERM U437 "Immunointervention en allo et xénotransplantation", Nantes Cedex, France.
G
G
Boulday
S
S
Coupel
F
F
Coulon
J P
JP
Soulillou
B
B
Charreau
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000906:Antibodies / Q000502:physiology; D000918:Antibody Specificity / Q000502:physiology; D016282:Aspartic Acid Endopeptidases; D002469:Cell Separation; D002478:Cells, Cultured; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014181:Transplantation Immunology / Q000276:immunology*; D014312:Trisaccharides / Q000276:immunology; D015854:Up-Regulation
D000906:Antibodies; D007132:Immunoglobulin Isotypes; D019715:Tissue Inhibitor of Metalloproteinase-1; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D008666:Metalloendopeptidases