Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation.
The major threat to long-term survival of solid organ allografts is chronic rejection. Progressive narrowing and ultimate luminal occlusion of the arteries and arterioles of the transplanted organ are the hallmarks of the disease. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA antibody-mediated injury to the endothelium. We have postulated that anti-HLA antibodies initiate chronic rejection by binding to class I molecules on the endothelium and transducing signals that result in endothelial cell activation and proliferation. Our data demonstrate that anti-HLA class I antibodies transduce signals in endothelial cells stimulating increased tyrosine phosphorylation of intracellular proteins. Antibody binding to class I antigens also leads to the generation of inositol phosphate and endothelial cell proliferation. These results indicate that anti-HLA antibodies can deliver functionally important signals to endothelial cells, a finding that may be fundamental to an understanding of the mechanisms of chronic rejection.
Bian
H
H
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Harris
P E
PE
Mulder
A
A
Reed
E F
EF
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006680:HLA Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010716:Phosphatidylinositols; D014443:Tyrosine; D015544:Inositol 1,4,5-Trisphosphate; D011505:Protein-Tyrosine Kinases