Pre-exposure to sub-saturating concentrations of HLA class I antibodies confers resistance to endothelial cells against antibody complement-mediated lysis by regulating Bad through the phosphatidylinositol 3-kinase/Akt pathway.
Allografts transplanted across HLA-sensitization results in an antibody-mediated rejection known as hyperacute rejection. Depleting anti-graft antibodies from the recipient by plasmapheresis prior to transplantation can prevent this rejection. We developed an in vitro model using polyclonal HLA class I antibodies obtained from highly sensitized patients awaiting transplantation,and analyzed their ability to provide signals following binding to human aortic endothelial cells (EC). Using this model, we show that EC undergo caspase 3-dependent cell death by apoptosis upon exposure to saturating concentrations of HLA class I antibodies and complement accompanied by loss of Akt activation and phosphorylation of Bad. In contrast, exposure of EC to sub-saturating concentrations of HLA class I antibodies conferred resistance towards antibody/complement-mediated lysis termed accommodation. Accommodated EC exhibited reduction in the expression of the adhesion molecules ICAM-1 and VCAM-1 and a significant increase in the expression of anti-apoptotic genes Bcl-xL, Bcl-2 and heme oxygenase-1. Further, induction of phosphatidylinositol 3-kinase (PI3K) and Akt activities that facilitate the phosphorylation of Bad were also noted. In conclusion, exposure of sub-saturating concentrations of HLA class I antibodies results in the induction of PI3K/Akt pathway that confers resistance to endothelial cells against antibody/complement-mediated cell death.
Narayanan
Kishore
K
Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Jaramillo
Andrés
A
Phelan
Donna L
DL
Mohanakumar
T
T
D000906:Antibodies / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D003165:Complement System Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D051025:bcl-Associated Death Protein
D000906:Antibodies; D002352:Carrier Proteins; D003165:Complement System Proteins; D015395:Histocompatibility Antigens Class I; D018799:Intercellular Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019010:Vascular Cell Adhesion Molecule-1; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C494918:AKT1 protein, human