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

被引:67
作者
Narayanan, K
Jaramillo, A
Phelan, DL
Mohanakumar, T
机构
[1] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA
[3] BJC Hosp, HLA Lab, St Louis, MO USA
关键词
antibodies; endothelial cells; MHC; signal transduction; transplantation;
D O I
10.1002/eji.200324843
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Allografts transplanted across HILA-sensitization results in an anti body-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 anti body/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 anti body/complement-mediated cell death.
引用
收藏
页码:2303 / 2312
页数:10
相关论文
共 21 条
[1]  
ALEXANDRE GPJ, 1987, TRANSPLANT P, V19, P4538
[2]   Protective genes expressed in endothelial cells: a regulatory response to injury [J].
Bach, FH ;
Hancock, WW ;
Ferran, C .
IMMUNOLOGY TODAY, 1997, 18 (10) :483-486
[3]   Accommodation of vascularized xenografts: Expression of ''protective genes'' by donor endothelial cells in a host Th2 cytokine environment [J].
Bach, FH ;
Ferran, C ;
Hechenleitner, P ;
Mark, W ;
Koyamada, N ;
Miyatake, T ;
Winkler, H ;
Badrichani, A ;
Candinas, D ;
Hancock, WW .
NATURE MEDICINE, 1997, 3 (02) :196-204
[4]   Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms [J].
Bonni, A ;
Brunet, A ;
West, AE ;
Datta, SR ;
Takasu, MA ;
Greenberg, ME .
SCIENCE, 1999, 286 (5443) :1358-1362
[5]  
Collins AB, 1999, J AM SOC NEPHROL, V10, P2208
[6]  
COOPER DKC, 1993, TRANSPLANT P, V25, P377
[7]   Cellular survival: a play in three Akts [J].
Datta, SR ;
Brunet, A ;
Greenberg, ME .
GENES & DEVELOPMENT, 1999, 13 (22) :2905-2927
[8]   Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery [J].
Datta, SR ;
Dudek, H ;
Tao, X ;
Masters, S ;
Fu, HA ;
Gotoh, Y ;
Greenberg, ME .
CELL, 1997, 91 (02) :231-241
[9]   In vitro accommodation of porcine endothelial cells by low dose human anti-pig antibody: Reduced binding of human lymphocytes by accommodated cells associated with increased nitric oxide production [J].
Dorling, A ;
Delikouras, A ;
Nohadani, M ;
Polak, J ;
Lechler, RI .
XENOTRANSPLANTATION, 1998, 5 (01) :84-92
[10]   In vitro accommodation of immortalized porcine endothelial cells - Resistance to complement mediated lysis and down-regulation of VCAM expression induced by low concentrations of polyclonal human IgG antipig antibodies [J].
Dorling, A ;
Stocker, C ;
Tsao, T ;
Haskard, DO ;
Lechler, RI .
TRANSPLANTATION, 1996, 62 (08) :1127-1136