Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis.
The vascular endothelium of transplanted organs represents an important target for allograft-directed immune responses. Although HLA antigens expressed on graft endothelial cells (EC) can become targets of the host immune response, the role of other, non-HLA-encoded EC antigens has been proposed but is still unclear. The aim of this study was to investigate the presence of and to characterize anti-EC antibodies (AECA) in 57 kidney transplant recipients according to their HLA-immunization status. Flow cytometry in pretransplant sera was used to detect AECA reactive with surface antigens on ABO and HLA-typed primary cultures of arterial ECs, stimulated or not with tumor necrosis factor-alpha (TNFalpha) or interferon-gamma (IFNgamma). FACS analysis revealed the presence of AECA in 47% of HLA-sensitized (PRA = 10%: mostly IgG) vs. 16.0% in nonsensitized patients (PRA < 10%) (p < 0.02). No significant correlation was found between the presence of AECA and acute rejection occurrence and graft outcome. Non-HLA reactive AECA are directed against TNFalpha- and IFNgamma-inducible membrane molecule(s), and react with two predominant antigens of approximately 35 kDa and approximately 50 kDa expressed on ECs but not on B cells. Binding of AECA decreases in vitro EC viability by 50-60% by promoting EC apoptosis, as demonstrated by DNA fragmentation assays.
Le Bas-Bernardet
Stéphanie
S
Institut National de la Santé et de la Recherche Médicale Unité 437 'Immunointervention en Allo et Xénotransplantation', Nantes, France.
Hourmant
Maryvonne
M
Coupel
Stéphanie
S
Bignon
Jean-Denis
JD
Soulillou
Jean-Paul
JP
Charreau
Béatrice
B
D000918:Antibody Specificity / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D004730:Endothelium, Vascular / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D007518:Isoantibodies / Q000097:blood / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D012016:Reference Values; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000954:Antigens, Surface; D001323:Autoantibodies; D006680:HLA Antigens; D007518:Isoantibodies; D014409:Tumor Necrosis Factor-alpha; C087589:anti-endothelial cell antibody; D007371:Interferon-gamma