Transplant accommodation in highly sensitized patients: a potential role for Bcl-xL and alloantibody.
Transplantation of renal allografts into recipients with circulating anti-HLA antibodies results in hyperacute rejection. In some cases, however, antibodies return without causing harm; this phenomenon has been termed 'accommodation'. We have investigated this process in human allotransplantation. We removed anti-HLA antibodies by immunoadsorption in seven highly sensitized dialysis patients who subsequently underwent renal transplantation. Immunohistochemistry of renal biopsies for IgG and antiapoptotic proteins was performed. We also developed a model of 'accommodation' using anti-HLA antibodies eluted from sensitized patients and incubated with human umbilical vein endothelial cells (HUVECs) at different concentrations. Their effect on HUVEC phenotype was then analysed. Anti-donor antibody returned in 4/7 patients, without evidence of hyperacute rejection. Three out of four of these 'accommodated' grafts showed specific endothelial up-regulation of Bcl-xL and 2/2 tested positive for endothelial IgG deposition. HUVECs incubated with subsaturating concentrations of anti-HLA antibody showed increased expression of Bcl-xL, were rendered refractory to endothelial cell activation and became resistant to complement-mediated lysis. In contrast, HUVECs incubated with saturating concentrations underwent activation and expressed low levels of Bcl-xL. In conclusion, endothelial Bcl-xL expression defines the accommodation process in human allografts and this phenotype may be initiated by exposure of endothelium to low concentrations of anti-donor HLA antibodies.
Salama
A D
AD
Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, UK. asalama@rics.bwh.harvard.edu
Delikouras
A
A
Pusey
C D
CD
Cook
H T
HT
Bhangal
G
G
Lechler
R I
RI
Dorling
A
A
D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis; D002196:Capillaries / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000379:methods; D007074:Immunoglobulin G / Q000032:analysis; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy / Q000379:methods; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007518:Isoantibodies / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D007684:Kidney Tubules / Q000098:blood supply / Q000473:pathology; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D013997:Time Factors; D014184:Transplantation, Homologous; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D006680:HLA Antigens; D007074:Immunoglobulin G; D007518:Isoantibodies; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D018799:Intercellular Adhesion Molecule-1