Endothelial cell antibodies associated with novel targets and increased rejection.
The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.
Departments of Medicine, ajackson@jhmi.edu minnie.sarwal@ucsf.edu.
Annette M
AM
Jackson
Department of Surgery, University of California, San Francisco, California; and.
Tara K
TK
Sigdel
Transplantation Rénale Adulte, Hôpital Necker, Paris, France.
Marianne
M
Delville
Department of Surgery, University of California, San Francisco, California; and.
Szu-Chuan
SC
Hsieh
Department of Surgery, University of California, San Francisco, California; and.
Hong
H
Dai
Pathology, and.
Serena
S
Bagnasco
Surgery, Johns Hopkins University, Baltimore, Maryland;
Robert A
RA
Montgomery
Department of Surgery, University of California, San Francisco, California; and ajackson@jhmi.edu minnie.sarwal@ucsf.edu.
Minnie M
MM
Sarwal
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000941:Antigens / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D040081:Protein Array Analysis; D040901:Proteomics / Q000379:methods; D012189:Retrospective Studies
D000906:Antibodies; D000941:Antigens; D006680:HLA Antigens
acute allograft rejection; endothelial cells; immunology and pathology; kidney transplantation