Late onset antibody-mediated rejection and endothelial localization of vascular endothelial growth factor are associated with development of cardiac allograft vasculopathy.
BACKGROUND
Improvements in cardiac transplant practice and immunosuppressive treatment have done much to curb the incidence of acute cellular rejection (ACR); however, antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) remain prevalent. Recent studies have shown that allograft rejection is governed by both allogeneic and nonallogeneic factors such as inflammation. Initial studies have suggested that vascular endothelial growth factor (VEGF), a leukocyte mitogen produced by activated endothelial cells and leukocytes, may play a specific role in not only leukocyte trafficking, but also in the augmentation of ACR and development of CAV.


METHODS
We investigated the localization of VEGF protein using immunohistochemistry in a cohort of 76 heart transplant patients during periods of ACR and AMR and assessed the development of CAV.


RESULTS
We showed a significant correlation between lymphocytic localization of VEGF protein and severe ACR (P<0.001). Antibody-mediated rejection positive biopsies taken at 12 months posttransplantation showed significantly greater endothelial localization of VEGF than time-matched AMR negative biopsies (P=0.006). Diffuse endothelial expression of VEGF was also associated with a 2.5-fold increase in the risk of developing CAV (P=0.001).


CONCLUSIONS
These results show that localization of VEGF protein to the vascular endothelium during AMR is significantly increased in patients who develop CAV. This study also highlights the potential pathogenic role of the endothelial cell in late onset AMR and the development of CAV.
Bayliss
Julianne
J
Department of Medicine, Monash University, Alfred Hospital, Prahran, VIC, Australia. julianne.bayliss@med.monash.edu.au
Bailey
Michael
M
Leet
Angeline
A
Stein
Alicia N
AN
Thomson
Napier M
NM
McLean
Catriona A
CA
D000328:Adult; D000368:Aged; D001706:Biopsy; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014184:Transplantation, Homologous / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D007166:Immunosuppressive Agents; D007518:Isoantibodies; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A