The indirect alloimmune response causes microvascular endothelial dysfunction-a possible role for alloantibody.
BACKGROUND
The causes of endothelial dysfunction after cardiac transplantation are unknown. Here, we have investigated whether the indirect alloimmune response mediates endothelial dysfunction in a major histocompatibility complex class I mismatch model.


METHODS
PVG.RT1 rat hearts were transplanted into thymectomized CD8 T-cell-depleted allogeneic (PVG.R8) or syngeneic (PVG.RT1) recipients. Alloantibody was assessed at 2, 4, and 8 weeks. Cardiac allograft vasculopathy, the nature of the inflammatory infiltrate, and origin of endothelial cells were examined at 1, 2, 4, and 8 weeks. Endothelial function was assessed by Langendorff preparations at 1, 2, and 4 weeks.


RESULTS
Recipients produced alloantibody and showed luminal occlusion at 1 (17.7%±8.0%), 2 (23.2%±4.9%), 4 (34.3%±5.0%), and 8 weeks (58.1%±1.8%) posttransplantation. The major inflammatory features of the allografts consisted of CD11b monocytes, CD4 T cells, and C4d deposition. At 1 week, the basal coronary flow and the vasodilator response to 5-hydroxytrytamine of syngeneic and allografted hearts were inhibited compared with normal hearts. At 4 weeks, the basal coronary flow of allografts was 54% lower than syngrafts (P<0.01), and 5- hydroxytrytamine and sodium nitroprusside did not evoke an increase in coronary flow in the allograft heart compared with syngeneic controls (P<0.01). Culture of aortic rings with antibody to major histocompatibility complex class I inhibited endothelium-dependent vasodilation to acetylcholine.


CONCLUSIONS
Transient microvascular endothelial dysfunction occurred in syngeneic and allogeneic cardiac grafts after transplantation. Syngeneic but not allogeneic grafts recovered, suggesting the indirect immune response, consisting of CD4 T cells, monocytes, and antibody, mediates endothelial dysfunction. A possible role for alloantibody in endothelial dysfunction is discussed.
National Heart and Lung Institute, Imperial College, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, UK.
Ying
Y
Xu
Adrian H
AH
Chester
Batool
B
Hariri
Ann
A
McCormack
Padmini
P
Sarathchandra
Marlene L
ML
Rose
D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015935:Complement C4b / Q000276:immunology; D003326:Coronary Circulation / Q000187:drug effects / Q000276:immunology; D054059:Coronary Occlusion / Q000276:immunology; D003331:Coronary Vessels / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology / Q000637:transplantation*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology / Q000637:transplantation*; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D007518:Isoantibodies / Q000097:blood*; D008833:Microcirculation / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010477:Perfusion; D051381:Rats; D013934:Thymectomy; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014664:Vasodilation / Q000187:drug effects / Q000276:immunology; D014665:Vasodilator Agents / Q000494:pharmacology
D039481:CD11b Antigen; D015395:Histocompatibility Antigens Class I; D018836:Inflammation Mediators; D007518:Isoantibodies; D010446:Peptide Fragments; D014665:Vasodilator Agents; D015935:Complement C4b; C032261:complement C4d