Inflammatory Ly-6C(hi) monocytes play an important role in the development of severe transplant arteriosclerosis in hyperlipidemic recipients.
OBJECTIVE
Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions.


METHODS
We studied TA in fully mismatched arterial allografts transplanted into hyperlipidemic ApoE(-/-) recipients compared to wild-type controls. The recruitment of distinct monocyte populations into the grafts was tracked by in vivo labelling with fluorescent microspheres. We used antibody-mediated depletion protocols to dissect the relative contribution of T lymphocytes and monocytes to disease development.


RESULTS
In the hyperlipidemic environment the progression of TA was highly exacerbated and the inflammatory CD11b(+)CD115(+)Ly-6C(hi) monocytes were preferentially recruited into the neointima. The number of macrophage-derived foam cells present in the grafts strongly correlated with plasma cholesterol and disease severity. Depletion of Ly-6C(hi) monocytes and neutrophils significantly inhibited macrophage accumulation and disease progression. The accelerated monocyte recruitment occurs through a T cell-independent mechanism, as T cell depletion did not influence macrophage accumulation into the grafts.


CONCLUSIONS
Our study identifies for the first time the involvement of inflammatory Ly-6C(hi) monocytes into the pathogenesis of TA, particularly in conditions of hyperlipidemia. Targeted therapies modulating the recruitment and activation of these cells could potentially delay coronary allograft vasculopathy and improve long-term survival of heart transplant recipients.
Transplantation Research Immunology Group, University of Oxford, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, UK. Alexandru.Schiopu@med.lu.se
Alexandru
A
Schiopu
Satish N
SN
Nadig
Ovidiu S
OS
Cotoi
Joanna
J
Hester
Nico
N
van Rooijen
Kathryn J
KJ
Wood
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D001011:Aorta / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D058426:Neointima; D009504:Neutrophils / Q000276:immunology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
D000950:Antigens, Ly; D001057:Apolipoproteins E; D015415:Biomarkers; D039481:CD11b Antigen; C494192:Ly-6C antigen, mouse; D002784:Cholesterol; D016186:Receptor, Macrophage Colony-Stimulating Factor