In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells.
Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis. Therefore, we designed this study to test the hypothesis that human regulatory T cells (T(reg) cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of T(reg) cells, sorted via two separate strategies, to prevent transplant arteriosclerosis in a clinically relevant chimeric humanized mouse system. We found that the in vivo development of transplant arteriosclerosis in human arteries was prevented by treatment of ex vivo-expanded human T(reg) cells. Additionally, we show that T(reg) cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional T(reg) cells. Our results demonstrate that human T(reg) cells can inhibit transplant arteriosclerosis by impairing effector function and graft infiltration. We anticipate our findings to serve as a foundation for the clinical development of therapeutics targeting transplant arteriosclerosis in both allograft transplantation and other immune-mediated causes of vasculopathy.
Nadig
Satish N
SN
Transplantation Research Immunology Group, Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Wieckiewicz
Joanna
J
Wu
Douglas C
DC
Warnecke
Gregor
G
Zhang
Wei
W
Luo
Shiqiao
S
Schiopu
Alexandru
A
Taggart
David P
DP
Wood
Kathryn J
KJ
D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001161:Arteriosclerosis / Q000276:immunology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D006084:Graft Rejection; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008323:Mammary Arteries / Q000637:transplantation*; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D007371:Interferon-gamma
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