In vivo prevention of transplant arteriosclerosis by ex vivo–expanded human regulatory T cells

Transplant arteriosclerosis is a leading cause of transplanted organ dysfunction. Human regulatory T cells expanded ex vivo can prevent transplant arteriosclerosis in a mouse model by preventing the immune infiltration of the graft. Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term 1 , 2 . These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts 2 . Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis 3 , 4 . 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 5 .