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

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Abstract

Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term1,2. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts2. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis3,4. Therefore, we designed this study to test the hypothesis that human regulatory T cells (Treg cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of Treg 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 Treg cells. Additionally, we show that Treg cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional Treg cells. Our results demonstrate that human Treg 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 vasculopathy5.

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Figure 1: Sorted and ex vivo–expanded human CD25hiCD4+ and CD127loCD4+ cells retain characteristic features of Treg cells and differ in suppressive activity in vitro.
Figure 2: Transplant arteriosclerosis mediated by allogeneic human PBMCs in human arterial interposition grafts is attenuated by human Treg cells.
Figure 3: Treg cells impair effector cell function.
Figure 4: Ex vivo–expanded CD127lo Treg cells are more potent than CD25hi Treg cells.

Change history

  • 26 May 2010

     In the version of this article initially published online, in Figure 1a, underneath ‘Silencing’, the text reading “2 d: 200 U ml–1 IL-2 + beads” was incorrect. It should read “2 d: 200 U ml–1 IL-2 no beads.” The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank the staff of the Biomedical Services Unit at the John Radcliffe Hospital for expert animal care, M. Barnardo and the staff at the Clinical Transplant Immunology Laboratory, The Oxford Transplant Centre for molecular human leukocyte antigen typing, M. Carvalho-Gaspar for advice on real-time PCR, F. Issa and R. Goto for assistance with some experiments, A. Bushell and N. Jones for valuable discussions and the cardiac surgical registrars and operating theater staff for assistance with the procurement of vessels. This work was supported by grants from The Wellcome Trust, the European Union Integrated Project, RISET, Medical Research Council UK and Garfield Weston Trust. S.N.N. is an International Society for Heart and Lung Transplantation Research Fellow; J.W. is a RISET investigator, G.W. is a Deutsche Forschungsgemeinschaft Fellow; W.Z. was supported by an unrestricted grant from Becton Dickinson; A.S. was supported by the Swedish Heart and Lung Foundation and the Swedish Research Council.

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Contributions

S.N.N., J.W., G.W. and K.J.W. designed the experiments; S.N.N. and J.W. performed the experiments and analyzed the data; D.C.W., G.W., W.Z., S.L. and A.S. assisted with the experiments; D.P.T. provided expertise and advice along with human tissue; and S.N.N., J.W. and K.J.W. wrote the manuscript.

Corresponding author

Correspondence to Kathryn J Wood.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7 and Supplementary Table 1 (PDF 704 kb)

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Nadig, S., Więckiewicz, J., Wu, D. et al. In vivo prevention of transplant arteriosclerosis by ex vivo–expanded human regulatory T cells. Nat Med 16, 809–813 (2010). https://doi.org/10.1038/nm.2154

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