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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.

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  • 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.

References

  1. Pucci, A.M., Forbes, R.D. & Billingham, M.E. Pathologic features in long-term cardiac allografts. J. Heart Transplant. 9, 339–345 (1990).

    CAS  PubMed  Google Scholar 

  2. Hillebrands, J.L. & Rozing, J. Chronic transplant dysfunction and transplant arteriosclerosis: new insights into underlying mechanisms. Expert Rev. Mol. Med. 33, 1–23 (2003).

    Article  Google Scholar 

  3. Mitchell, R.N. & Lichtman, A.H. The link between IFN-γ and allograft arteriopathy: is the answer NO? J. Clin. Invest. 114, 762–764 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Taylor, D.O. et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report–2006. J. Heart Lung Transplant. 25, 869–879 (2006).

    Article  Google Scholar 

  5. Tullius, S.G. et al. Contribution of early acute rejection episodes to chronic rejection in a rat kidney retransplantation model. Kidney Int. 53, 465–472 (1998).

    Article  CAS  Google Scholar 

  6. Nankivell, B.J. et al. The natural history of chronic allograft nephropathy. N. Engl. J. Med. 349, 2326–2333 (2003).

    Article  CAS  Google Scholar 

  7. Kobashigawa, J.A. et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J. Am. Coll. Cardiol. 45, 1532–1537 (2005).

    Article  Google Scholar 

  8. Tellides, G. et al. Interferon-γ elicits arteriosclerosis in the absence of leukocytes. Nature 403, 207–211 (2000).

    Article  CAS  Google Scholar 

  9. Godfrey, W.R. et al. In vitro–expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell–stimulated MLR cultures. Blood 104, 453–461 (2004).

    Article  CAS  Google Scholar 

  10. Hoffmann, P., Eder, R., Kunz-Schughart, L.A., Andreesen, R. & Edinger, M. Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells. Blood 104, 895–903 (2004).

    Article  CAS  Google Scholar 

  11. Wood, K.J. & Sakaguchi, S. Regulatory T cells in transplantation tolerance. Nat. Rev. Immunol. 3, 199–210 (2003).

    Article  CAS  Google Scholar 

  12. Wang, Y. et al. Interferon-γ induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation. Circ. Res. 101, 560–569 (2007).

    Article  CAS  Google Scholar 

  13. Tellides, G. & Pober, J.S. Interferon-γ axis in graft arteriosclerosis. Circ. Res. 100, 622–632 (2007).

    Article  CAS  Google Scholar 

  14. Cuffy, M.C. et al. Induction of indoleamine 2,3-dioxygenase in vascular smooth muscle cells by interferon-γ contributes to medial immunoprivilege. J. Immunol. 179, 5246–5254 (2007).

    Article  CAS  Google Scholar 

  15. Oberle, N., Eberhardt, N., Falk, C.S., Krammer, P.H. & Suri-Payer, E. Rapid suppression of cytokine transcription in human CD4+CD25 T cells by CD4+Foxp3+ regulatory T cells: independence of IL-2 consumption, TGF-β and various inhibitors of TCR signaling. J. Immunol. 179, 3578–3587 (2007).

    Article  CAS  Google Scholar 

  16. Lin, C.Y., Graca, L., Cobbold, S.P. & Waldmann, H. Dominant transplantation tolerance impairs CD8+ T cell function but not expansion. Nat. Immunol. 3, 1208–1213 (2002).

    Article  CAS  Google Scholar 

  17. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  18. Warnecke, G., Bushell, A., Nadig, S.N. & Wood, K.J. Regulation of transplant arteriosclerosis by CD25+CD4+ T cells generated to alloantigen in vivo. Transplantation 83, 1459–1465 (2007).

    Article  CAS  Google Scholar 

  19. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  Google Scholar 

  20. Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).

    Article  CAS  Google Scholar 

  21. Putnam, A.L. et al. Expansion of human regulatory T cells from patients with type 1 diabetes. Diabetes 58, 652–662 (2009).

    Article  CAS  Google Scholar 

  22. Ermann, J. et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105, 2220–2226 (2005).

    Article  CAS  Google Scholar 

  23. Jutila, M.A., Watts, G., Walcheck, B. & Kansas, G.S. Characterization of a functionally important and evolutionarily well-conserved epitope mapped to the short consensus repeats of E-selectin and L-selectin. J. Exp. Med. 175, 1565–1573 (1992).

    Article  CAS  Google Scholar 

  24. Koenen, H.J., Fasse, E. & Joosten, I. CD27/CFSE-based ex vivo selection of highly suppressive alloantigen-specific human regulatory T cells. J. Immunol. 174, 7573–7583 (2005).

    Article  CAS  Google Scholar 

  25. Mussa, S., Choudhary, B.P. & Taggart, D.P. Radial artery conduits for coronary artery bypass grafting: current perspective. J. Thorac. Cardiovasc. Surg. 129, 250–253 (2005).

    Article  Google Scholar 

  26. Koulack, J. et al. Development of a mouse aortic transplant model of chronic rejection. Microsurgery 16, 110–113 (1995).

    Article  CAS  Google Scholar 

  27. Trzonkowski, P. et al. Homeostatic repopulation by CD28CD8+ T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression. Am. J. Transplant. 8, 338–347 (2008).

    Article  CAS  Google Scholar 

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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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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.

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Correspondence to Kathryn J Wood.

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The authors declare no competing financial interests.

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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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