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Bone marrow mesenchymal stromal cells protect allograft lung transplants from acute rejection via the PD-L1/IL-17A axis

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Abstract

Purpose

Using a rat model of allograft lung transplantation, we investigated the effectiveness of mesenchymal stromal cells (MSCs) as prophylactic and therapeutic agents against the acute rejection of lung grafts.

Methods

Lung grafts were harvested from donor rats and transplanted orthotopically into major histocompatibility complex-mismatched rats. MSCs were administered to the recipients once (on day 0) or twice (on days 0 and 3) after transplantation. The grade of acute rejection was evaluated both macroscopically and microscopically 6 days after transplantation. To elucidate the related mechanism, mRNA levels of inflammatory cytokines and immunomodulatory receptors in the transplanted grafts were measured using quantitative RT-PCR.

Results

The lung graft tissue from the rats that received MSCs post-surgically was protected from acute rejection significantly better than that from the untreated controls. Notably, the rats administered MSCs twice after surgery exhibited the least signs of rejection, with a markedly upregulated mRNA level of PD-L1 and a downregulated mRNA level of IL-17A.

Conclusion

This study assessed MSC protection of lung allografts from acute rejection by modulating T cell activity via enforced expression of PD-L1 in transplants and downregulation of IL-17A.

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References

  1. Hartert M, Senbaklavacin O, Gohrbandt B, Fischer BM, Buhl R, Vahld CF. Lung transplantation: a treatment option in end-stage lung disease. Dtsch Arztebl Int. 2014;111(7):107–16. https://doi.org/10.3238/arztebl.2014.0107. (Epub 2014/03/14; PubMed PMID: 24622680; PubMed Central PMCID: PMCPmc3957052).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Yusen RD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Dobbels F, et al. The registry of the international society for heart and lung transplantation: thirty-first adult lung and heart–lung transplant report–2014; focus theme: retransplantation. J Heart Lung Transpl. 2014;33(10):1009–24. https://doi.org/10.1016/j.healun.2014.08.004. (Epub 2014/09/23; PubMed PMID: 25242125).

    Article  Google Scholar 

  3. Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. 2012;20(1):14–20. https://doi.org/10.1038/mt.2011.211 (Epub 2011/10/20; PubMed PMID: 22008910; PubMed Central PMCID: PMCPmc3255583).

    Article  PubMed  CAS  Google Scholar 

  4. Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18(5):759–65. https://doi.org/10.1038/nm.2736. (Epub 2012/04/17; PubMed PMID: 22504485; PubMed Central PMCID: PMCPmc3727429).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Oh JY, Kim MK, Shin MS, Lee HJ, Ko JH, Wee WR, et al. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells (Dayton, Ohio). 2008;26(4):1047–55. https://doi.org/10.1634/stemcells.2007-0737. (Epub 2008/01/15; PubMed PMID: 18192235).

    Article  CAS  Google Scholar 

  6. Ohtaki H, Ylostalo JH, Foraker JE, Robinson AP, Reger RL, Shioda S, et al. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses. Proc Natl Acad Sci USA. 2008;105(38):14638–43. https://doi.org/10.1073/pnas.0803670105. (Epub 2008/09/17; PubMed PMID: 18794523; PubMed Central PMCID: PMCPmc2567180).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhu XY, Lerman A, Lerman LO. Concise review: mesenchymal stem cell treatment for ischemic kidney disease. Stem Cells (Dayton, Ohio). 2013;31(9):1731–6. https://doi.org/10.1002/stem.1449 (Epub 2013/06/15. PubMed PMID: 23766020; PubMed Central PMCID: PMCPmc3795813)

    Article  CAS  Google Scholar 

  8. Ben Nasr M, Vergani A, Avruch J, Liu L, Kefaloyianni E, D’Addio F, et al. Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site. Acta Diabetol. 2015;52(5):917–27. https://doi.org/10.1007/s00592-015-0735-y. (Epub 2015/03/27; PubMed PMID: 25808641; PubMed Central PMCID: PMCPmc4968999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Muroi K, Miyamura K, Okada M, Yamashita T, Murata M, Ishikawa T, et al. Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study. Int J Hematol. 2016;103(2):243–50. https://doi.org/10.1007/s12185-015-1915-9. (Epub 2015/11/27; PubMed PMID: 26608364).

    Article  PubMed  CAS  Google Scholar 

  10. Okada Y, Marchevsky AM, Zuo XJ, Pass JA, Kass RM, Matloff JM, et al. Accumulation of platelets in rat syngeneic lung transplants: a potential factor responsible for preservation-reperfusion injury. Transplantation. 1997;64(6):801–6. (Epub 1997/10/27; PubMed PMID: 9326401).

    Article  PubMed  CAS  Google Scholar 

  11. Oishi H, Okada Y, Kikuchi T, Hoshikawa Y, Sado T, Noda M, et al. Transbronchial human interleukin-10 gene transfer reduces acute inflammation associated with allograft rejection and intragraft interleukin-2 and tumor necrosis factor-alpha gene expression in a rat model of lung transplantation. J Heart Lung Transpl. 2010;29(3):360–7. https://doi.org/10.1016/j.healun.2009.10.002. (Epub 2010/03/06; PubMed PMID: 20202600).

    Article  Google Scholar 

  12. Zha Y, Blank C, Gajewski TF. Negative regulation of T-cell function by PD-1. Crit Rev Immunol. 2004;24(4):229–37. (Epub 2004/12/14; PubMed PMID: 15588223).

    Article  PubMed  CAS  Google Scholar 

  13. Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. Autoimmun Rev. 2013;12(11):1091–100. https://doi.org/10.1016/j.autrev.2013.05.003. (Epub 2013/06/25. PubMed PMID: 23792703).

    Article  PubMed  CAS  Google Scholar 

  14. Dong Y, Sun Q, Zhang X. PD-1 and its ligands are important immune checkpoints in cancer. Oncotarget. 2016. https://doi.org/10.18632/oncotarget.13895. (Epub 2016/12/16; PubMed PMID: 27974689).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Akhmetzyanova I, Drabczyk M, Neff CP, Gibbert K, Dietze KK, Werner T, et al. PD-L1 expression on retrovirus-infected cells mediates immune escape from CD8 + T Cell killing. PLoS Pathog. 2015;11(10):e1005224. https://doi.org/10.1371/journal.ppat.1005224. (Epub 2015/10/21; PubMed PMID: 26484769; PubMed Central PMCID: PMCPmc4617866).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Davies LC, Heldring N, Kadri N, Le Blanc K. Mesenchymal stromal cell secretion of programmed death-1 ligands regulates t cell mediated immunosuppression. Stem Cells (Dayton, Ohio). 2016. https://doi.org/10.1002/stem.2509. (Epub 2016/10/27; PubMed PMID: 27671847).

    Article  Google Scholar 

  17. Bamoulid J, Staeck O, Halleck F, Khadzhynov D, Brakemeier S, Durr M, et al. The need for minimization strategies: current problems of immunosuppression. Transpl Int Off J Eur Soc Organ Transpl. 2015;28(8):891–900. https://doi.org/10.1111/tri.12553. (Epub 2015/03/11; PubMed PMID: 25752992).

    Article  CAS  Google Scholar 

  18. Uluckan O, Wagner EF. Role of IL-17A signalling in psoriasis and associated bone loss. Clin Exp Rheumatol. 2016;34(4 Suppl 98):17–20. (Epub 2016/09/03; PubMed PMID: 27586798).

    PubMed  Google Scholar 

  19. Qian X, Chen H, Wu X, Hu L, Huang Q, Jin Y. Interleukin-17 acts as double-edged sword in anti-tumor immunity and tumorigenesis. Cytokine. 2017;89:34–44. https://doi.org/10.1016/j.cyto.2015.09.011. (Epub 2016/02/18; PubMed PMID: 26883678).

    Article  PubMed  CAS  Google Scholar 

  20. Srenathan U, Steel K, Taams LS. IL-17 + CD8 + T cells: differentiation, phenotype and role in inflammatory disease. Immunol Lett. 2016;178:20–6. https://doi.org/10.1016/j.imlet.2016.05.001. (Epub 2016/05/14; PubMed PMID: 27173097; PubMed Central PMCID: PMCPmc5046976).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Nirula A, Nilsen J, Klekotka P, Kricorian G, Erondu N, Towne JE, et al. Effect of IL-17 receptor A blockade with brodalumab in inflammatory diseases. Rheumatology. 2016;55(suppl 2):ii43–ii55. https://doi.org/10.1093/rheumatology/kew346. (Epub 2016/11/20; PubMed PMID: 27856660).

    Article  PubMed  Google Scholar 

  22. Wasilewska A, Winiarska M, Olszewska M, Rudnicka L. Interleukin-17 inhibitors. A new era in treatment of psoriasis and other skin diseases. Postepy Dermatologii i Alergologii. 2016;33(4):247–52. https://doi.org/10.5114/ada.2016.61599. (Epub 2016/09/09; PubMed PMID: 27605893; PubMed Central PMCID: PMCPmc5004212).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank FASTEK Ltd. (www.fastekjapan.com) for the English language review. This work was supported, in part, by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (24592080 and 26870042) (Tokyo, Japan). Masahiko Kanehira, Akira Sakurada, and Yoshinori Okada received a research grant from Ono Pharmaceutical Co. Ltd.

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Author notes

  1. Naoya Ishibashi and Tatsuaki Watanabe contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Naoya Ishibashi, Tatsuaki Watanabe, Masahiko Kanehira, Yui Watanabe, Hirotsugu Notsuda, Masafumi Noda, Akira Sakurada & Yoshinori Okada

  2. Department of Thoracic Surgery, Fujita Health University, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan

    Yasushi Hoshikawa

  3. Department of Occupational Health, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Shinya Ohkouchi

  4. Department of Thoracic Surgery, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan

    Naoya Ishibashi & Takashi Kondo

Authors
  1. Naoya Ishibashi
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  2. Tatsuaki Watanabe
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  11. Yoshinori Okada
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Corresponding author

Correspondence to Masahiko Kanehira.

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Ishibashi, N., Watanabe, T., Kanehira, M. et al. Bone marrow mesenchymal stromal cells protect allograft lung transplants from acute rejection via the PD-L1/IL-17A axis. Surg Today 48, 726–734 (2018). https://doi.org/10.1007/s00595-018-1643-x

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  • DOI: https://doi.org/10.1007/s00595-018-1643-x

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