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

Naoya Ishibashi; Tatsuaki Watanabe; Masahiko Kanehira; Yui Watanabe; Yasushi Hoshikawa; Hirotsugu Notsuda; Masafumi Noda; Akira Sakurada; Shinya Ohkouchi; Takashi Kondo; Yoshinori Okada

doi:10.1007/s00595-018-1643-x

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

Naoya Ishibashi, Tatsuaki Watanabe, Masahiko Kanehira, Yui Watanabe, Yasushi Hoshikawa, Hirotsugu Notsuda, Masafumi Noda, Akira Sakurada, Shinya Ohkouchi, Takashi Kondo, Yoshinori Okada

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5 Citations (Scopus)

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.

Original language	English
Pages (from-to)	726-734
Number of pages	9
Journal	Surgery Today
Volume	48
Issue number	7
DOIs	https://doi.org/10.1007/s00595-018-1643-x
Publication status	Published - 2018 Jul 1

Keywords

Acute rejection
IL-17A
Lung transplantation
Mesenchymal stromal cells
PD-L1

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10.1007/s00595-018-1643-x

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

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.",

keywords = "Acute rejection, IL-17A, Lung transplantation, Mesenchymal stromal cells, PD-L1",

author = "Naoya Ishibashi and Tatsuaki Watanabe and Masahiko Kanehira and Yui Watanabe and Yasushi Hoshikawa and Hirotsugu Notsuda and Masafumi Noda and Akira Sakurada and Shinya Ohkouchi and Takashi Kondo and Yoshinori Okada",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2018, Springer Nature Singapore Pte Ltd.",

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doi = "10.1007/s00595-018-1643-x",

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T1 - Bone marrow mesenchymal stromal cells protect allograft lung transplants from acute rejection via the PD-L1/IL-17A axis

AU - Ishibashi, Naoya

AU - Watanabe, Tatsuaki

AU - Kanehira, Masahiko

AU - Watanabe, Yui

AU - Hoshikawa, Yasushi

AU - Notsuda, Hirotsugu

AU - Noda, Masafumi

AU - Sakurada, Akira

AU - Ohkouchi, Shinya

AU - Kondo, Takashi

AU - Okada, Yoshinori

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2018, Springer Nature Singapore Pte Ltd.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

KW - Acute rejection

KW - IL-17A

KW - Lung transplantation

KW - Mesenchymal stromal cells

KW - PD-L1

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JO - Surgery Today

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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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Keywords

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