Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT

Senjo, Hajime; Harada, Shinpei; Kubota, Shimpei I. et al.

Blood, 2023, 142(5), 477-492

Permalink : https://hdl.handle.net/2115/93075

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論文情報

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アクセス権
open access
URI
https://hdl.handle.net/2115/93075
タイトル
Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT
著者
Senjo, Hajime ; Harada, Shinpei ; Kubota, Shimpei I. ; Tanaka, Yuki ; Tateno, Takahiro ; Zhang, Zixuan ; Okada, Satomi ; Chen, Xuanzhong ; Kikuchi, Ryo ; Miyashita, Naoki ; Onozawa, Masahiro ; Goto, Hideki ; Endo, Tomoyuki ; Hasegawa, Yuta ; Ohigashi, Hiroyuki ; Ara, Takahide ; Hasegawa, Yoshinori ; Murakami, Masaaki ; Teshima, Takanori ; Hashimoto, Daigo
著者名
Senjo, Hajime
著者名
Harada, Shinpei
著者名
Kubota, Shimpei I.
著者名
Tanaka, Yuki
著者名
Tateno, Takahiro
著者名
Zhang, Zixuan
著者名
Okada, Satomi
著者名
Chen, Xuanzhong
著者名
Kikuchi, Ryo
著者名
Miyashita, Naoki
著者名
Onozawa, Masahiro
著者名
Goto, Hideki
著者名
Endo, Tomoyuki
著者名
Hasegawa, Yuta
著者名
Ohigashi, Hiroyuki
著者名
Ara, Takahide
著者名
Hasegawa, Yoshinori
e-Rad_Researcher
00250514
著者名
Murakami, Masaaki
e-Rad_Researcher
40284096
著者名
Teshima, Takanori
e-Rad_Researcher
20419576
著者名
Hashimoto, Daigo
言語
英語
発行日
2023-08-03
出版者
American Society of Hematology
収録物名
Blood
巻(号)
142(5)
ページ
477-492
抄録
Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD (cGVHD) in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1* TIGIT* terminally exhausted T cells (terminal Tex). GVHD prophylaxis with cyclosporine (CSP) sup-pressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory Tex), expressing both inhibitory receptors and effector molecules, into terminal Tex, and inhibited tolerance induction. Adoptive transfer of transitory Tex, but not terminal Tex, into secondary recipients developed cGVHD. Transitory Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory Tex and not terminal Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse.
資源タイプ
学術雑誌論文
出版タイプ
Version of Record
PISSN
0006-4971
関連情報 (isIdenticalTo)
出版社版DOI
https://doi.org/10.1182/blood.2023019875