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

被引：21

作者：

Senjo, Hajime ^{[1
]}

Harada, Shinpei ^{[1
]}

Kubota, Shimpei I. ^{[2
]}

Tanaka, Yuki ^{[3
]}

Tateno, Takahiro ^{[1
]}

Zhang, Zixuan ^{[1
]}

Okada, Satomi ^{[1
]}

Chen, Xuanzhong ^{[1
]}

Kikuchi, Ryo ^{[1
]}

Miyashita, Naoki ^{[1
]}

Onozawa, Masahiro ^{[1
]}

Goto, Hideki ^{[1
]}

Endo, Tomoyuki ^{[1
]}

Hasegawa, Yuta ^{[1
]}

Ohigashi, Hiroyuki ^{[1
]}

Ara, Takahide ^{[1
]}

Hasegawa, Yoshinori ^{[4
]}

Murakami, Masaaki ^{[2
,3
,5
,6
]}

Teshima, Takanori ^{[1
]}

Hashimoto, Daigo ^{[1
,7
]}

机构：

[1] Hokkaido Univ, Inst Genet Med, Grad Sch Med, Dept Hematol,Fac Med, Sapporo, Japan

[2] Hokkaido Univ, Inst Genet Med, Grad Sch Med, Mol Psychoimmunol, Sapporo, Japan

[3] Natl Inst Quantum & Radiol Sci & Technol, Inst Quantum Life Sci, Grp Quantum Immunol, Chiba, Japan

[4] Kazusa DNA Res Inst, Dept Appl Genom, Chiba, Japan

[5] Natl Inst Nat Sci, Natl Inst Physiol Sci, Dept Homeostat Regulat, Div Mol Neuroimmunol, Okazaki, Aichi, Japan

[6] Hokkaido Univ, Inst Vaccine Res & Dev, Div Biol Response Anal, Sapporo, Japan

[7] Hokkaido Univ, Dept Hematol, Dept Rheumatol Endocrinol & Nephrol, Fac Med, N15W7,Kita Ku, Sapporo 0608638, Japan

来源：

BLOOD | 2023年 / 142卷 / 05期

关键词：

VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; LATE DEATHS; FOLLOW-UP; BLOCKADE; PD-1; METHOTREXATE; CYCLOSPORINE; RUXOLITINIB; PROGENITOR;

D O I：

10.1182/blood.2023019875

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：477 / 492

页数：16

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