Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease

Sugiyama, Haruko; Maeda, Yoshinobu; Nishimori, Hisakazu; Yamasuji, Yoshiko; Matsuoka, Ken; Fujii, Nobuharu; Kondo, Eisei; Shinagawa, Katsuji; Tanaka, Takehiro; Takeuchi, Kengo; Teshima, Takanori; Tanimoto, Mitsune

doi:10.1016/j.bbmt.2013.11.018

Cited by 16 publications

(9 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the major therapeutic effect of RAPA was not attributed to T cells, alterations in the induction and function of immunoregulatory cells were investigated. As shown previously and confirmed by our data, induction of T regs is not impaired under RAPA treatment due to their relative independence on mTOR activation [47][48][49]. Accumulation of T regs in the skin of RAPA-treated BMT mice was observed when high doses of 3-5 mg/kg were administered [40], but not at doses of 1•5 mg/kg, which are applied in our studies.…”

Section: Discussionsupporting

confidence: 89%

Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity

Scheurer

Reisser

Leithäuser

et al. 2020

Clinical and Experimental Immunology

View full text Add to dashboard Cite

The immunosuppressant rapamycin (RAPA) inhibits mammalian target of rapamycin (mTOR) functions and is applied after allogeneic bone marrow transplantation (BMT) to attenuate the development of graft-versus-host disease (GVHD), although the cellular targets of RAPA treatment are not well defined. Allogeneic T cells are the main drivers of GVHD, while immunoregulatory myeloid-derived suppressor cells (MDSCs) were recently identified as potent disease inhibitors. In this study, we analyzed whether RAPA prevents the deleterious effects of allogeneic T cells or supports the immunosuppressive functions of MDSCs in a BMT model with major histocompatibility complex (MHC) classes I and II disparities. RAPA treatment efficiently attenuated clinical and histological GVHD and strongly decreased disease-induced mortality. Although splenocyte numbers increased during RAPA treatment, the ratio of effector T cells to MDSCs was unaltered. However, RAPA treatment induced massive changes in the genomic landscape of MDSCs preferentially up-regulating genes responsible for uptake or signal transduction of lipopeptides and lipoproteins. Most importantly, MDSCs from RAPA-treated mice exhibited increased immunosuppressive potential, which was primarily inducible nitric oxide synthase (iNOS)-dependent. Surprisingly, RAPA treatment had no impact on the genomic landscape of T cells, which was reflected by unchanged expression of activation and exhaustion markers and cytokine profiles in T cells from RAPA-treated and untreated mice. Similarly, T cell cytotoxicity and the graft-versus-tumor effect were maintained as co-transplanted tumor cells were efficiently eradicated, indicating that the immunosuppressant RAPA might be an attractive approach to strengthen the immunosuppressive function of MDSCs without affecting T cell immunity.

show abstract

Section: Discussionsupporting

confidence: 89%

Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity

Scheurer

Reisser

Leithäuser

et al. 2020

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…Liver slides were scored based on bile duct injury and inflammation (0-4 for each category), and the maximum score was 8 (33). Salivary slides were scored on mononuclear cell infiltration and follicular destruction, and the maximum score was 4 (34).…”

Section: Tissue Histopathologymentioning

confidence: 99%

Anti–IL-12/23 p40 Antibody Attenuates Experimental Chronic Graft-versus-Host Disease via Suppression of IFN-γ/IL-17–Producing Cells

Okamoto

Fujiwara

Nishimori

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17−) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb–treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb–treated allogeneic recipients. T-bet expression of donor IL-17+ CD4+ T cells was reduced significantly in anti-p40 mAb–treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17–producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.

show abstract

“…Liver slides were also scored according to bile duct injury and inflammation (0-4 for each category; the maximum score was 8) (25). Salivary gland slides were scored based on atrophy and inflammation (0-3 for each category) and the maximum score was 6 (26).…”

Section: Tissue Histopathologymentioning

confidence: 99%

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

Fujiwara

Maeda

Kobayashi

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2d) donor to BALB/c (H-2d) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti–PD-1, anti–PD-L1, or anti–PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17+IFN-γ+ T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17+IFN-γ+ T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1−/− recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.

show abstract

Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease

Cited by 16 publications

References 46 publications

Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity

Rapamycin-based graft-versus-host disease prophylaxis increases the immunosuppressivity of myeloid-derived suppressor cells without affecting T cells and anti-tumor cytotoxicity

Anti–IL-12/23 p40 Antibody Attenuates Experimental Chronic Graft-versus-Host Disease via Suppression of IFN-γ/IL-17–Producing Cells

Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease

Contact Info

Product

Resources

About