Alloreaction increases or restores CD40, CD54, and/or HLA molecule expression in acute myelogenous leukemia blasts, through secretion of inflammatory cytokines: dominant role for TNFβ, in concert with IFNγ

Signal transducer and activator of transcription (STAT)-3 inhibitors play an important role in regulating immune responses. Galiellalactone (GL) is a fungal secondary metabolite known to interfere with the binding of phosphorylated signal transducer and activator of transcription (pSTAT)-3 as well of pSTAT-6 dimers to their target DNA in vitro. Intra nasal delivery of 50 μg GL into the lung of naive Balb/c mice induced FoxP3 expression locally and IL-10 production and IL-12p40 in RNA expression in the airways in vivo. In a murine model of allergic asthma, GL significantly suppressed the cardinal features of asthma, such as airway hyperresponsiveness, eosinophilia and mucus production, after sensitization and subsequent challenge with ovalbumin (OVA). These changes resulted in induction of IL-12p70 and IL-10 production by lung CD11c(+) dendritic cells (DCs) accompanied by an increase of IL-3 receptor α chain and indoleamine-2,3-dioxygenase expression in these cells. Furthermore, GL inhibited IL-4 production in T-bet-deficient CD4(+) T cells and down-regulated the suppressor of cytokine signaling-3 (SOCS-3), also in the absence of STAT-3 in T cells, in the lung in a murine model of asthma. In addition, we found reduced amounts of pSTAT-5 in the lung of GL-treated mice that correlated with decreased release of IL-2 by lung OVA-specific CD4(+) T cells after treatment with GL in vitro also in the absence of T-bet. Thus, GL treatment in vivo and in vitro emerges as a novel therapeutic approach for allergic asthma by modulating lung DC phenotype and function resulting in a protective response via CD4(+)FoxP3(+) regulatory T cells locally.

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“…7D, lower right panels). Taken together, these data show an induction of Treg cells dependent on DCs upon GL treatment (17,34).…”

Section: Gl Mediated the Induction Of Lung Foxp3 And Il-10-producing Cd4 + T Cells In Vivosupporting

confidence: 62%

Induction of tolerogenic lung CD4+ T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma

Hausding¹,

Tepe²,

Übel³

et al. 2010

International Immunology

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“…This positive effect was also demonstrated on AML blast differentiation (35). In contrast, we have shown herein that IFN-␥ secreted during an alloresponse induces differentiation of Mo into Tol-DC, which are able to induce generation of FoxP3 ϩ regulatory T cells.…”

Section: Discussionmentioning

confidence: 45%

IFN-γ, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3+ Regulatory T Cell Promotion

Eljaafari

Miossec

2009

The Journal of Immunology

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IFN-γ has been shown to inhibit monocyte (Mo) differentiation into mature dendritic cells (DC). Because IFN-γ also plays a role in tolerance induction, we asked whether this could be related to generation of tolerogenic DC (Tol-DC). Toward this aim, we cultured Mo with GM-CSF plus IL-4 in the presence or absence of IFN-γ for 6 days and induced their maturation with TNF-α for 2 additional days. We showed that IFN-γ deviated Mo differentiation from mature DC toward Tol-DC. Indeed, IFN-γ-generated DC 1) expressed moderate levels of costimulatory molecules, but high levels of Langerin and CD123 molecules, 2) were maturation resistant, and 3) were unable to efficiently present alloantigen to T cells. More interestingly, naive CD4+ T cells primed with IFN-γ-generated DC expressed FoxP3 mRNA at high levels and exerted regulatory functions upon secondary stimulation with alloantigen. To address whether endogenously secreted IFN-γ mediates a similar effect, we used the alloreaction as a model. We showed that cell-free supernatant harvested from an HLA-mismatched, but not HLA-identical, alloresponse induced differentiation of Mo into Tol-DC able to promote regulatory T cell generation. Moreover, when supplemented with GM-CSF plus IL-4, HLA-mismatched cell-free supernatant inhibited differentiation of Mo into mature DC. Finally, by adding Abs directed against inflammatory cytokines, we demonstrated that IFN-γ plays a preponderant role in this inhibition. In conclusion, our results clearly demonstrate that exogenous or endogenous IFN-γ, as well, induces differentiation of Mo toward Tol-DC, which results in FoxP3+ regulatory T cell promotion.

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“…It will be important to determine the importance of IFN-γ in GVL against other mouse myeloid leukemias and against human AML samples. (48,(55)(56)(57)(58)(59)(60)(61)(62), with both basal and IFN-γ-induced STAT1 phosphorylation (58) and MHCI and MHCII upregulation. We hope our results demonstrating a critical role for IFN-γ in GVL responses against two clinically relevant mouse models of myeloblastic leukemias will both stimulate a broader evaluation of the IFN-γ responsiveness of additional mouse AML models and of human AML specimens classified by molecular features, and the development of approaches to safely deliver IFN-γ in the clinic. )…”

Section: Discussionmentioning

confidence: 99%

Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

Matte-Martone¹,

Liu²,

Zhou³

et al. 2017

Journal of Clinical Investigation

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CD8-mediated GVL against mCP-CML experiments, some mice reached predetermined criteria for sacrifice due to GVHD. If spleens were small and the most recent analysis of peripheral blood showed, at most, only a few NGFR + CP-CML cells, these mice were scored as having GVHD and were censored (see Figure 2, G and H). Differences in cell percentages were determined by 2-tailed Mann-Whitney U test. Study approvalAll animal studies were approved by the

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Alloreaction increases or restores CD40, CD54, and/or HLA molecule expression in acute myelogenous leukemia blasts, through secretion of inflammatory cytokines: dominant role for TNFβ, in concert with IFNγ

Cited by 8 publications

References 30 publications

Induction of tolerogenic lung CD4+ T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma

Induction of tolerogenic lung CD4+ T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma

IFN-γ, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3+ Regulatory T Cell Promotion

Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

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