Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Leclerc, Mathieu; Naserian, Sina; Pilon, C.; Thiolat, Allan; Martin, Gaëlle H.; Pouchy, Charlotte; Dominique, Claude; Belkacémi, Yazid; Charlotte, F.; Maury, Sébastien; Salomon, Benoı̂t L.; Cohen, José L.

doi:10.1182/blood-2016-02-700849

Cited by 99 publications

(110 citation statements)

References 36 publications

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“…This observation is in line with prior reports showing the efficacy of therapy blocking TNFα for xGVHD prevention in NSG mice (20), despite a recent study unraveled a “Treg promoting role” for TNFα trough TNFR2 stimulation (51). Also, in concordance with the lack of Th17 gene upregulation observed in RNAseq analysis in T cells harvested from mice spleen on day 7, day 14 flow cytometry analyses demonstrated that only a low percentage of CD4 + T cells expressed IL-17.…”

Section: Discussionsupporting

confidence: 91%

Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice

et al. 2018

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Despite the increasing use of humanized mouse models to study new approaches of graft-versus-host disease (GVHD) prevention, the pathogenesis of xenogeneic GVHD (xGVHD) in these models remains misunderstood. The aim of this study is to describe this pathogenesis in NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice infused with human PBMCs and to assess the impact of the expression of HLA-A0201 by NSG mice cells (NSG-HLA-A2/HHD mice) on xGVHD and graft-versus-leukemia (GvL) effects, by taking advantage of next-generation technologies. We found that T cells recovered from NSG mice after transplantation had upregulated expression of genes involved in cell proliferation, as well as in TCR, co-stimulatory, IL-2/STAT5, mTOR and Aurora kinase A pathways. T cells had mainly an effector memory or an effector phenotype and exhibited a Th1/Tc1-skewed differentiation. TCRβ repertoire diversity was markedly lower both in the spleen and lungs (a xGVHD target organ) than at infusion. There was no correlation between the frequencies of specific clonotypes at baseline and in transplanted mice. Finally, expression of HLA-A0201 by NSG mice led to more severe xGVHD and enhanced GvL effects toward HLA-A2+ leukemic cells. Altogether our data demonstrate that the pathogenesis of xGVHD shares important features with human GVHD and that NSG-HLA-A2/HHD mice could serve as better model to study GVHD and GvL effects.

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Section: Discussionsupporting

confidence: 91%

Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice

et al. 2018

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“…In concordance with other studies [24], we found that infliximab therapy for SR-aGVHD was associated with early clinical responses that were not durable. As has been suggested in experimental models [42], the lack of long-term efficacy of anti-TNF medications in GVHD patients may be due to the inhibition of regulatory T cell function, which promotes a vigorous alloreactive T cell response and counteracts the potential benefit of these drugs. Intestinal barrier loss because of the effects of conditioning regimens, sustained neutropenia, and increased susceptibility to infection are other mechanisms contributing to infliximab failure.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Infliximab Therapy in the Setting of Steroid-Refractory Acute Graft-versus-Host Disease

Yalniz

Hefazi

McCullough

et al. 2017

Biology of Blood and Marrow Transplantation

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Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first-line treatment; however, less than one-half of patients achieve durable remission. Studies suggest that TNF-α, a cytokine released from the bone marrow during conditioning, is involved in the pathogenesis of aGVHD. We retrospectively evaluated the outcome of anti-TNF-α therapy with infliximab in 35 patients with steroid refractory (SR) aGVHD. Infliximab was administered intravenously at 10 mg/kg for a median of 4 doses (range, 1 to 6) on a weekly basis. The overall response rates were 40% (17% complete response [CR], 23% partial response [PR]) at 4 weeks, 23% (9% CR, 14% PR) at 8 weeks, and 17% (all CR) at 12 weeks. Twenty-nine (83%) patients had infectious complications within 12 weeks of initiation of infliximab. These infections included 40 bacterial infections, 6 invasive fungal infections, and 5 viral reactivations. Twelve patients (34%) died secondary to infections. Overall survival at 12 weeks and 6 months from the start of infliximab therapy was 37% (13 of 35) and 17% (6 of 35), respectively; with most deaths secondary to complications from GVHD and infections. In conclusion; the use of infliximab therapy in patients with SR-aGVHD is associated with a modest poorly sustained response along with a heightened risk of severe infections. Future studies with more effective and less toxic therapies are needed for these patients.

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“…The relevance of TNFRII signaling on Treg cells was shown in other experimental models. In graft‐versus‐host disease, a blocking antibody against TNFRII abolished the disease control exerted by Treg cells , whereas TNFRII agonists could protect against graft‐versus‐host disease and ameliorate CIA by promoting Treg cell expansion . TNFRII expression in other immunomodulatory cells, such as myeloid‐derived suppressor cells (MDSCs), could also be associated with protection against inflammation, because TNFRII −/− mouse MDSCs are less suppressive .…”

Section: Discussionmentioning

confidence: 99%

Involvement of Tumor Necrosis Factor Receptor Type II in FoxP3 Stability and as a Marker of Treg Cells Specifically Expanded by Anti–Tumor Necrosis Factor Treatments in Rheumatoid Arthritis

Santinon

Batignes

Mebrek

et al. 2020

Arthritis & Rheumatology

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Objective To study the involvement of Treg cells expressing tumor necrosis factor receptor type II (TNFRII) in exerting control of inflammation in experimental models and in the response to anti‐TNF treatments in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA). Methods The role of TNFRII in Treg cells was explored using a multilevel translational approach. Treg cell stability was evaluated by analyzing the methylation status of the Foxp3 locus using bisulfite sequencing. Two models of inflammation (imiquimod‐induced skin inflammation and delayed‐type hypersensitivity arthritis [DTHA]) were induced in TNFRII−/− mice, with or without transfer of purified CD4+CD25+ cells from wild‐type (WT) mice. In patients with RA and those with SpA, the evolution of the TNFRII+ Treg cell population before and after targeted treatment was monitored. Results Foxp3 gene methylation in Treg cells was greater in TNFRII−/− mice than in WT mice (50% versus 36.7%). In cultured Treg cells, TNF enhanced the expression, maintenance, and proliferation of Foxp3 through TNFRII signaling. Imiquimod‐induced skin inflammation and DTHA were aggravated in TNFRII−/− mice (P < 0.05 for mice with skin inflammation and P < 0.0001 for mice with ankle swelling during DTHA compared to WT mice). Adoptive transfer of WT mouse Treg cells into TNFRII−/− mice prevented aggravation of arthritis. In patients with RA receiving anti‐TNF treatments, but not those receiving tocilizumab, the frequency of TNFRII+ Treg cells was increased at 3 months of treatment compared to baseline (mean ± SEM 65.2 ± 3.1% versus 49.1 ± 5.5%; P < 0.01). In contrast, in anti‐TNF–treated patients with SpA, the frequency of TNFRII+ Treg cells was not modified. Conclusion TNFRII expression identifies a subset of Treg cells that are characterized by stable expression of Foxp3 via gene hypomethylation, and adoptive transfer of TNFRII‐expressing Treg cells ameliorates inflammation in experimental models. Expansion and activation of TNFRII+ Treg cells may be one of the mechanisms by which anti‐TNF agents control inflammation in RA, but not in SpA.

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Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

Cited by 99 publications

References 36 publications

Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice

Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice

Safety and Efficacy of Infliximab Therapy in the Setting of Steroid-Refractory Acute Graft-versus-Host Disease

Involvement of Tumor Necrosis Factor Receptor Type II in FoxP3 Stability and as a Marker of Treg Cells Specifically Expanded by Anti–Tumor Necrosis Factor Treatments in Rheumatoid Arthritis

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