Selective Activation of Tumor Necrosis Factor Receptor <scp>II</scp> Induces Antiinflammatory Responses and Alleviates Experimental Arthritis

Fischer, Roman; Proske, Marcel; Duffey, Maëlle; Stangl, Hubert; Martinez, George F.; Peters, Nathalie; Kraske, Alexandra; Straub, Rainer H.; Bethea, John R.; Kontermann, Roland E.; Pfizenmaier, Klaus

doi:10.1002/art.40413

Cited by 38 publications

(45 citation statements)

References 52 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

“…Most of the proinflammatory effects of TNF are generally considered to be mediated by TNFRI , whereas the immunosuppressive effects of TNF are considered to be mediated by TNFRII . In particular, the antiinflammatory effects of TNF may be dependent on its ability to activate and expand TNFRII‐expressing Treg cells .…”

Section: Introductionmentioning

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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“…Interestingly, expression of TNFR2 defines a maximally suppressive subset of mouse Tregs (Chen et al, 2008), indicating that TNFR2 activation regulates suppressive activity of Tregs. Indeed, it was shown that exogenous activation of TNFR2 leads to expansion of Tregs, alleviates arthritic disease and protects from acute graft versus host disease (Chopra et al, 2016;Fischer et al, 2018;Lamontain et al, 2018). Our published data indicate that presence of IL-2 dramatically increases TNFR2-dependent Treg expansion in vitro (Fischer et al, 2017;Fischer et al, 2018).…”

Section: Introductionmentioning

confidence: 64%

“…Indeed, it was shown that exogenous activation of TNFR2 leads to expansion of Tregs, alleviates arthritic disease and protects from acute graft versus host disease (Chopra et al, 2016;Fischer et al, 2018;Lamontain et al, 2018). Our published data indicate that presence of IL-2 dramatically increases TNFR2-dependent Treg expansion in vitro (Fischer et al, 2017;Fischer et al, 2018). Because of the apparent requirement of a combined activation of IL-2 and TNFR2 signal pathways we have developed a novel, dualacting cytokine fusion protein, where IL-2 is fused by genetic engineering to a TNFR2-selective TNF mutein.…”

Section: Introductionmentioning

confidence: 99%

Superior Treg-Expanding Properties of a Novel Dual-Acting Cytokine Fusion Protein

et al. 2019

Self Cite

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Autoimmune diseases are caused by uncontrolled endogenous immune responses against healthy cells. They may develop due to an impaired function of regulatory T cells (Tregs), which normally suppress self-specific effector immune cells. Interleukin 2 (IL-2) and tumor necrosis factor (TNF) have been identified as key players that promote expansion, function, and stability of Tregs. In vivo, both low-dose IL-2 therapy and TNF receptor 2 (TNFR2) agonism were shown to expand Tregs and alleviate autoimmunity. We here designed a novel dimeric dual-acting fusion cytokine, where mouse IL-2 is genetically linked to a TNFR2-selective single-chain TNF mutein (IL2-EHD2-sc-mTNF R2). IL2-EHD2sc-mTNF R2 showed high affinity to TNFR2 and efficiently activated IL-2 and TNFR2selective signaling pathways. Further, IL2-EHD2-sc-mTNF R2 promoted superior Treg expansion, with both the IL-2 and the TNFR2 agonist (sc-mTNF R2) component necessary for this biological response. Ultimately, we propose that IL2-EHD2-sc-mTNF R2 is a dualacting cytokine that efficiently promotes Treg expansion and might have a superior therapeutic window than conventional IL-2-based drugs.

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“…The efficacy of TNFR2 activation in a murine model of arthritis with EHD2‐sc‐mTNFR2 was reported. TNFR2 activation in mice with CIA resulted in the expansion of Treg cells and in a decrease of clinical symptoms 170 . Specifically, administration of TNFR2 agonist EHD2‐sc‐mTNFR2 before clinical symptoms led to delayed EAE disease onset with decreased clinical scores, mechanical allodynia, and T cell infiltration in CNS, 171 whereas therapeutic administration of TNFR2 agonist EHD2‐sc‐mTNFR2 resulted in disease amelioration, expansion Treg cells, and decreased demyelination 171 …”

Section: Introductionmentioning

confidence: 99%

Distinct modes of TNF signaling through its two receptors in health and disease

Atretkhany

Гоголева

Drutskaya

et al. 2020

Journal of Leukocyte Biology

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TNF is a key proinflammatory and immunoregulatory cytokine whose deregulation is associated with the development of autoimmune diseases and other pathologies. Recent studies suggest that distinct functions of TNF may be associated with differential engagement of its two receptors: TNFR1 or TNFR2. In this review, we discuss the relative contributions of these receptors to pathogenesis of several diseases, with the focus on autoimmunity and neuroinflammation. In particular, we discuss the role of TNFRs in the development of regulatory T cells during neuroinflammation and recent findings concerning targeting TNFR2 with agonistic and antagonistic reagents in various murine models of autoimmune and neuroinflammatory disorders and cancer.

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Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis

Abstract: Our findings support the use of TNFRII-selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases.

Cited by 38 publications

References 52 publications

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

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

Superior Treg-Expanding Properties of a Novel Dual-Acting Cytokine Fusion Protein

Distinct modes of TNF signaling through its two receptors in health and disease

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