Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD

Chopra, Martin; Brandl, Andreas; Siegmund, Daniela; Mottok, Anja; Schäfer, Viktoria; Biehl, Marlene; Kraus, Sabrina; Bäuerlein, Carina A.; Ritz, Miriam; Martini, Katharina; Schwinn, Stefanie; Seher, Axel; Grabinger, Thomas; Einsele, Hermann; Rosenwald, Andreas; Brunner, Thomas; Beilhack, Andreas; Wajant, Harald

doi:10.1182/blood-2015-01-620583

Cited by 26 publications

(26 citation statements)

References 55 publications

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“…C57BL/6 mice were treated with an Fn14-specific blocking human immunoglobulin G1 antibody variant (18D1-dead), generously provided by Harald Wajant of University Hospital Würzburg, Würzburg, Germany (19). Control mice were treated with Rituximab, a therapeutic human IgG1 antibody recognizing human, but not murine, CD20 as an isotype control antibody.…”

Section: Methodsmentioning

confidence: 99%

Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis

et al. 2016

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Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its pro-apoptotic effects. Colitis was in Fn14-/- and Fn14+/+ wild type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2 weeks recovery; azoxymethane (AOM) administration followed by 2 cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and non-hematopoietic-specific effector tissues. Fn14-/- mice had enhanced susceptibility to colitis compared to Fn14+/+ controls as assessed by endoscopic and histological inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and non-hematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14-/- mice, but not Fn14+/+ controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14-/- mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer.

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Section: Methodsmentioning

confidence: 99%

Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis

et al. 2016

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“…It is also relevant in regard to anti-TNF treatment that is sometimes administered to patients with severe GVHD. The activation of TNF receptor type 1 (TNFR1) could be associated with increased inflammation and tissue damage in allo-HCT 19 and blocking this pathway could ameliorate GVHD by reducing cell death of gastrointestinal cells. Thus, one may hypothesize that anti-TNF treatment would have a beneficial effect by blocking TNFR1 triggering but a detrimental effect by blocking TNFR2 triggering on Tregs, the latter phenomenon being assessed in this work.…”

Section: Foxp3mentioning

confidence: 99%

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

Leclerc

Naserian

Pilon

et al. 2016

Blood

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Key Points• In vivo Treg effect depends on TNFa produced by T cells.• TNF/TNFR2 interaction represents a novel immune checkpoint therapy to modulate alloreactivity after allo-HCT. Therapeutic CD41 Foxp3 1 natural regulatory T cells (Tregs) can control experimental graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by suppressing conventional T cells (Tconvs). Treg-based therapies are currently tested in clinical trials with promising preliminary results in allo-HCT. Here, we hypothesized that as Tregs are capable of modulating Tconv response, it is likely that the inflammatory environment and particularly donor T cells are also capable of influencing Treg function. Indeed, previous findings in autoimmune diabetes revealed a feedback mechanism that renders Tconvs able to stimulate Tregs by a mechanism that was partially dependent on tumor necrosis factor (TNF). We tested this phenomenon during alloimmune response in our previously described model of GVHD protection using antigen specific Tregs. Using different experimental approaches, we observed that control of GVHD by Tregs was fully abolished by blocking TNF receptor type 2 (TNFR2) or by using TNF-deficient donor T cells or TNFR2-deficient Tregs. Thus, our results show that Tconvs exert a powerful modulatory activity on therapeutic Tregs and clearly demonstrate that the sole defect of TNF production by donor T cells was sufficient to completely abolish the Treg suppressive effect in GVHD. Importantly, our findings expand the understanding of one of the central components of Treg action, the inflammatory context, and support that targeting TNF/TNFR2 interaction represents an opportunity to efficiently modulate alloreactivity in allo-HCT to either exacerbate it for a powerful antileukemic effect or reduce it to control GVHD. (Blood. 2016;128(12):1651-1659

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“…[138] Fn14 receptor expression was increased specifically on intestinal epithelial cells during GVHD and was observed only in GVHD samples. [139] An Fn14-specific antibody reduces experimental GVHD [139] through a mechanism specific to the target tissue and did not impair a GVL effect.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease

Renteria

Levine

Ferrara

2016

Expert Opinion on Orphan Drugs

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Introduction Graft-versus-host disease (GVHD) continues to be the major lethal complication of allogeneic hematopoietic stem cell transplantation (HCT) but the standard of care, high dose steroids, has not changed in 40 years. Approximately 50% of GVHD patients will develop steroid refractory disease, typically involving the gastrointestinal (GI) tract, which has a very poor prognosis. Newly developed GVHD biomarker-based risk scores provide the first opportunity to treat patients at the onset of symptoms according to risk of steroid failure. Furthermore, improvements in our understanding of the pathobiology of GVHD, its different signaling pathways, involved cytokines, and the role of post-translational and epigenetic modifications, has identified new therapeutic targets for clinical trials. Areas covered This manuscript summarizes the pathophysiology, diagnosis, staging, current and new targeted therapies for GVHD, with an emphasis on GI GVHD. A literature search on PubMed was undertaken and the most relevant references included. Expert Opinion The standard treatment for GVHD, high dose steroids, offers less than optimal outcomes as well as significant toxicities. Better treatments, especially for GI GVHD, are needed to reduce non-relapse mortality after allogeneic HCT. The identification of high risk patients through a biomarker-defined scoring system offers a personalized approach to a disease that still requires significant research attention.

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Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD

Abstract: Key Points Fn14 activation is involved in intestinal apoptosis after allo-HCT and contributes to gastrointestinal GVHD. Fn14 blockade with an ADCC-defective human immunoglobulin G1 antibody reduces GVHD severity without modulating GVL responses.

Cited by 26 publications

References 55 publications

Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis

Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis

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

Therapeutic targets and emerging treatment options in gastrointestinal acute graft-versus-host disease

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