Neutralization of LIGHT ameliorates acute dextran sodium sulphate‐induced intestinal inflammation

Jungbeck, Michaela; Daller, Barbara; Federhofer, Josef; Wege, Anja K.; Wimmer, Nadin; Männel, Daniela N.; Hehlgans, Thomas

doi:10.1111/j.1365-2567.2009.03131.x

Cited by 27 publications

(25 citation statements)

References 19 publications

(30 reference statements)

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“…Therefore, in two different mouse models of colitis, the absence of LIGHT expression led to exacerbated disease. In a previous study, the absence of LIGHT was shown to ameliorate acute DSS-induced colitis 10 . To elucidate whether this discrepancy was due to acute versus chronic DSS administration, we performed acute DSS-induced colitis experiments.…”

Section: Resultsmentioning

confidence: 87%

“…HVEM-deficiency did not lead to more severe disease (Figure 5A). Additionally, blocking HVEM:LIGHT binding using a specific anti-HVEM antibody (LH1), which only blocks binding of HVEM to LIGHT but not to BTLA 10 , did not induce accelerated weight loss in the transfer model of colitis (Figure 5B). In contrast, administration of a LTβR antibody (LLTB2), which specifically blocks LTβR:LIGHT binding, but not LTβR binding to lymphotoxin (LTα 1 β 2 ) 11 , recapitulated the LIGHT-deficient phenotype of severe body weight loss in both the chronic DSS-induced and the T cell transfer model (Figure 5C, D).…”

Section: Resultsmentioning

confidence: 99%

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The Tumor Necrosis Factor Family Member TNFSF14 (LIGHT) Is Required for Resolution of Intestinal Inflammation in Mice

et al. 2014

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Background & Aims The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice. Methods We studied the role of LIGHT in intestinal inflammation using Tnfsf14−/− and wild-type mice. Colitis was induced by transfer of CD4+CD45RBhigh T cells into Rag1−/− or Tnfsf14−/−Rag1−/− mice, or by administration of dextran sulfate sodium salt (DSS) to Tnfsf14−/− or wild-type C57BL/6J mice. Mice were weighed; colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT. Results Following administration of DSS, Tnfsf14−/− mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin β receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14−/− mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT therefore appears to regulate inflammation in the colon. Conclusion Tnfsf14−/− mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin β receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

The Tumor Necrosis Factor Family Member TNFSF14 (LIGHT) Is Required for Resolution of Intestinal Inflammation in Mice

et al. 2014

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“…Although numerous reports in mouse models of inflammatory diseases have provided indirect experimental evidence that LIGHT may be involved in the pathogenesis of these immune-related diseases (10,38-42), this information contrasts with the lack of appropriate reagents for the detection of endogenous mouse LIGHT. The reason for this gap was the difficulty to engineer a genetic construct that produced a bioactive mouse LIGHT molecule with binding affinity for membrane-bound LIGHT receptors.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Blockade of LIGHT Interaction With Herpesvirus Entry Mediator and Lymphotoxin β Receptor Attenuates In Vivo Cytotoxic Allogeneic Responses

Rio¹,

Fernández-Renedo²,

Scheu

et al. 2014

Transplantation

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Background TNF/TNFR superfamily members conform a group of molecular interaction pathways of essential relevance during the process of T cell activation and differentiation towards effector cells and particularly for the maintenance phase of the immune response. Specific blockade of these interacting pathways, such as CD40/CD40L, contributes to modulate the deleterious outcome of allogeneic immune responses. We postulated that antagonizing the interaction of LIGHT expression on activated T cells with its receptors, HVEM and LTβR may decrease T cell-mediated allogeneic responses. Methods A flow cytometry competition assay was designed to identify anti-LIGHT monoclonal antibodies capable to prevent the interaction of mouse LIGHT with its receptors expressed on transfected cells. An antibody with the desired specificity was evaluated in a short-term in vivo allogeneic cytotoxic assay and tested for its ability to detect endogenous mouse LIGHT. Results We provide evidence for the first time that in mice, as previously described in humans, LIGHT protein is rapidly and transiently expressed after T cell activation, and this expression was stronger on CD8 T cells than on CD4 T cells. Two anti-LIGHT antibodies prevented interactions of mouse LIGHT with its two known receptors HVEM and LTβR. In vivo administration of anti-LIGHT antibody (clone 10F12) ameliorated host anti-donor short-term cytotoxic response in WT B6 mice, although to a lesser extent than that observed in LIGHT-deficient mice. Conclusions The therapeutic targeting of LIGHT may contribute to achieve a better control of cytotoxic responses refractory to current immunosuppressive drugs in transplantation.

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“…In both diseases LTβ expression was mostly increased on plasma cells and a subset of CD4 + lymphocytes located in the lamina propria, whereas CD8 + cells did not express LTβ. In a follow-up study they were able to show that LTβR activation by LTα 1 β 2 has a crucial effect on downregulation of the inflammatory process [75]. The Gram-negative bacterium Citrobacter rodentium, a natural mouse extracellular enteric pathogen, is widely used to analyze molecular mechanisms in gut immune responses.…”

Section: Lt and Gastrointestinal Immune Homoeostasismentioning

confidence: 99%

Lymphotoxin, NF-ĸB, and Cancer: The Dark Side of Cytokines

Bauer

Namineni²,

Reisinger³

et al. 2012

Dig Dis

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Cytokines have been implicated in a variety of physiological processes involving lymphoid tissue development, lymphocyte activation, and control of regenerative processes such as wound healing. The first characterization of a cytokine implicated in abolishing or killing tumor cells – the tumor necrosis factor (TNF) – fostered and boosted a completely new field of research that in addition to cancer research started to generate an overwhelming amount of knowledge in immunology, various pathological processes, and other fields of research. Due to the complex networks and versatile functions of cytokines, it soon became clear that cytokines can possess diametric functions in various biological processes. As for tumor research it was shown that some cytokines – depending on the type of organ, the time of action, gender, and the cellular environment – can have either pro- or anticarcinogenic action. For those cytokines reported to be procarcinogenic, this could be accomplished by directly acting as oncogenes or generating an inflammatory environment that is procarcinogenic. Here we review a novel role for TNF family members – in particular lymphotoxin (LT) α and β – in physiology and in driving tumorigenesis, with special focus on the liver. We believe that recent findings on this particular cytokine might have strong implications for the therapy of liver cancer or other inflammation-induced cancer types.

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Neutralization of LIGHT ameliorates acute dextran sodium sulphate‐induced intestinal inflammation

Cited by 27 publications

References 19 publications

The Tumor Necrosis Factor Family Member TNFSF14 (LIGHT) Is Required for Resolution of Intestinal Inflammation in Mice

The Tumor Necrosis Factor Family Member TNFSF14 (LIGHT) Is Required for Resolution of Intestinal Inflammation in Mice

Therapeutic Blockade of LIGHT Interaction With Herpesvirus Entry Mediator and Lymphotoxin β Receptor Attenuates In Vivo Cytotoxic Allogeneic Responses

Lymphotoxin, NF-ĸB, and Cancer: The Dark Side of Cytokines

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