ABSTRACT
The pivotal role of TL1A in modulating immune pathways crucial for inflammatory bowel disease (IBD) and intestinal fibrosis offers a promising therapeutic target. Phase 2 trials (TUSCANY and ARTEMIS-UC) evaluating an anti-TL1A antibody show progress in expanding IBD therapeutic options. First-in-human data reveal reduced expression of genes associated with extracellular matrix remodeling and fibrosis post-anti-TL1A treatment. Investigational drug TEV-48574, potentially exerting dual antifibrotic and anti-inflammatory effects, is undergoing a phase 2 basket study in both ulcerative colitis (UC) and Crohn disease (CD). Results are eagerly awaited, marking advancements in IBD therapeutics. This critical review comprehensively examines the existing literature, illuminating TL1A and the intricate role of DR3 in IBD, emphasizing the evolving therapeutic landscape and ongoing clinical trials, with potential implications for more effective IBD management.
Subject(s)
Fibrosis , Inflammatory Bowel Diseases , Tumor Necrosis Factor Ligand Superfamily Member 15 , Humans , Fibrosis/drug therapy , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15/genetics , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Inflammation/drug therapy , Inflammation/immunology , Crohn Disease/drug therapy , Crohn Disease/immunology , Crohn Disease/pathology , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Colitis, Ulcerative/pathology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacologyABSTRACT
BACKGROUND: The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. METHODS: Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. RESULTS: Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. CONCLUSIONS: The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.
Subject(s)
Colitis, Ulcerative , Colitis, Ulcerative/drug therapy , Fibrosis/drug therapy , Humans , Inflammation/drug therapy , Inflammation/metabolism , Ligands , Necrosis , Proteomics , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/geneticsABSTRACT
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. In the last few years, the development of biological agents targeting cytokines and receptors involved in IBD pathogenesis has led to better outcomes and has improved the course of the disease. Despite their effectiveness, drugs such as tumor necrosis factor (TNF) inhibitors, anti-Interleukin-12/23 and anti-integrins, do not induce a response in about one-third of patients, and 40% of patients lose response over time. Therefore, more efficient therapies are required. Recent studies showed that TL1A (Tumor necrosis factor-like cytokine 1A) acts as a regulator of mucosal immunity and participates in immunological pathways involved in the IBD pathogenesis. In this review article, we analyze the role of TL1A as a new potential target therapy in IBD patients.
Subject(s)
Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Humans , Inflammatory Bowel Diseases/drug therapyABSTRACT
BACKGROUND: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.
Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Tumor Necrosis Factor Ligand Superfamily Member 15/blood , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/genetics , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Humans , Methotrexate/therapeutic use , Mice , Synovial Fluid , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor-alphaABSTRACT
TL1A, as a master regulatory cytokine, plays a key role in the development of diverse T-cell-mediated inflammatory and autoimmune diseases. Our study is to further understand the roles of TL1A in the pathogenic mechanism of psoriasis and to find a possible new therapeutic strategy in the treatment of psoriasis. The direct effects of TL1A injection in mice skin and the therapeutic effects of TL1A blockade in imiquimod (IMQ)-induced psoriasis-like mouse model were researched in this study. First, we found that the expressions of TL1A in IMQ-treated lesions were significantly higher than Vaseline control group. And then, the results showed that TL1A injection exacerbated the psoriasiform phenotype on IMQ-treated skin (including clinical score, epidermal thickness changes, and Baker score) by increasing the number of T cells, neutrophils, and DCs, and upregulating the mRNA expression of IFN-γ and IL-17. However, anti-TL1A mAb can alleviate psoriasis-like lesions in clinical and effectively improved the histopathologic changes in IMQ-induced psoriasis-like mice after treatment. Moreover, anti-TL1A mAb also reduced the number of infiltrated CD3+ T cells, MPO+ neutrophils, and CD11c+ DCs in psoriasis-like lesions, and obviously decreased the expression of IFN-γ and IL-17 in psoriasis-like lesions. Data suggested that TL1A might be involved in the pathogenesis of psoriasis, and targeting TL1A by anti-TL1A mAb might provide a solid foundation and novel therapeutic sight in the treatment of psoriasis.
Subject(s)
Psoriasis/immunology , Skin/pathology , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolism , Animals , Disease Models, Animal , Humans , Imiquimod/administration & dosage , Imiquimod/toxicity , Male , Mice , Psoriasis/chemically induced , Psoriasis/drug therapy , Psoriasis/pathology , Signal Transduction/drug effects , Signal Transduction/immunology , Skin/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/administration & dosage , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Mechanistic studies have improved our understanding of molecular and cellular components involved in asthma and our ability to treat severe patients. An mAb directed against IgE (omalizumab) has become an established add-on therapy for patients with uncontrolled allergic asthma and mAbs specific for IL-5 (reslizumab, mepolizumab), IL-5R (benralizumab), and IL-4R (dupilumab) have been approved as add-on treatments for uncontrolled eosinophilic (type 2) asthma. While these medications have proven highly effective, some patients with severe allergic and/or eosinophilic asthma, as well as most patients with severe non-type-2 disease, have poorly controlled disease. Agents that have recently been evaluated in clinical trials include an antibody directed against thymic stromal lymphopoietin, small molecule antagonists to the chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) and the receptor for stem cell factor on mast cells (KIT), and a DNA enzyme directed at GATA3. Antibodies to IL-33 and its receptor, ST2, are being evaluated in ongoing clinical studies. In addition, a number of antagonists directed against other potential targets are under consideration for future trials, including IL-25, IL-6, TNF-like ligand 1A, CD6, and activated cell adhesion molecule (ALCAM). Clinical data from ongoing and future trials will be important in determining whether these new medications will offer benefits in place of or in addition to existing therapies for asthma.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Activated-Leukocyte Cell Adhesion Molecule/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , Asthma/immunology , Asthma/physiopathology , Cytokines/antagonists & inhibitors , Cytokines/immunology , DNA, Catalytic/therapeutic use , Eosinophils/immunology , GATA3 Transcription Factor , Humans , Imatinib Mesylate/therapeutic use , Indoleacetic Acids/therapeutic use , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Interleukin-6/immunology , Lymphocytes/immunology , Mast Cells/immunology , Molecular Targeted Therapy , Omalizumab/therapeutic use , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Proto-Oncogene Proteins c-kit/immunology , Pyridines/therapeutic use , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/immunology , Receptors, Interleukin-17/antagonists & inhibitors , Receptors, Interleukin-17/immunology , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/immunology , Ribonucleases/therapeutic use , Th2 Cells/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/immunologyABSTRACT
TL1A is an attractive therapeutic target for the treatment of mucosal inflammation associated with inflammatory bowel disease (IBD) and asthma. Blockade of the TL1A pathway has been shown to reduce inflammatory responses while leaving baseline immunity intact, and to be beneficial in animal models of colitis and asthma. Given the therapeutic potential of blocking this pathway in IBD and asthma, we developed C03V, a human antibody that binds with high affinity to soluble and membrane-bound TL1A. In an assay measuring apoptosis induced by exogenous TL1A, C03V was 43-fold more potent than the next most potent anti-TL1A antibody analyzed. C03V also potently inhibited endogenous TL1A activity in a primary cell-based assay. This potency was linked to the C03V-binding epitope on TL1A, encompassing the residue R32. This residue is critical for the binding of TL1A to its signaling receptor DR3 but not to its decoy receptor DcR3, and explains why C03V inhibited TL1A-DR3 binding to a much greater extent than TL1A-DcR3 binding. This characteristic may be advantageous to preserve some of the homeostatic functions of DcR3, such as TL1A antagonism. In colitis models, C03V significantly ameliorated microscopic, macroscopic and clinical aspects of disease pathology, and in an asthma model it significantly reduced airways inflammation. Notable in both types of disease model was the reduction in fibrosis observed after C03V treatment. C03V has the potential to address unmet medical needs in asthma and IBD.
Subject(s)
Antibodies, Monoclonal/pharmacology , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Animals , Antibodies, Monoclonal/chemistry , Asthma/immunology , Humans , Inflammatory Bowel Diseases/immunologyABSTRACT
Tumor necrosis factor like cytokine 1A (TL1A) is a member of the TNF superfamily. Accumulating evidence demonstrated the importance of TL1A in the pathogenesis of inflammatory bowel disease (IBD) and suggested a potential role of TL1A blocking in IBD therapy. Here we aimed to explore whether the anti-TL1A antibody could ameliorate intestinal inflammation and fibrosis in IBD. A T cell transfer model of chronic colitis was induced by intraperitoneal injection of CD4+CD45RBhigh naive T cells isolated from either C57BL/6 wild type (WT) mice or LCK-CD2-Tl1a-GFP transgenic (L-Tg) mice into recombinase activating gene-1-deficient (RAG-/-) mice. The colitis model mice were treated prophylactically or therapeutically with anti-Tl1a antibody or IgG isotype control. Haematoxylin and eosin staining (H&E staining), Masson's trichrome staining (MT staining) and sirius red staining were used to detect histopathological changes in colonic tissue; immunohistochemical staining was used to detect the expressions of collagen I, collagen III, TIMP1, vimentin, α-SMA and TGF-ß1/Smad3. Results showed that anti-Tl1a antibody could reduce intestinal inflammation and fibrosis by inhibiting the activation of intestinal fibroblasts and reducing the collagen synthesis in the T cell transfer model of chronic colitis. The mechanism may be related to the inhibition of TGF-1/Smad3 signaling pathway.
Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Colitis/metabolism , Inflammation/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Animals , Chronic Disease , Disease Models, Animal , Fibrosis/metabolism , Homeostasis/physiology , Male , Mice, Inbred C57BL , Tumor Necrosis Factor Ligand Superfamily Member 15/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolismABSTRACT
BACKGROUND: Vascular endothelial growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily, identified as an anti-angiogenic cytokine. However, the effect of VEGI on epithelial-mesenchymal transition (EMT) in renal cell carcinoma (RCC) is still unknown. MATERIALS AND METHODS: In this study, protein VEGI174 was designed and synthesized. Renal cell carcinoma A498 cells were implanted into immune-deficient mice to establish tumor models. Two groups were included: control group treated with saline, and VEGI174-treated group. Data of tumor growth were collected every 3 to 4 days. Two weeks later, the tumor specimens were harvested for immunohistochemical staining of EMT markers (E-cadherin, N-cadherin, vimentin). RESULTS: Compared to the saline-treated group, the VEGI174-treated group showed significant inhibition of tumor growth (p<0.05). The expression of E-cadherin was significantly higher in the VEGI174-treated group compared to the saline-treated group (p<0.01). However, the expression of N-cadherin and vimentin were reduced in the VEGI174-treated group. CONCLUSION: Our findings indicate that VEGI174 prevents progression and tumor metastasis through inhibiting EMT in RCC in vivo. This may provide a new approach for the treatment of RCC.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Tumor Necrosis Factor Ligand Superfamily Member 15/genetics , Animals , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Cell Movement/genetics , Gene Expression Regulation, Neoplastic/drug effects , Growth Inhibitors/administration & dosage , Humans , Mice , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/biosynthesis , Xenograft Model Antitumor AssaysABSTRACT
TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases.
Subject(s)
Molecular Targeted Therapy , Rheumatic Diseases/drug therapy , Rheumatic Diseases/immunology , Tumor Necrosis Factor Inhibitors , Tumor Necrosis Factors/metabolism , 4-1BB Ligand/antagonists & inhibitors , 4-1BB Ligand/metabolism , Animals , CD27 Ligand/antagonists & inhibitors , CD27 Ligand/metabolism , CD40 Ligand/antagonists & inhibitors , CD40 Ligand/metabolism , Cell Death , Cytokine TWEAK , Dendritic Cells/immunology , Fas Ligand Protein/antagonists & inhibitors , Fas Ligand Protein/metabolism , Humans , Immune Tolerance , Lymphocyte Activation , Lymphotoxin-alpha/antagonists & inhibitors , Lymphotoxin-alpha/metabolism , OX40 Ligand/antagonists & inhibitors , OX40 Ligand/metabolism , Signal Transduction , T-Lymphocytes/immunology , TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 14/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 14/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolism , Tumor Necrosis Factors/immunologyABSTRACT
High glucoseinduced endothelial cell apoptosis is considered to be the initiator of diabetesassociated vascular complications. Experiments in vivo and in vitro have demonstrated that high glucose levels contribute to the apoptosis of endothelial cells by mediating cellular dysfunction and metabolic disorder via the production of various cytokines. As the most important endogenous vascular regulators, the balance between proproliferative effector vascular endothelial growth factor (VEGF) and antiproliferative effector tumor necrosis factorlike cytokine 1A (TL1A) is important in the modulation of endothelial cell survival and proliferation, and neovascularization. The present study aimed to explore whether the imbalance between VEGF and TL1A affected the apoptosis of human umbilical vein endothelial cells (HUVECs) exposed to high glucose conditions and then further investigated the potential mechanism. The results showed that the downregulation of VEGF in combination with the upregulation of TL1A in response to high glucose levels led to enhanced HUVEC apoptosis. Further experiments revealed that silencing high glucoseinduced TL1A expression using TL1A small interfering (si)RNA or the overexpression of VEGF by transfection with VEGF DNA resulted in a reduced HUVEC apoptosis rate compared with the controls. The effects occurred by attenuating and activating the phosphoinositide 3kinase/Akt/endothelial nitric oxide synthase pathway, respectively. In addition, VEGF and TL1A inhibited each other in hyperglycemia. In conclusion, these findings provide theoretical support for the further investigation of novel therapeutic strategies designed to maintain the balance between VEGF and TL1A and, thus, to prevent the onset and progression of endothelial cell apoptosis in response to high glucose stimuli.
Subject(s)
Apoptosis/drug effects , Down-Regulation/drug effects , Glucose/pharmacology , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolism , Up-Regulation/drug effects , Vascular Endothelial Growth Factor A/metabolism , Blotting, Western , Human Umbilical Vein Endothelial Cells , Humans , Nitric Oxide Synthase Type III/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Messenger/metabolism , RNA, Small Interfering/metabolism , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effects , Transfection , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/genetics , Vascular Endothelial Growth Factor A/geneticsABSTRACT
Intestinal fibrostenosis is among the hallmarks of severe Crohn's disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. In addition, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody (Ab). Treatment with neutralizing Tl1a Ab reversed colonic fibrosis back to the original pre-inflamed levels, potentially as a result of lowered expression of connective tissue growth factor, Il31Ra, transforming growth factor ß1 and insulin-like growth factor-1. In addition, blocking Tl1a function by either neutralizing Tl1a Ab or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A-DR3 signaling in tissue fibrosis and that modulation of TL1A-DR3 signaling could inhibit gut fibrosis.
Subject(s)
Colon/immunology , Crohn Disease/immunology , Signal Transduction/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Colon/pathology , Crohn Disease/genetics , Crohn Disease/pathology , Fibrosis , Humans , Mice , Mice, Knockout , Myofibroblasts/immunology , Myofibroblasts/pathology , Receptors, Interleukin/genetics , Receptors, Interleukin/immunology , Receptors, Tumor Necrosis Factor, Member 25/genetics , Receptors, Tumor Necrosis Factor, Member 25/immunology , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/geneticsABSTRACT
Atsttrin, a progranulin (PGRN)-derived molecule composed of three TNFR-binding domains of PGRN, binds to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we screened the associations of Atsttrin and other members in TNFR subfamily, which led to the discovery of TNFRSF25 (DR3) as an additional Atsttrin-interacting member in TNFR family. Similar to TNFR1 and TNFR2, DR3 also directly bound to Atsttrin. The first three cysteine-rich domains (CRD) in the extracellular portion of DR3 were required for this interaction. Atsttrin inhibited the interaction between DR3 and its TNF-Like Ligand 1A (TL1A). In addition, Atsttrin inhibited TL1A-stimulated target gene expressions and neutralized TL1A-enhanced osteoclastogenesis in vitro. Furthermore, Atsttrin ameliorated the pathology in dextran sulfate sodium induced colitis. Taken together, these findings not only provide the new insights into Atsttrin's therapeutic action in inflammatory arthritis, but may also present Atsttrin as a novel biological agent for treating various types of diseases associated with TL1A/DR3 pathway.
Subject(s)
Receptors, Tumor Necrosis Factor, Member 25/metabolism , Recombinant Fusion Proteins/metabolism , Recombinant Fusion Proteins/pharmacology , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Animals , Body Weight/drug effects , Cell Line , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Cysteine/chemistry , Dextran Sulfate/adverse effects , Disease Models, Animal , Dose-Response Relationship, Drug , Hemorrhage/prevention & control , Macrophages/metabolism , Mice , Multigene Family , Protein Binding/drug effects , Protein Interaction Domains and Motifs , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/metabolism , Receptors, Tumor Necrosis Factor, Member 25/chemistry , Receptors, Tumor Necrosis Factor, Member 25/genetics , Tumor Necrosis Factor Ligand Superfamily Member 15/metabolismABSTRACT
BACKGROUND & AIMS: TL1A is a tumor necrosis factor-like molecule that mediates a strong costimulation of T-helper (T(H)) 1 cells. Expression of TL1A is increased in the mucosa of Crohn's disease patients and murine models of ileitis. The aim of this study was to determine the possible role of TL1A in chronic intestinal inflammation. METHODS: We used dextran sodium sulfate (DSS)-induced chronic colitis to investigate the effects of TL1A on the development of colitis. The cytokine profile in the gut-associated lymphoid tissue (GALT) was measured. Neutralizing anti-TL1A antibodies were injected intraperitoneally into DSS-induced chronic colitis and G protein alphai2(-/-) T-cell transfer colitis models. Severity of colitis was evaluated by body weight, colon length, histology, and cytokine production. RESULTS: DSS-induced chronic colitis was characterized by the infiltration of CD4(+) T cells. TL1A, death receptor 3, interferon (IFN)-gamma, and interleukin (IL)-17 were increased significantly in GALT of DSS-treated mice. TL1A up-regulated both IFN-gamma production from T(H)1 cells and IL-17 production from T(H)17 cells in GALT CD4(+) T cells. Furthermore, IFN-gamma and IL-17 production from CD4(+) T cells, induced by IL-12 and IL-23 respectively, was enhanced synergistically by combination with TL1A. Anti-TL1A antibody prevented chronic colitis and attenuated established colitis by down-regulation of both T(H)1 and T(H)17 activation. CONCLUSIONS: Our results reveal that TL1A is an important modulator in the development of chronic mucosal inflammation by enhancing T(H)1 and T(H)17 effector functions. The central role of TL1A represents an attractive, novel therapeutic target for the treatment of Crohn's disease patients.