Review Article

TL1A: A New Potential Target in the Treatment of Inflammatory Bowel Disease

Author(s): Federica Furfaro*, Ludovico Alfarone, Daniela Gilardi, Carmen Correale, Mariangela Allocca, Gionata Fiorino, Marjorie Argollo, Alessandra Zilli, Eirini Zacharopoulou, Laura Loy, Giulia Roda and Silvio Danese

Volume 22, Issue 7, 2021

Published on: 20 January, 2021

Page: [760 - 769] Pages: 10

DOI: 10.2174/1389450122999210120205607

Price: $65


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.

Keywords: Ulcerative colitis, Crohn's disease, Inflammatory Bowel Diseases, TL1A, DR3, anti-TL1A, inflammation, fibrosis, mucosal immune system.

Graphical Abstract
Ahluwalia B, Magnusson MK, Öhman L. Mucosal immune system of the gastrointestinal tract: maintaining balance between the good and the bad. Scand J Gastroenterol 2017; 52(11): 1185-93.
[] [PMID: 28697651]
Xu XR, Liu CQ, Feng BS, Liu ZJ. Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014; 20(12): 3255-64.
[] [PMID: 24695798]
Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci 2017; 38(2): 127-42.
[] [PMID: 27916280]
Sokol H, Seksik P, Cosnes J. Complications and surgery in the inflammatory bowel diseases biological era. Curr Opin Gastroenterol 2014; 30(4): 378-84.
[] [PMID: 24840000]
Sabino J, Verstockt B, Vermeire S, Ferrante M. New biologics and small molecules in inflammatory bowel disease: an update. Therap Adv Gastroenterol 2019; 12: 1756284819853208.
[] [PMID: 31205488]
Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory system of cytokines with diverse functions in gut mucosal immunity. Front Immunol 2019; 10: 583.
[] [PMID: 30972074]
Meylan F, Davidson TS, Kahle E, et al. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 2008; 29(1): 79-89.
[] [PMID: 18571443]
Zhan C, Yan Q, Patskovsky Y, et al. Biochemical and structural characterization of the human TL1A ectodomain. Biochemistry 2009; 48(32): 7636-45.
[] [PMID: 19522538]
Bamias G, Martin C III, Marini M, et al. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol 2003; 171(9): 4868-74.
[] [PMID: 14568967]
Tan KB, Harrop J, Reddy M, et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 1997; 204(1-2): 35-46.
[] [PMID: 9434163]
Bittner S, Ehrenschwender M. Multifaceted death receptor 3 signaling-promoting survival and triggering death. FEBS Lett 2017; 591(17): 2543-55.
[] [PMID: 28686297]
Wroblewski VJ, Witcher DR, Becker GW, et al. Decoy receptor 3 (DcR3) is proteolytically processed to a metabolic fragment having differential activities against Fas ligand and LIGHT. Biochem Pharmacol 2003; 65(4): 657-67.
[] [PMID: 12566095]
Taraban VY, Slebioda TJ, Willoughby JE, et al. Sustained TL1A expression modulates effector and regulatory T-cell responses and drives intestinal goblet cell hyperplasia. Mucosal Immunol 2011; 4(2): 186-96.
[] [PMID: 20962771]
Prehn JL, Mehdizadeh S, Landers CJ, et al. Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clin Immunol 2004; 112(1): 66-77.
[] [PMID: 15207783]
Pappu BP, Borodovsky A, Zheng TS, et al. TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med 2008; 205(5): 1049-62.
[] [PMID: 18411337]
Papadakis KA, Zhu D, Prehn JL, et al. Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes. J Immunol 2005; 174(8): 4985-90.
[] [PMID: 15814728]
Meylan F, Song YJ, Fuss I, et al. The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol 2011; 4(2): 172-85.
[] [PMID: 20980995]
Jones GW, Stumhofer JS, Foster T, et al. Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation. FASEB J 2011; 25(1): 409-19.
[] [PMID: 20826539]
Takedatsu H, Michelsen KS, Wei B, et al. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology 2008; 135(2): 552-67.
[] [PMID: 18598698]
Richard AC, Tan C, Hawley ET, et al. The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. J Immunol 2015; 194(8): 3567-82.
[] [PMID: 25786692]
Gerlach K, Hwang Y, Nikolaev A, et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 2014; 15(7): 676-86.
[] [PMID: 24908389]
Heidemann SC, Chavez V, Landers CJ, Kucharzik T, Prehn JL, Targan SR. TL1A selectively enhances IL-12/IL-18-induced NK cell cytotoxicity against NK-resistant tumor targets. J Clin Immunol 2010; 30(4): 531-8.
[] [PMID: 20349123]
Slebioda TJ, Rowley TF, Ferdinand JR, et al. Triggering of TNFRSF25 promotes CD8⁺ T-cell responses and anti-tumor immunity. Eur J Immunol 2011; 41(9): 2606-11.
[] [PMID: 21688261]
Meylan F, Hawley ET, Barron L, et al. The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. Mucosal Immunol 2014; 7(4): 958-68.
[] [PMID: 24368564]
Buchan SL, Taraban VY, Slebioda TJ, James S, Cunningham AF, Al-Shamkhani A. Death receptor 3 is essential for generating optimal protective CD4⁺ T-cell immunity against Salmonella. Eur J Immunol 2012; 42(3): 580-8.
[] [PMID: 22259035]
Shih DQ, Michelsen KS, Barrett RJ, et al. Insights into TL1A and IBD pathogenesis. Adv Exp Med Biol 2011; 691: 279-88.
[] [PMID: 21153332]
Yamazaki K, McGovern D, Ragoussis J, et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 2005; 14(22): 3499-506.
[] [PMID: 16221758]
Michelsen KS, Thomas LS, Taylor KD, et al. IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One 2009; 4(3): e4719.
[] [PMID: 19262684]
Baskaran K, Pugazhendhi S, Ramakrishna BS. Protective association of tumor necrosis factor superfamily 15 (TNFSF15) polymorphic haplotype with Ulcerative Colitis and Crohn’s disease in an Indian population. PLoS One 2014; 9(12): e114665.
[] [PMID: 25501099]
Liu JZ, van Sommeren S, Huang H, et al. International multiple sclerosis genetics consortium; international ibd genetics consortium. association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015; 47(9): 979-86.
[] [PMID: 26192919]
Pernat Drobež C, Ferkolj I, Potočnik U, Repnik K. Crohn’s disease candidate gene alleles predict time to progression from inflammatory B1 to stricturing B2, or penetrating B3 phenotype. Genet Test Mol Biomarkers 2018; 22(3): 143-51.
[] [PMID: 29446656]
Connelly TM, Berg AS, Hegarty JP, et al. The TNFSF15 gene single nucleotide polymorphism rs7848647 is associated with surgical diverticulitis. Ann Surg 2014; 259(6): 1132-7.
[] [PMID: 24814505]
Zucchelli M, Camilleri M, Andreasson AN, et al. Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut 2011; 60(12): 1671-7.
[] [PMID: 21636646]
Slebioda TJ, Bojarska-Junak A, Cyman M, et al. Expression of death receptor 3 on peripheral blood mononuclear cells differes in adult IBD patients and children with newly diagnosed IBD. Cytometry B Clin Cytom 2017; 92(2): 165-9.
[] [PMID: 27001939]
Antoniou E, Margonis GA, Angelou A, et al. The TNBS-induced colitis animal model: An overview. Ann Med Surg (Lond) 2016; 11: 9-15.
[] [PMID: 27656280]
Pizarro TT, Pastorelli L, Bamias G, et al. SAMP1/YitFc mouse strain: a spontaneous model of Crohn’s disease-like ileitis. Inflamm Bowel Dis 2011; 17(12): 2566-84.
[] [PMID: 21557393]
Li Z, Buttó LF, Buela KA, et al. Death receptor 3 signaling controls the balance between regulatory and effector lymphocytes in SAMP1/YitFc mice with crohn’s disease-like ileitis. Front Immunol 2018; 9: 362.
[] [PMID: 29545797]
Nalleweg N, Chiriac MT, Podstawa E, et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 2015; 64(5): 743-55.
[] [PMID: 24957265]
de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2016; 13(1): 13-27.
[] [PMID: 26627550]
Latella G, Rieder F. Intestinal fibrosis: ready to be reversed. Curr Opin Gastroenterol 2017; 33(4): 239-45.
[] [PMID: 28402994]
Biancheri P, Pender SL, Ammoscato F, et al. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair 2013; 6(1): 13.
[] [PMID: 23834907]
Latella G, Rogler G, Bamias G, et al. Results of the 4th scientific workshop of the ECCO (I): pathophysiology of intestinal fibrosis in IBD. J Crohn’s Colitis 2014; 8(10): 1147-65.
[] [PMID: 24731838]
Shih DQ, Zheng L, Zhang X, et al. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol 2014; 7(6): 1492-503.
[] [PMID: 24850426]
Barrett R, Zhang X, Koon HW, et al. Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. Am J Pathol 2012; 180(2): 636-49.
[] [PMID: 22138299]
Li H, Song J, Niu G, et al. TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice. Pathol Res Pract 2018; 214(2): 217-27.
[] [PMID: 29254800]
Bamias G, Filidou E, Goukos D, et al. Crohn’s disease-associated mucosal factors regulate the expression of TNF-like cytokine 1A and its receptors in primary subepithelial intestinal myofibroblasts and intestinal epithelial cells. Transl Res 2017; 180: 118-130.e2.
[] [PMID: 27665176]
Targownik LE, Bernstein CN. Infectious and malignant complications of TNF inhibitor therapy in IBD. Am J Gastroenterol 2013; 108(12): 1835-42.
[] [PMID: 24042192]
Meylan F, Richard AC, Siegel RM. TL1A and DR3, a TNF family ligand-receptor pair that promotes lymphocyte costimulation, mucosal hyperplasia, and autoimmune inflammation. Immunol Rev 2011; 244(1): 188-96.
[] [PMID: 22017439]
Sidhu-Varma M, Shih DQ, Targan SR. Differential Levels of Tl1a affect the expansion and function of regulatory T cells in modulating murine colitis. Inflamm Bowel Dis 2016; 22(3): 548-59.
[] [PMID: 26818423]
Twohig JP, Marsden M, Cuff SM, et al. The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+; and CD8+; T-cell immunity. FASEB J 2012; 26(8): 3575-86.
[] [PMID: 22593543]
Clarke AW, Poulton L, Shim D, et al. An anti-TL1A antibody for the treatment of asthma and inflammatory bowel disease. MAbs 2018; 10(4): 664-77.
[] [PMID: 29436901]
Banfield C, Rudin D, Bhattacharya I, et al. First-in-human, randomized dose-escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy subjects. Br J Clin Pharmacol 2020; 86(4): 812-24.
[] [PMID: 31758576]
[53] Pfizer: National Library of Medicine (US). Identifier NCT02840721, Safety, Efficacy, and Tolerability Study of PF-06480605 in Subjects With Moderate to Severe Ulcerative Colitis. 2016 Jul. [cited 8th Jun 2020]. Available from: =TL 1A&cond=IBD&draw=2&rank=4
[54] Pfizer: National Library of Medicine (US). Identifier NCT04090411, A Study to Evaluate the Efficacy and Safety of PF-06480605 in Adult Participants With Moderate to Severe Ulcerative Colitis. 2019 Sep. [cited 10th Jun 2020]. Available from: =TL 1A&cond=IBD&draw=1&rank=3

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