Our Science

Chronic inflammation plays a key role in the development and progression of many diseases, including many for which fibrosis is a major pathological feature, such as scleroderma, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis

• Chronic inflammation represents a long-term reaction to an inflammatory stimulus characterized by continued recruitment of mononuclear leukocytes (monocytes and lymphocytes) accompanied by tissue injury due to the sustained inflammatory response
• In addition to the accumulation of monocyte-derived macrophages and lymphocytes, chronic inflammation is characterized by changes associated with wound healing, such as proliferation of fibroblasts
• Normal tissue repair can evolve into a pathologic fibrotic response, characterized by excessive accumulation of fibrous connective tissue, if the tissue injury is repetitive or if the wound-healing response itself becomes dysregulated, as happens with many chronic inflammatory diseases

Tumor necrosis factor-like ligand 1A (TL1A) is a cytokine that independently mediates both inflammation and fibrosis

• Receptor for TL1A is death domain receptor 3 (DR3)

• When bound to DR3, TL1A signaling serves as a key co-stimulatory signal that amplifies the immune response and leads to activation, proliferation, and differentiation of multiple effector cell types (see figure to the right)

• TL1A and the DR3 receptor are both expressed and upregulated in response to pro-inflammatory stimuli

• TL1A also directly acts on fibroblasts to mediate fibrosis that can occur alongside chronic inflammatory diseases

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TL1A Amplifies Inflammation and Fibrosis via Signaling Through T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17) Cells and Fibroblasts

TL1A provides a compelling therapeutic target to treat inflammatory bowel diseases (IBD)

• Blocking TL1A does not suppress the immune system, but instead can restore balance to the immune system by blocking over-amplification of the inflammatory response, as well as downregulate fibroblasts that mediate fibrosis

• Genome-wide association studies have linked polymorphisms in the TL1A gene to IBD in multiple ethnic populations

• Human inflamed IBD tissues show high levels of TL1A and DR3 expression

Inflammatory bowel diseases are chronic inflammatory diseases of the gastrointestinal (GI) tract. It is estimated that up to 2 million US adults suffer from inflammatory bowel diseases, which include ulcerative colitis and Crohn's disease.  These conditions can be treated but not cured and may significantly affect a patient's quality of life.

Ulcerative Colitis:

• Ulcerative colitis (UC) is characterized by recurrent episodes of inflammation of the rectum and often adjacent portions of the colon in a continuous fashion
• Inflammation in UC is limited to the mucosal layer on the surface of the colon

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Crohn’s Disease:

• Crohn’s disease (CD) is characterized by inflammation in one or more portions of the GI tract, including the mouth, small intestine, or colon, with segments of normal tissue in between
• Inflammation in CD can affect all layers of tissue, and may lead to fibrosis and obstructions

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Signs and symptoms of IBD

These features contribute to a potentially significant mental health burden from IBD.

Unmet need for IBD patients

• Therapeutic response to medications varies across patients, and poor prognostic indicators and lack of biomarkers lead to a “trial and error” treatment paradigm.
• Even the best advanced therapies typically result in 10-15% remission of disease, leaving frequent flare-ups, continued worsening of disease, or serious complications like intestinal fibrosis that may require surgery.
• Many patients that achieve remission on a therapy will stop responding to it over time, and no approved medication directly addresses the fibrotic component of IBD.

• Aiba Y and Nakamura M. The Role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators Inflamm 2013; 2013:258164.
• Crohn’s & Colitis Foundation of America. The facts about inflammatory bowel diseases. 2014.
• Fleit HB. Chronic inflammation. In: Pathobiology of human disease: a dynamic encyclopedia of disease mechanisms. Amsterdam: Elsevier Inc.; 2014. p. 300–14.
• GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet Gastroenterol Hepatol 2020; 5:17.
• Hassan-Zahraee, et al. Antitumor necrosis factor-like ligand 1A therapy targets tissue inflammation and fibrosis pathways and reduces gut pathobionts in ulcerative colitis. Inflamm Bowel Dis 2022; 28:434.
• Hopkinsmedicine.org, Inflammatory Bowel Disease.
• Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142:46.
• Valatas V, Kolios G and 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.
• Wynn TA, and Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012 Jul 6; 18(7):1028-40.