Our Science

Our Science

Targeting TL1A to treat inflammatory and fibrotic diseases like inflammatory bowel diseases

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
TL1A Cascade

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

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
GI Tract Inflammation

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
IBD Symptoms

Signs and symptoms of IBD

Symptoms related to 
inflammation of the GI tract:

  • Diarrhea
  • Abdominal pain
  • Bleeding
  • Frequent bathroom 

Constitutional symptoms associated with IBD:

  • Weight loss
  • Fever
  • Fatigue
  • Loss of appetite

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.



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  • Crohn’s & Colitis Foundation of America. The facts about inflammatory bowel diseases. 2014.
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  • 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.