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Case Western Reserve University School of Medicine Study Reveals Immune System Pathway Target for Crohn’s Disease Therapy

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Case Western Reserve University School of Medicine Study Reveals Immune System Pathway Target for Crohn’s Disease Therapy

Case Western Reserve University School of Medicine researchers have published the results of a three-year study investigating the chronic inflammation associated with Crohn’s disease. This new research centers on the potential option for targeted pathway in the immune system to help create superior treatments.

The Problem

Crohn’s disease is a kind of debilitating inflammatory bowel disease (IBD) that triggers chronic inflammation of the gastrointestinal tract. About 3 million struggle with IBD and 1.6 million of those have Crohn’s disease in the United States. The percentage of people with Crohn’s disease in the U.S. is about 6 to 7.1:100,000. The Crohn’s and Colitis Foundation of America cites this number as approximately 149:100,000; NIH cites 28 to 199 per 100,000. It is generally more common in northern countries. The incidents of the disease are thought to be similar in Europe as with the U.S. but lower in Asia and Africa. It is reported that Ashkenazi Jews and smokers experience Crohn’s disease at higher levels. Rates are growing in Europe as well as newly industrialized countries. For example, Brazil has experienced an annual increase of 11% in the incidence of Crohn’s disease since 1990.

Current treatment options can help reduce problematic symptoms and at times manage remission but there is no cure—investigators are in pursuit of targeted treatments.

The Study

The three-year study “TWEAK/Fn14 Is Overexpressed in Crohn’s Disease and Mediates Experimental Ileitis by Regulating Critical Innate and Adaptive Pathways” was recently published in the journal Cellular and Molecular Gastroenterology and Hepatology.

The Cleveland team, led by Dr. Fabio Cominelli, chief of gastroenterology at University Hospitals, Cleveland Medical Center, sought to investigate the chronic inflammation that patients genetically prone to Crohn’s disease often face.

The team summarized members of the tumor necrosis factor superfamily are key regulators of intestinal inflammation and specifically tumor necrosis factor—like weak inducer apoptosis (TWEAK) and its receptor, fibroblast growth factor—inducible 14 (Fn14), are involved in normal and pathologic tissue remodeling. Their aim was to determine the role of TWEAK/Fn14 in Crohn’s disease and a murine model of Crohn’s disease-like ileitis (i.e. SAMP 1/YitFc[SAMP] strain).

Study Methods

The team led by Dr. Cominelli developed SAMP mice deficient in Fn14 (SAMP x Fn14) and conducted a detailed time-course study evaluating ileal tissues by histology and stereomicroscopy, as well as quantitative polymerase chain reaction and Nanostring technology. Additionally, the study team generated reciprocal bone marrow chimeras to assess the relevance of Fn14 in hematopoietic vs nonhematopoietic compartments. The team thereafter analyzed surgically resected intestinal tissues and mucosal biopsy specimens from patients with not only Crohn’s disease but also ulcerative colitis while using healthy controls to analyze for the expression of TWEAK/Fn14 by quantitative polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence.

The Findings

The Cleveland team found an increased expression of TWEAK and Fn14 in tissue lesions from Crohn’s disease patients compared with ulcerative colitis and healthy controls. The preclinical models reveal those without receptors had less severe inflammation. Hence, they concluded that TWEAK/Fn14 are up-regulated in Crohn’s disease, and also mediate experimental Crohn’s disease-like ileitis, by regulation of multiple innate and adaptive cellular pathways. Therefore, TWEAK/Fn14 could represent a novel therapeutic target for the treatment of small intestinal inflammation in Crohn’s disease.

Comments

The results reveal that if researchers can uncover an approach to impede Fn14 via new medication, it could possibly have transformative impact on Crohn’s disease patients. The envisioned pharmacological intervention represents a new way to dramatically reduce inflammation and reduce associated scarring. Moreover this breakthrough could possibly have other applications in other therapeutic areas, such as colorectal cancer, as those who are afflicted with inflammatory bowel disease can face chronic inflammation and higher risks of colon cancer.

Lead Research/Investigator

Dr. Fabio Cominelli, chief of gastroenterology at University Hospitals, Cleveland Medical Center

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