Neutralizing IL-15 Inhibits Tissue-Damaging Immune Response in Ex Vivo Cultured Untreated Celiac Intestinal Mucosa

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Interleukin 15 (IL-15) plays a key role in celiac disease (CeD) pathogenesis.
• IL-15 contributes to epithelial barrier damage via intraepithelial lymphocytes, interferon gamma (IFN-γ) production, and enterocyte apoptosis.
• The Fas/Fas ligand system is implicated in IL-15-induced enterocyte apoptosis.

Purpose of the Study:

• To investigate the therapeutic potential of a monoclonal antibody against IL-15 (aIL-15).
• To assess the effects of aIL-15 on the tissue-damaging immune response in ex vivo organ cultures of untreated CeD jejunal biopsies.
• To evaluate the impact of aIL-15 on epithelial expression of key molecules and apoptosis.

Main Methods:

• Organ culture of jejunal biopsies from 10 untreated CeD patients with or without aIL-15.
• Immunohistochemistry to analyze epithelial expression of CD95/Fas and perforin.
• TUNEL assay to detect epithelial apoptosis.
• Laser capture microdissection (LCM) and qRT-PCR to quantify epithelial IFN-γ expression.

Main Results:

• Biopsies treated with aIL-15 showed reduced epithelial expression of Fas, HLA-E, and perforin.
• aIL-15 treatment led to a significant decrease in epithelial apoptosis (TUNEL+ cells).
• Epithelial IFN-γ expression was downregulated in biopsies incubated with aIL-15.

Conclusions:

• Neutralizing IL-15 ex vivo can inhibit apoptosis and reduce cytotoxic protein release in CeD intestinal mucosa.
• Anti-IL-15 therapy can dampen the hyperactive immune response by decreasing IFN-γ expression.
• These findings support IL-15 as a viable therapeutic target for celiac disease and other inflammatory conditions involving IL-15 upregulation.