Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function

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2024年5月7日

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Jingxi Mu,
Keiko Maeda,
Ayako Ohashi,
Takeshi Urano,
Yuko Nariai,
Hiroki Kamino,
Masanao Nakamura,
Takeshi Yamamura,
Tsunaki Sawada,
Eri Ishikawa,
Kentaro Murate,
Kenta Yamamoto,
Takashi Hirose,
Kazuhiro Furukawa,
Mitsuhiro Fujishiro,
Hiroki Kawashima

摘要

Background

Numerous biological interventions and small molecules are used to treat Crohn’s disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn’s disease.

Aims

The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn’s disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue.

Methods

We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn’s disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed.

Results

Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn’s disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer.

Conclusions

The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn’s disease.