Cutting Edge: Anti-TIM-3 Treatment Exacerbates Pulmonary Inflammation and Fibrosis in Mice
Takuma Isshiki1,2, Hisaya Akiba3, Masafumi Nakayama4
1Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Abstract:
Promising results of immune checkpoint inhibitors have indicated the use of immunotherapy against malignant tumors. However, they cause serious side effects, including autoimmune diseases and pneumonitis. T cell Ig and mucin domain (TIM)-3 is a new candidate immune checkpoint molecule; however, the potential toxicity associated with anti-TIM-3 treatment is unknown. In this study, we investigated the pathological contribution of anti-TIM-3 mAb in a bleomycin-induced lung inflammation and fibrosis model. Anti-TIM-3-treated mice showed more severe inflammation and peribronchiolar fibrosis compared with control IgG-treated mice. Anti-TIM-3 mAb was associated with increased numbers of myofibroblasts, collagen deposition, and TGF-β1 production in lungs. TIM-3 expression was only detected on alveolar macrophages that protect against fibrosis by apoptotic cell clearance. Treatment with anti-TIM-3 mAb inhibited the phagocytic ability of alveolar macrophages in vivo, resulting in the defective clearance of apoptotic cells in lungs. In summary, anti-TIM-3 mAb treatment might cause pneumonitis and it should be used with caution in clinical settings.
Insights
Anti-T cell Ig and mucin domain (TIM)-3 antibody treatment worsened lung inflammation and fibrosis in mice. This suggests potential risks of pneumonitis with anti-TIM-3 therapies, necessitating cautious clinical use.
Area of Science:
- Immunology
- Oncology
- Pulmonology
Background:
- Immune checkpoint inhibitors show promise in cancer immunotherapy.
- However, these therapies can cause severe side effects like autoimmune diseases and pneumonitis.
- T cell Ig and mucin domain (TIM)-3 is a novel immune checkpoint target, but its toxicity is unknown.
Purpose of the Study:
- To investigate the potential pathological contribution of anti-TIM-3 monoclonal antibody (mAb) in a bleomycin-induced lung inflammation and fibrosis model.
- To assess the safety and toxicity of anti-TIM-3 mAb in a preclinical setting.
Main Methods:
- Utilized a bleomycin-induced lung inflammation and fibrosis mouse model.
- Administered anti-TIM-3 mAb or control IgG to mice.
- Analyzed lung pathology, myofibroblast numbers, collagen deposition, TGF-β1 levels, and alveolar macrophage phagocytic activity.
Main Results:
- Anti-TIM-3 mAb treatment led to exacerbated lung inflammation and peribronchiolar fibrosis compared to controls.
- Increased myofibroblast accumulation, collagen deposition, and TGF-β1 production were observed in anti-TIM-3 treated lungs.
- TIM-3 was expressed on alveolar macrophages crucial for apoptotic cell clearance; anti-TIM-3 mAb impaired this function, leading to defective clearance.
Conclusions:
- Anti-TIM-3 mAb treatment may induce pneumonitis by impairing alveolar macrophage function and apoptotic cell clearance.
- The use of anti-TIM-3 mAb in clinical settings warrants caution due to potential pulmonary toxicity.
