AX-024 Inhibits Antigen-Specific T-Cell Response and Improves Intracerebral Hemorrhage Outcomes in Mice.

Abstract

Stroke-induced opposite T-cell responses in the peri-lesion area and periphery worsen stroke outcomes by aggravating brain injury or increasing infectious complications, respectively. Despite their well-known role in T lymphocyte activation, the impact of TCRs (T-cell receptors) on stroke remains poorly understood. In this study, we investigated the causal link between TCRs and the opposite T-cell responses observed in intracerebral hemorrhage (ICH). We established the ICH model by injecting the collagenase VII-S into the left striatum of young adult (10-12 weeks) male and female and aged (18-20 months) male C57BL/6 mice. We intraperitoneally administered AX-024, a small molecule inhibitor of TCR signaling, and evaluated the results using flow cytometry, Western blotting, immunofluorescence staining, histological staining, bacterial culture, and behavioral tests. Our findings in young adult male mice indicate that administering AX-024 within 48 hours suppressed the activation of nonspecific and antigen-specific CD3 (cluster of differentiation 3)⁺CD4⁺ and CD3⁺CD8⁺ cells in the brain 36 hours and 3 days after ICH but not 7 days after. Additionally, it temporarily inhibited antigen-specific T-cell activation in the periphery at the above 2 time points. It also reduced molecular and cellular neuroinflammation in the hemorrhagic brain early after ICH. These effects in the brain and periphery of young adult male mice ultimately improved ICH outcomes while having no impact on lung bacterial loads. This can be further supported by similar findings in young adult female and aged male mice with ICH. AX-024 may represent a promising option for mitigating the detrimental effects of T cells entering the damaged brain without increasing bacterial loads in the lung in ICH. The potential of AX-024 as a potent immunosuppressive treatment for ICH is an exciting prospect that warrants further investigation.