Antagonism of CD28 blocks allergic responses in the ovalbumin-induced asthmatic model mice.

Allergen-reactive T helper (Th) 2 cells play a pivotal role in initiating asthma pathogenesis. The absence or interruption of CD28 signaling causes significant consequences for T-cell activation, leading to reduced cell proliferation and interleukin (IL)-2 production. A novel compound, Cyn-1324, exhibits a higher binding affinity to CD28 than CD80. Thus, targeting the CD28-CD80 interaction emerges as a promising therapeutic approach for allergic asthma. However, the impact of CD28 antagonists on allergen-induced asthma remains unreported. In this study, we explored the effects of intranasally administered Cyn-1324 on airway inflammation in the ovalbumin (OVA)-induced murine allergic model. The results revealed a significant reduction in airway hyper-responsiveness (AHR), eosinophil recruitment, and cell infiltration in lung tissues, as well as decreased OVA-specific IgE in serum and Th2 cytokine levels in OVA-stimulated lymphocyte cultures. Additionally, we demonstrated the immunosuppressive effects of Cyn-1324 in vitro, including decreased T-cell proliferation and IL-2 secretion, together with increased p27kip1 expression via inhibiting the PI3K signaling pathway. Notably, Cyn-1324 not only inhibited the NF-κB pathway, but also appeared to suppress p38 activation, which is downstream of CD3 signaling, and reduced calcium-induced NFAT protein expression. These findings suggest that Cyn-1324 alleviates allergic responses by inhibiting the CD28-CD80 interaction and holds promise as an immunosuppressive agent for allergic patients.