The effect of small molecular inhibitors of CD4 on experimental allergic encephalomyelitis
Experimental allergic encephalomyelitis (EAE) in mice is a model for the human demyelinating disease, multiple sclerosis (MS). Studies in both EAE and MS demonstrated that CD4+ T cells have an important role in mediating the pathogenesis of disease. We have taken the approach to specifically inhibit the function of these autoreactive CD4+ T cells by disrupting the interaction between CD4 and the MHC class II molecule. A structure-base designed approach was used in which a synthetic peptide analog (802-2) of the D1CC′loop region of CD4 was developed and a small organic molecule (TJU103) was chosen by computer screening methods to specifically affect activated CD4+ T cells by disrupting the oligomerization and stabilization of the CD4-MHC class II interaction. These immunotherapeutics were tested for inhibitory activity in EAE. 802-2 and TJU103 when administered shortly before or after the onset of clinical symptoms significantly reduced the severity of disease in both the SJL and SWXJ-14 mouse models of EAE. In addition, long-term inhibitory activity of a single injection of 802-2 or TJU103 has been demonstrated in EAE rechallenge studies. In vitro and in vivo memory responses to proteolipid protein (PLP) were shown to be inhibited by these therapeutics. Studies with keyhole limpet hemocyanin (KLH), PLP, and alloantigen demonstrated that the inhibitors specifically affect only CD4+ T cells that are activated in the presence of either the 802-2 peptide or TJU103 organic molecule. Elispot analysis demonstrated a reduction in the frequency of antigen-specific cytokine-producing cells after in vivo 802-2 and TJU103 treatment. By utilizing a transgenic mouse model, the extent of inhibitory ability, as well as the mechanism of action of the therapeutics, was analyzed. TUNEL analysis suggested that apoptosis is the mechanism of action of both 802-2 and TJU103. These results indicate that CD4 inhibitors can reduce EAE severity and show potential for future clinical application.
Edling, Andrea Elizabeth, "The effect of small molecular inhibitors of CD4 on experimental allergic encephalomyelitis" (1999). ProQuest ETD Collection - Thomas Jefferson University. AAI9963595.