A CD4-CDER3 peptide analog inhibits both primary and secondary CD4T cell responses in experimental allergic encephalomyelitis

Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system. Experimental Allergic Encephalomyelitis (EAE), an inducible inflammatory and demyelinating disease in animals, shares many of the same clinical and pathological symptoms. Due to these similarities, EAE serves as the animal model of MS. In both MS and EAE, the pathogenesis of disease is mediated by autoreactive CD4 T cells. A structure-based design approach was used to develop a peptide analog of the CDR3-like region of the mouse CD4 molecule as a potential inhibitor of the activation of CD4 T cells. This analog, referred to as rD-mPGPtide, was previously shown to be a potent inhibitor of in vitro CD4-mediated responses. It was hypothesized that the in vivo inhibition of autoreactive CD4 T cells during the course of EAE would lead to an amelioration in the symptoms of disease. In vivo results indicated that the rD-mPGPtide was able to significantly inhibit the clinical and pathological symptoms of disease in the mouse model of EAE. The optimum effective dosage regimen for the rD-mPGPtide was to inject between 0.125 and 0.5 mg intravenously on day 12 post-induction of EAE. Treated mice had normal levels of lymphocytes less than two weeks later and exhibited normal in vitro primary responses to alloantigen and secondary responses to keyhole limpet hemocyanin (KLH) antigen. The specificity of the rD-mPGPtide treatment for autoreactive T cells was demonstrated by inhibiting proteolipid protein (p139-151)-induced EAE and finding that the lymph node T cells from these mice had suppressed responses to this antigen, but normal responses to alloantigen or other nominal antigens. Importantly, rD-mPGPtide was found to be effective on the inhibition of secondary T cell responses in an EAE rechallenge situation and was able to establish conditions for long term resistance to further antigen exposure. In addition the rD-mPGPtide was able to affect the further development of EAE once clinical symptoms had already appeared. Analysis of the cytokine profile of responding T cells during late effector stages of disease revealed that the levels of IFN-$\gamma$ and IL-4 are significantly reduced in rD-mPGPtide-treated mice. These results strongly suggest that the administration of a peptide analog of the CDR3-like region of the CD4 molecule is an effective therapeutic approach for the inhibition of the CD4 T cell-mediated autoimmune response in EAE. It is hoped that this approach may represent a novel therapeutic agent for the treatment of MS