Suppressors of cytokine signaling (SOCS) play an indispensable role in normal homeostatic function. Knockout of SOCS-1 gene in mice, for example, results in embryo lethal effects. Lethality has been shown to be due to unregulated gamma interferon activity. SOCS-1 inhibits cytokines, such as IFN function by binding to the autophosphorylation site of the tyrosine kinase JAK2. We have developed a short 12-mer peptide, WLVFFVIFYFFR, which specifically binds to the autophosphorylation site of JAK2, resulting in inhibition of its autophosphorylation as well as it is phosphorylation of receptor subunit IFNGR-1 and transcription factor STAT1. Thus, the peptide possesses functions similar to SOCS-1. We propose to test the hypothesis that the tyrosine kinase inhibitory peptide (Tkip) has anti-inflammatory effects in the experimental allergic encephalomyelitis (EAE) mouse model of multiple sclerosis. We will test this hypothesis via the following Specific Aims with particular focus on immunological mechanisms. 1. Determine ability of Tkip and variants to protect NZW and C57BL/6 mice against acute EAE. 2. Determine ability of Tkip and variants to protect SJL/J mice against induction and reactivation of relapsing/remitting EAE by myelin basic protein. 3. Determine ability of Tkip and variants to block reactivation of EAE via superantigen. 4. Therapeutic effect of cell-penetrating form of SOCS-1 recombinant protein in treatment of EAE. The studies proposed here are directly related to a natural indispensable host regulatory system against autoimmunity as well as other essential functions. As such, this is a novel approach to treatment and prevention of immunological diseases. ? ? ?
