ps1145 and myelin-oligodendrocyte-glycoprotein-(35-55)

The NF-kappaB family of transcription factors plays a pivotal role in T cell activation and survival during (auto) immune responses. IkappaB kinase 2/beta (IKK2) is part of the IkappaB kinase complex, a central component of the intracellular signaling pathway mediating NF-kappaB activation. We studied the role of IKK2 in autoantigen-specific T cell activation and induction of autoimmune disease using mice that lack this kinase specifically in T cells (IKK2(DeltaT cell) mice). We found highly impaired myelin-oligodendrocyte-glycoprotein (MOG)(35-55)-specific T cell activation in vitro and complete resistance to MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) in IKK2(DeltaT cell) C57BL/6 mice in vivo. By contrast, transgenic expression of a pathogenic MOG(35-55)-specific TCR (2D2 TCR) rendered IKK2(DeltaT cell) mice susceptible to MOG(35-55)-induced EAE and restored in vitro MOG(35-55)-specific T cell responses, indicating an expansion defect in IKK2-deficient T cells. Treatment with the IKK2-inhibitory compound PS-1145 reduced MOG(35-55)-specific proliferation and cytokine production of 2D2 transgenic spleen cells in vitro and diminished clinical signs of EAE in vivo. Our data underscore the potential of therapeutic IKK inhibition in autoimmune diseases.

Topics: Amino Acid Sequence; Animals; Autoantigens; Cell Differentiation; Cell Proliferation; Encephalomyelitis, Autoimmune, Experimental; Epitopes, T-Lymphocyte; Female; Glycoproteins; Heterocyclic Compounds, 3-Ring; I-kappa B Kinase; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Protein Kinase Inhibitors; Pyridines; T-Lymphocyte Subsets