s-3483 and Autoimmune-Diseases

The involvement of IL-17-producing CD8(+)T cells (TC17) in various conditions, such as infection, cancer and autoimmune inflammation, has been documented in both humans and mice; however, TC17 cells have received only marginal attention.. Here, we provide an overview of the cytokines, chemokines, and cytokine and chemokine receptors that characterize the murine and human TC17 cell phenotype. We also discuss signaling pathways, molecular interactions, and transcriptional and epigenetic events that contribute to TC17 differentiation and acquisition of effector functions. Heterogeneity and inherent phenotypic instability of TC17 cells were shown both in humans and murine models. Aberrant expression of TC17 cells was observed in many autoimmune conditions. Moreover, functional analysis demonstrated in vivo plasticity of TC17 cells may be a key feature of TC17 cell biology in autoimmune diseases.. Due to its important roles in inflammation and autoimmunity, TC17 cell pathway may have promise as a potential therapeutic target for autoimmune diseases. The strategies include the suppression of TC17 cell generation and migration and the blockade of TC17 cell instability and heterogeneity. TMP778 may open an avenue to novel therapeutic strategies.

Topics: Animals; Autoimmune Diseases; Autoimmunity; CD8-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Heterocyclic Compounds, 4 or More Rings; Humans; Interleukin-17; Mice; Molecular Targeted Therapy; Th17 Cells

Experimental autoimmune uveitis (EAU), an animal model for severe intraocular inflammatory eye diseases, is mediated by both Th1 and Th17 cells. Here, we examined the capacity of TMP778, a selective inhibitor of RORγt, to inhibit the development of EAU, as well as the related immune responses. EAU was induced in B10.A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP). Treatment with TMP778 significantly inhibited the development of EAU, determined by histological examination. In addition, the treatment suppressed the cellular immune response to IRBP, determined by reduced production of IL-17 and IFN-γ, as well as lower percentages of lymphocytes expressing these cytokines, as compared to vehicle-treated controls. The inhibition of IFN-γ expression by TMP778 is unexpected in view of this compound being a selective inhibitor of RORγt. The observation was further confirmed by the finding of reduced expression of the T-bet (Tbx21) gene, the transcription factor for IFN-γ, by cells of TMP778-treated mice. Thus, these data demonstrate the capacity of TMP778 to inhibit pathogenic autoimmunity in the eye and shed new light on its mode of action in vivo.

Topics: Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Eye Proteins; Female; Heterocyclic Compounds, 4 or More Rings; Interferon-gamma; Interleukin-17; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Retinol-Binding Proteins; T-Box Domain Proteins; Th1 Cells; Th17 Cells; Uveitis