A distinct role for PI3Kgamma in suppressing the development and progression of experimental autoimmune encephalomyelitis (EAE) (129.30)

Abstract Phosphoinositide 3-kinases (PI3K) are intracellular signaling proteins involved in cellular responses such as chemotaxis, proliferation and apoptosis. Selective inhibitors of the PI3Kγ-isoform have recently become available. This study explores the role of PI3Kγ in the development and progression of EAE. PI3Kγ +/+ (wt) and PI3Kγ −/− (ko) mice were immunized for EAE using myelin oligodendrocyte glycoprotein p35-55 (MOG) and assessed for clinical signs, CNS histopathology and T cell activation. WT mice showed a progressive disease course with elevations in inflammatory cytokines increased CNS mononuclear infiltrates. In contrast, ko mice exhibited a delayed onset and dramatically less severe EAE course characterized by decreased T cell activation and inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-12p40, IL-6, IL-17 and MCP-1). Male ko mice were significantly more protected than ko females. Adoptive transfer of MOG-activated T cells into ko recipients show that ko mice are resistant to passive disease induction. Interestingly, wt recipients of ko donors immunized for EAE were also protected. Furthermore, adoptive transfer of activated GFP+ T cells show marked decreased infiltration of GFP+ T cells into the CNS. Taken together, these findingssuggest that depletion of PI3Kγ results in a down-regulation of the inflammatoryresponse caused by impaired trafficking of cells critical to generation of the immune response. (Supported by NIH grant AI 064320 and National MS Society Grant RG 3272).