title: Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production.
abstract: Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom.
authors.forename: Ariana
authors.initials: A
authors.lastname: Barbera Betancourt
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom.
authors.forename: Juliet L
authors.initials: JL
authors.lastname: Emery
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom.
authors.forename: Asha
authors.initials: A
authors.lastname: Recino
authors.affiliation: Diabetes Research Group, Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom.
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QP Cambridge, United Kingdom.
authors.forename: Maja
authors.initials: M
authors.lastname: Wallberg
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
chemical_list: D000225:Adenine; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; C477872:IC 87114; C421683:Pik3cd protein, mouse