title: Selective pharmacological inhibition of phosphoinositide 3-kinase p110delta opposes the progression of autoimmune diabetes in non-obese diabetic (NOD) mice.
abstract: During the progression of autoimmune (type 1) diabetes, T cells and macrophages infiltrate the pancreas, disrupt islet function, and destroy insulin-producing beta cells. B-lymphocytes, particularly innate like B-cell populations such as marginal zone B cells and B-1 cells, have been implicated in many autoimmune diseases, and non-obese diabetic (NOD) mice that lack B cells do not develop spontaneous autoimmune diabetes. Hence, inhibitors of B cell signaling pathways could be useful for limiting the autoimmune processes that contribute to type 1 diabetes. Signaling via phosphoinositide 3-kinase (PI3K) regulates many cellular processes. The p110δ isoform of PI3K is expressed primarily in cells of hematopoietic origin and the catalytic activity of p110δ is important for B cell migration, activation, proliferation, and antigen presentation. Because innate-like B cells are particularly sensitive to inhibition of p110δ activity, and p110δ inhibitors also suppress pro-inflammatory functions of other cell types that contribute to autoimmunity, we tested whether a p110δ inhibitor could delay the onset or reduce the incidence of autoimmune diabetes in NOD mice. We found that long-term preventative treatment of pre-diabetic NOD mice with IC87114, a highly selective small molecule inhibitor of p110δ, reduced the infiltration of inflammatory cells into the pancreatic islets and, accordingly, delayed and reduced the loss of glucose homeostasis. Moreover in a therapeutic treatment mode, IC87114 treatment conferred prolonged protection from progression to overt diabetes in a number of animals. These findings suggest that PI3Kδ inhibitors could be useful for managing type 1 diabetes.
authors.affiliation: Department of Microbiology and Immunology, Infection, Inflammation, and Immunity (I3) Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Caylib A
authors.initials: CA
authors.lastname: Durand
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Richer
authors.forename: Kathrin
authors.initials: K
authors.lastname: Brenker
authors.forename: Marcia
authors.initials: M
authors.lastname: Graves
authors.forename: Iryna
authors.initials: I
authors.lastname: Shanina
authors.forename: Kate
authors.initials: K
authors.lastname: Choi
authors.forename: Marc S
authors.initials: MS
authors.lastname: Horwitz
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gold
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006651:Histocytochemistry; D050417:Insulin-Secreting Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D018709:Statistics, Nonparametric
chemical_list: D000225:Adenine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C477872:IC 87114