| Selective pharmacological inhibition of phosphoinositide 3-kinase p110delta opposes the progression of autoimmune diabetes in non-obese diabetic (NOD) mice. | |
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MedLine Citation:
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PMID: 23039284 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. Although 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. |
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Authors:
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Caylib A Durand; Martin J Richer; Kathrin Brenker; Marcia Graves; Iryna Shanina; Kate Choi; Marc S Horwitz; Kamal D Puri; Michael R Gold |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-8 |
Journal Detail:
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Title: Autoimmunity Volume: - ISSN: 1607-842X ISO Abbreviation: Autoimmunity Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8900070 Medline TA: Autoimmunity Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Microbiology and Immunology, Infection, Inflammation, and Immunity (I3) Research Group, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia , Canada V6T 1Z3. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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