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Selective pharmacological inhibition of phosphoinositide 3-kinase p110delta opposes the progression of autoimmune diabetes in non-obese diabetic (NOD) mice.
MedLine Citation:
PMID:  23039284     Owner:  NLM     Status:  Publisher    
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.
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:
Type:  JOURNAL ARTICLE     Date:  2012-10-8
Journal Detail:
Title:  Autoimmunity     Volume:  -     ISSN:  1607-842X     ISO Abbreviation:  Autoimmunity     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8900070     Medline TA:  Autoimmunity     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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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