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- Title
Selective Pharmacological Inhibition of Phosphoinositide 3-Kinase p110delta Inhibits Marginal Zone B-cell Function and Abrogates the Development of Autoimmune Diabetes in NOD Mice.
- Authors
Durand, Caylib A.; Richer, Martin; Horwitz, Marc; Graves, Marcia; Puri, Kamal D.; Gold, Michael R.
- Abstract
In non-obese diabetic (NOD) mice, B-lymphocytes promote the development of type 1 diabetes (T1D) by acting as antigen-presenting cells (APCs) for T cells that mediate the destruction of insulin-producing pancreatic beta cells. Splenic marginal zone (MZ) B cells, which have been associated with multiple autoimmune diseases, are potent APCs that can take up blood-borne antigens, including beta-cell antigens released during the islet destruction in T1D. Recent work has shown that MZ B cells migrate to, and accumulate in, the pancreatic lymph nodes of NOD mice prior to the development of frank diabetes and that they can act as APCs that promote diabetogenic T cell proliferation. Thus modulating MZ B cell function may be a novel approach for preventing the progression of T1D. We have shown (J. Immunol. 183:5673, 2009) that the catalytic activity of p110delta is important for the migration, activation, function, and in vivo localization of MZ B cells. We now show that treating NOD mice with IC87114, a p110delta-selective inhibitor, prevents the expansion of splenic MZ B cells and delays the onset of T1D. We found that a short-term 4 week treatment or a longer-term 10-week treatment with IC87114 reduced the incidence and caused a significant delay in the development of diabetes in NOD mice. Diabetes developed in >80% of vehicle-treated NOD mice by 20 weeks of age but in only 40% of IC87114-treated animals. Histopathological evaluation demonstrated that p110delta inhibitor decreased the infiltration of inflammatory cells into pancreatic islets. We also observed that once blood glucose levels were >300 mg/dL, they rapidly increased from 300 to >500 mg/dl within 7 days in vehicle-treated NOD mice. By contrast, administering IC87114 immediately after blood glucose levels were >300 mg/dl substantially delayed disease progression in more than one-third of mice. The data indicate that IC87114 can slow disease progression. Current studies are aimed at identifying the immunological and metabolic processes in NOD mice that are inhibited by IC87114 in order to better understand the drug's mode of action and to further characterize its potential as a therapeutic agent to prevent the progression of T1D.
- Subjects
PHOSPHOINOSITIDES; B cells; AUTOIMMUNE diseases; DIABETES; ANTIGEN presenting cells
- Publication
UBC Medical Journal, 2011, Vol 2, Issue 2, p51
- ISSN
1920-7425
- Publication type
Abstract