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.

Keywords::

• Type 1 diabetes
• NOD mice
• phosphoinositide 3-kinase
• IC87114
• marginal zone B cells

Acknowledgements

We thank Hao Chen for determining the levels of IC87114 in the plasma of NOD mice that had received the drug by oral gavage and Costanza Casiraghi for helpful advice on designing the antigen presentation experiments.

Declaration of interest : This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to M.R.G. (grant MOP-11651) as well as grants from the CIHR and the Canadian Diabetes Association to M.S.H. K.D.P. is an employee of Gilead Sciences Inc., the manufacturer of IC87114. The other authors report no conflict of interest. The authors alone are responsible for the content and writing of the manuscript.