Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production.

Ariana Barbera Betancourt,F Susan Wong,Klaus Okkenhaug,Juliet L Emery,Anne Cooke,Maja Wallberg,Asha Recino

doi:10.1371/journal.pone.0146516

Ariana Barbera Betancourt, F Susan Wong + Show 5 more

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https://doi.org/10.1371/journal.pone.0146516

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Abstract

Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.

Highlights

Type 1 diabetes is an autoimmune inflammatory disease that is caused by immune cell mediated destruction of the insulin-producing beta cells in the pancreas
We assessed the effects of increasing levels of IC87114 on T cells from diabetes-prone non obese diabetic (NOD) mice in in vitro culture, looking at anti-CD3 and anti-CD28 induced proliferation of CD4+ T cells (Fig 1A, left hand panel) and CD8+ T cells (Fig 1A, right hand panel) and production of IFN-γ (Fig 1B)
We performed an extended analysis of the effects on cytokine production by IC87114, and found that increasing concentration of IC87114 suppressed all the pro-inflammatory cytokines assessed in supernatants from peptide-stimulated BDC2.5 CD4+ T cells, including IFN-γ, IL-2, GM-CSF, and IL-6, while there was a trend towards increased production of anti-inflammatory cytokine IL-10 and Th2 associated cytokines IL-4 and IL-5 (S1 Fig)

Summary

Introduction

Type 1 diabetes is an autoimmune inflammatory disease that is caused by immune cell mediated destruction of the insulin-producing beta cells in the pancreas. T cells are assumed to play a considerable role in the pathogenesis of this disease which comes from the demonstration that its strongest genetic risk is conferred by the HLA locus and other loci affecting the biology of these cells [1, 2]. Islet specific CD4+ and CD8+ cells mediate diabetogenesis in NOD mice [3] and have been identified in human type 1 diabetes patients [4,5,6]. Other cell types including B cells, dendritic cells and macrophages are necessary for the initiation of the anti-islet immune responses (reviewed in [7]). Once the beta cell pool is destroyed by the immune system, insufficient amounts of insulin are produced to sustain glucose uptake into insulin.

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