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Inhibition of phosphoinositide 3-Kinase p110delta does not affect T cell driven development of Type 1 diabetes despite significant effects on cytokine production

Barbera Betancourt, Ariana, Emery, Juliet L., Recino, Asha, Wong, Florence Susan, Cooke, Anne, Okkenhaug, Klaus and Wallberg, Maja 2016. Inhibition of phosphoinositide 3-Kinase p110delta does not affect T cell driven development of Type 1 diabetes despite significant effects on cytokine production. PLoS ONE 11 (1) , e0146516. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 5 July 2017
Date of Acceptance: 18 December 2015
Last Modified: 19 Jun 2019 10:14
URI: http://orca.cf.ac.uk/id/eprint/102071

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