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
Wong, F Susan
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Barbera, B. A., Emery, J. L., Recino, A., Wong, F. S., Cooke, A., Okkenhaug, K., & Wallberg, M. (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 (e0146516)https://doi.org/10.1371/journal.pone.0146516
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.
This work was supported by Grant number 09/0003840, Diabetes UK https://www.diabetes.org.uk/ (MW); Grant number 5-2006-229, Juvenile Diabetes Research Foundation https://www.jdrf.org.uk/ (KO); Grant number BBS/E/B/0000C236 Biotechnology and Biological Sciences Research Council (KO); Grant number health-f5-2009-241883 European Research Council 7th Frame Programme http://ec.europa.eu/research/fp7/index_en.cfm (AC); and Grant number 02BX12ACYD, the Britain Israel Research and Academic Exchange Partnership (BIRAX) http://www.britishcouncil.org.il/en/programmes/science/birax.
Diabetes UK (09/0003840)
External DOI: https://doi.org/10.1371/journal.pone.0146516
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253733
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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