The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases



Edward Banham-Hall1, Menna R Clatworthy2, Klaus Okkenhaug*, 1
1 Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, CB22 3AT, UK
2 Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, UK


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© Banham-Hall et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, CB22 3AT, UK; Tel: (01223) 496000; Fax: (01223) 496002; E-mail: klaus.okkenhaug@babraham.ac.uk


Abstract

The class 1 PI3Ks are lipid kinases with key roles in cell surface receptor-triggered signal transduction pathways. Two isoforms of the catalytic subunits, p110γ and p110δ, are enriched in leucocytes in which they promote activation, cellular growth, proliferation, differentiation and survival through the generation of the second messenger PIP3. Genetic inactivation or pharmaceutical inhibition of these PI3K isoforms in mice result in impaired immune responses and reduced susceptibility to autoimmune and inflammatory conditions. We review the PI3K signal transduction pathways and the effects of inhibition of p110γ and/or p110δ on innate and adaptive immunity. Focusing on rheumatoid arthritis and systemic lupus erythematosus we discuss the preclinical evidence and prospects for small molecule inhibitors of p110γ and/or p110δ in autoimmune disease.

Keywords: PI3K inhibitors, humoral immune, systemic lupus erythematosus, pleckstrin homology, autoimmunity, rheumatoid arthritis, PI3K..