Modulating TH17/Treg balance in immune-mediated arthritis
The type 17/23 axis plays a key role in the pathogenesis of Ankylosing Spondylitis and realted human diseases including Psoriatic Arthritis, Psoriasis and Inflammatory Bowel Disease. Understanding the immune pathogenesis of Type17 responses in AS has opened up opportunities for more effective targeted therapy. This project will take candidates from novel datasets (eg RNA seq) obtained from type 17 cells AS, and address their potential pathogenicity.
We have previously shown using in vitro assays with patient-derived cells that small molecule inhibitors of ERAP1, of the transcription factor ROR gamma T, of the (epigenetic) bromodomain readers and transcriptional co-activators CBP and p300 and of JAKs can all inhibit Type17 responses in vitro.
We will also luse established immunological assays to look for evidence of reciprocal regulation of regulatory T cell responses in SpA.
The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. Training will be provided in techniques including FACS and FACS analysis, cell culture, immunoassays, bacterial culture and metagenome analysis.
- Hammitzsch A, Tallant C, Fedorov O, O’Mahony A, Brennan PE, Hay DA, Martinez FO, Al-Mossaw MH, de Wit J, Vecellio M, Wells C, Wordsworth BP, Müller S, Knapp S* and Bowness P* CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10768-73. doi: 10.1073/pnas.1501956112. PMID: 26261308.
- de Wit J*, Al-Mossawi MH*, Hühn MH, Arancibia-Cárcamo CV, Doig K, Kendrick B, Gundle R, Taylor P, Mcclanahan T, Murphy E, Zhang H, Barr K, Miller JR, Hu X, Aicher TD, Morgan RW, Glick GD, Zaller D, Correll C, Powrie F, Bowness P. RORgt inhibitors suppress Th17 responses in inflammatory arthritis and inflammatory bowel disease. J Allergy Clin Immunol. 2016 Mar;137(3):960-3. doi: * equal contribution
- Chen L, Ridley A, Hammitzsch A, Al-Mossawi MH, Bunting H, Georgiadis D, Chan A, Kollnberger S, Bowness P. Silencing or inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) suppresses free heavy chain expression and Th17 responses in ankylosing spondylitis. Ann Rheum Dis. 2016 May; 75(5): 916–923. pii: annrheumdis-2014-206996. doi: 10.1136/annrheumdis-2014-206996. PMID: 26130142
- Chen L, Shi H, Yuan J, Bowness P. Position 97 of HLA-B, a residue implicated in pathogenesis of ankylosing spondylitis, plays a key role in cell surface free heavy chain expression. Ann Rheum Dis. 2017a Mar;76(3):593-601.
- Chen L, Al-Mossawi MH, Ridley A, Sekine T, Hammitzsch A, de Wit J, Simone D, Shi H, Penkava F, Kurowska-Stolarska M, Pulyakhina I, Knight JC, Kim TJ, Bowness P. miR-10b-5p is a novel Th17 regulator present in Th17 cells from ankylosing spondylitis. Ann Rheum Dis 2017 Mar;76(3):620-625.