Gezielte Inhibierung intrazellulärer Kinaseaktivität bei ankylosierender Spondylitis
Immunologie
Zusammenfassung der Projektergebnisse
The current therapeutic options for Ankylosing Spondylitis (AS), a common rheumatic disease of young adults leading to painful inflammation and debilitating new bone formation of joints and spine, are still limited. Next to non-steroidal anti-inflammatory drugs (NSAID), such as ibuprofen, only antibodies against tumor necrosis factor (TNF) or interleukin 17 (IL-17) are currently available. These antibodies are still very expensive and one third of patients do not respond adequately. An urgent need for new therapeutic concepts remains. This work has highlighted two new concepts as treatment options for AS: Janus kinase inhibition and p300 bromodomain inhibition: Janus kinases (JAK) are widely used in the cells of the human immune system, such as T helper cells (Th cells), to transmit signals from the cell surface to the nucleus. Each cytokine requires different combinations of JAK family members, therefore allowing for either pro- or anti-inflammatory effects. Interleukin 23 is one of the major cytokines leading to the production of the proinflammatory cytokine IL-17 by Th cells in AS and utilizes JAK. One JAK family member, TYK2, is of special importance in this pathway. Our data show that most JAK inhibitors can pivotally reduce the amount of IL-17 produced by Th cells isolated from individuals with AS in vitro. JAK inhibitors do also reduce amounts of additional cytokines (e.g. IL-17F and IL-22) produced by AS T helper cells, making them more efficacious than antibodies targeting only one cytokine. Although there was no specific TYK2 inhibitor available to us, our results reinforce interest in development of a TYK2 inhibitor as a more targeted therapeutic for AS. Production of small molecule inhibitors of JAK is much cheaper and they can be taken orally. Our data suggest that already established JAK inhibitors should be repurposed for clinical trials in AS. In addition we evaluated for the first time the concept of interacting with so called epigenetics in AS. Epigenetics refers to genetic information that is not encoded in the DNA sequence of an organism. Epigenetic modifications, being for example DNA methylation or histone acetylation, determine the expression of genes. Bromodomains are readers of such epigenetic modifications and help to direct parts of the universal transcriptional machinery, e.g. p300, to the genes. CBP30, the inhibitor we tested, interacts and blocks the bromodomain of p300, which has been shown to be part of the transcriptional complex necessary for the expression of IL-17 in Th cells. Our results of in-vitro testing of CBP30 on human AS T cells show, that it is very potent and rather selective compared to other bromodomain inhibitors. This information can be used to further develop this compound into a drug, which could be used for in-vivo studies in mouse models of AS. Depending on those results, the drug could further be investigated in humans as an alternative to anti-TNF treatment.
Projektbezogene Publikationen (Auswahl)
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Bromodomain inhibitors reduce Th17-type responses in Spondyloarthritis in vitro. 9th International Congress on Spondyloarthropathies 2014
Hammitzsch A, de Wit J, Ridley A, Al-Mossawi MH, Knapp S, Bowness P
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Comparison of in vitro effects of kinase and epigenetic inhibitors on Th17 responses in inflammatory arthritis. Annual European Congress of Rheumatology 2014
Hammitzsch A., de Wit J., Ridley A., Al-Mossawi MH., Bowness P.
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CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci USA. 2015 Aug 25;112(34):10768-73
Hammitzsch A, Tallant C, Fedorov O, O'Mahony A, Brennan PE, Hay DA, Martinez FO, Al- Mossawi MH, de Wit J, Vecellio M, Wells C, Wordsworth P, Müller S, Knapp S, Bowness P
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CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses Th17 responses in human inflammatory arthritis. 4th Oxford Symposium on Epigenetic mechanisms on Health & Disease 2015
Bowness P, Hammitzsch A.
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Deciphering the in vitro therapeutic potential of JAK inhibitors in ankylosing spondylitis. Annual European Congress of Rheumatology 2016
Hammitzsch A., Chen L., Al-Mossawi MH., Simone D., Ridley A., Bowness P.
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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):916-23
Chen L, Ridley A, Hammitzsch A, Al-Mossawi MH, Bunting H, Georgiadis D, Chan A, Kollnberger S, Bowness P
