Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases

Atreya I, Diall A, Dvorsky R, Atreya R, Henninger C, Gruen M, Hofmann U, Schaeffeler E, Lopez Posadas R, Daehn I, Zenker S, Doebroenti M, Neufert C, Billmeier U, Zundler S, Fritz G, Schwab M, Neurath M (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 10

Pages Range: 1132-43

Journal Issue: 10

DOI: 10.1093/ecco-jcc/jjw091

Abstract

The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD].Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potential toxicity, and immunosuppression. Activation of the Vav1/Rac1 pathway in lymphocytes was studied in IBD patients and in lamina propria immune cells in the presence or absence of thiopurine-analogues.Several thiopurine-analogues induced significantly higher T cell apoptosis than 6-mercaptopurine. We identified a compound, denoted B-0N, based on its capacity to mediate earlier and stronger induction of T cell apoptosis than 6-mercaptopurine. B-0N-treatment resulted in accelerated inhibition of Rac1 activity in primary peripheral blood T cells as well as in intestinal lamina propria immune cells. Compared with 6-thio-GTP and 6-mercaptopurine, B-0N-treatment was associated with decreased myelo- and hepatotoxicity.The Vav1/Rac1 pathway is activated in mucosal immune cells in IBD. The designer thiopurine-analogue B-0N induces immunosuppression more potently than 6-mercaptopurine.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Düsseldorf Germany (DE) Johannes Gutenberg-Universität Mainz (JGU) Germany (DE) Max-Planck-Institut für molekulare Physiologie / Max Planck Institute of Molecular Physiology Germany (DE) Jena Bioscience GmbH Germany (DE) Robert-Bosch-Krankenhaus Germany (DE) Cancer Research UK United Kingdom (GB)

How to cite

APA:

Atreya, I., Diall, A., Dvorsky, R., Atreya, R., Henninger, C., Gruen, M.,... Neurath, M. (2016). Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases. Journal of Crohns & Colitis, 10(10), 1132-43. https://doi.org/10.1093/ecco-jcc/jjw091

MLA:

Atreya, Imke, et al. "Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases." Journal of Crohns & Colitis 10.10 (2016): 1132-43.

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