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Immunology

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

Leukemia volume 26, pages 1617–1629 (2012)Cite this article

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Abstract

Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as a consequence of multiple activating events in antigen-presenting cells (APCs) and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase involved in multiple signaling events of immune cells. Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, which involves activation of different immune cell populations. In vivo expansion of luciferase+ donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity. Importantly, in vivo and in vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus immune responses were not impacted by Fostamatinib. In APCs Syk inhibition reduced the expression of costimulatory molecules and disrupted cytoskeletal organization with consecutive APC migratory defects in vitro and in vivo while phagocytic activity remained intact. On the basis of these immunomodulatory effects on different cell populations, we conclude that Syk targeting in alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already applied successfully in anti-lymphoma therapy, has clinical potential to reduce GvHD, especially as anti-leukemia and anti-viral immunity were preserved.

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Acknowledgements

We are grateful to Sophie Krüger and Volker Schmidt for excellent technical assistance and to Dr Marie Follo for critically reading the manuscript. We thank E Hobeika, H Jumaa and M Reth for helpful discussions, H Pircher for help with the MCMV experiments and Rigel and AstraZeneca Pharmaceuticals for valuable suggestions and for providing R406 and Fostamatinib. This study was supported by the Deutsche Forschungsgemeinschaft, Germany, individual grant to RZ (DFG ZE 872/1-1) and partly by the BIOSS Centre for Biological Signaling Studies (RZ).

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

    F Leonhardt, K Zirlik, G Prinz, A-K Hechinger & R Zeiser

  2. Department of Biology, Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany

    F Leonhardt & A-K Hechinger

  3. Department of Hematology, Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA

    M Buchner

  4. Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

    U V Gerlach, P Fisch & A Schmitt-Gräff

  5. Department of Radiology/Medical Physics, University Hospital Freiburg, Freiburg, Germany

    W Reichardt

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AUTHOR CONTRIBUTIONS

FL helped to design the experiments, performed experiments, analyzed data and helped to write the manuscript; KZ helped to design the study and to write the manuscript; MB, GP and AKP helped to perform experiments; UVG and ASG analyzed GvHD target organs; PF helped with chromium release assays; WR helped to design experiments and to write the manuscript and RZ designed experiment, analyzed data and wrote the paper.

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Leonhardt, F., Zirlik, K., Buchner, M. et al. Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels. Leukemia 26, 1617–1629 (2012). https://doi.org/10.1038/leu.2012.10

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