PhD Scientific Days 2025

Molecular Medicine IV.

The effect of the Syk-selective inhibitor entospletinib in immune complex-mediated inflammation

Name of the presenter

Káposztás Eszter

Institute/workplace of the presenter

Department of Physiology, Semmelweis University, Budapest

Authors

Eszter Káposztás*¹, Zita Panka Nagymihály*¹, Attila Mócsai¹, Tamás Németh¹

1: Department of Physiology, Semmelweis University, Budapest

Text of the abstract

Introduction: Immune complex-mediated processes are crucial in the pathogenesis of several autoimmune diseases. In significant proportion of patients sustained remission is not available, so it is important to find new therapeutic options. It has been shown that the absence of the Syk tyrosine-kinase from the hematopoietic compartment resulted in a total protection from the development of experimental arthritis. This result with further observations raised the possibility that Syk could be a potential therapeutic target in the treatment of immune complex-triggered autoimmune diseases.
Aims: Here, we tested the effect of entospletinib, a Syk-selective inhibitor on the development of the immune complex-mediated Arthus reaction.
Methods: Entospletinib or vehicle alone was administered orally twice a day. Arthus reaction was triggered by the intravenous injection of ovalbumin, which was followed by the intradermal administration of anti-ovalbumin antibodies to the ears. The severity of oedema was followed by the intravenous injection of Evans blue and by ear thickness measurement. The local immune cell accumulation was measured by flow cytometry, while the levels of cytokines were quantified by ELISA. The immune complex-triggered superoxide release of isolated neutrophils was followed by a cytochrome c-reduction assay.
Results: Entospletinib massively reduced the extravasation of the plasma protein-bound Evans blue, while the inhibitor also decreased the ear thickness changes. Moreover, entospletinib reduced the immune cell recruitment to the ears, while showing a tendency to decrease the levels of local proinflammatory cytokines. Entospletinib dose-dependently reduced the investigated immune complex-triggered in vitro cell responses of neutrophils.
Conclusions: Entospletinib could effectively decrease the severity of the immune complex-mediated Arthus reaction, which is likely due to the impared neutrophil cell responses in the presence of the inhibitor. These data indicate that entospletinib could be a drug candidate in the treatment of immune complex-mediated human autoimmune diseases in the future.
Funding: *These authors contributed equally to this project. This work was funded by the Hungarian National Research, Development and Innovation Office and the Lendület program of the Hungarian Academy of Sciences. E. K. is a recipient of a SE 250+ Scholarship.