A new model system developed at FIMM to study the effect of drugs and drug candidates on innate immunity

A team led by FIMM-EMBL group leader Denis Kainov has developed a novel system for evaluating the effect of drugs on cellular immune responses.

The group showed the utility of the model system by testing four anticancer/antiviral agents and showing that these therapeutics at non-toxic concentrations modulate cellular responses to viral and bacterial pathogen associated molecular patterns (PAMPs). Moreover, all four therapeutics were able to inhibit influenza A virus infection, whereas only one of them allowed activation of innate immune responses in virus infected cells. This FDA-approved anticancer drug, called gemcitabine, has potential to be used in patients having severe infections.

Influenza A viruses cause yearly epidemics and thus have an enormous impact on public health. Occasionally the mutated viruses overcome the prevailing immunity in the human population and cause global pandemics. Although several antiviral drugs exist and many are under development, drug-resistant influenza variants emerge.  Therefore, more research is still needed both to develop new drugs and to better understand the properties of the existing molecules.

The presently known influenza antiviral molecules have various mechanisms of action and are directed towards different steps of the virus replication cycle. An intriguing line of research is now emerging in which drug molecules cooperating with host’s own immune system are in focus. However, it is not yet known whether the influenza antivirals modify or regulate immune functions.

To be able to study this, a research team led by Group Leader Denis Kainov from the Institute for Molecular Medicine Finland, FIMM, developed a novel model system where human macrophages were infected with influenza A virus variant. This model was then utilized to evaluate the immuno-modulatory effect of four anticancer agents which can inhibit influenza A virus infection at non-cytotoxic concentrations.

We were able to show that only one of the four tested drugs, gemcitabine, both limited viral replication and allowed the infected cells to produce cytokines and activate antiviral signaling cascades in infected human macrophages, said Dr. Kainov.

Anti-influenza drugs are typically used only in patients having severe infections, which are often associated with viral and bacterial co-infections. The results showed that gemcitabine has potential to be developed further to treat these severe influenza infections since by activating the immune system it could prime immune responses in non-infected cells and protect patients from co-infections. Furthermore, the drug has potential to become a broad-spectrum antiviral agent.

The model system we developed is very flexible since different immune cells can be treated with different immune stimuli. Thus, it could be useful in many other drug development projects to test the immunomodulatory properties of available and prospective drugs and to exploit or minimize side-effects of the therapeutics.

The study was done in collaboration with researchers from the Institute of Biotechnology of the University of Helsinki and Finnish Institute of Occupational Health (TTL).

Original publication:

Söderholm S, Anastasina M, Islam MM, Tynell J, Poranen MM, Bamford DH, Stenman J, Julkunen I, Šaulienė I, De Brabander JK, Matikainen S, Nyman TA, Saelens X,Kainov D. Immuno-modulating properties of saliphenylhalamide, SNS-032, obatoclax, and gemcitabine. Antiviral Res.  2016. 126: 69–80. doi:10.1016/j.antiviral.2015.12.011.