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Probing safety of nano-objects by defining immune responses of environmental organisms

Periodic Reporting for period 2 - PANDORA (Probing safety of nano-objects by defining immune responses of environmental organisms)

Berichtszeitraum: 2018-01-01 bis 2019-12-31

PANDORA aims at identifying the effects of nanoparticles on the immune responses of environmental organisms.
The rapid worldwide development of nanotechnologies has fostered intense studies addressing the safety of engineered nanoparticles (NP), which enter in an increasingly larger number of consumers’ products and industrial applications and can be released into the environment. The effects of NP on human health are actively studied also in relation to the development of nanomedicine. The immunosafety of NP is a major issue for human health, because of the possibility that NP, even if not directly toxic, may alter the functionality of immune cells thereby posing significant health risks. Environmental nanotoxicology, on the other hand, has dedicated little/no attention to the effects of NP on the immune responses of environmental species, despite the central role of defensive immune mechanisms in ensuring the fitness of all environmental organisms.
PANDORA has merged immunology, environmental sciences and nanotoxicology into a broader approach to environmental nanosafety aiming to attain a deeper vision of the problem, and to propose valid tools and realistic solutions.
PANDORA’s work aimed to give answers to the following questions:

1. Do nanoparticles have a detrimental effect on the immunity of environmental species?
PANDORA selected six living species, plants (A. thaliana), worms (E. foetida, E. andrei), terrestrial invertebrates (P. scaber), marine molluscs (M. galloprovincialis), sea urchins (P. lividus) and humans (H. sapiens). For each organism, researchers designed experimental models able to assess immune reactions to infectious bacteria or viruses and used NP in two ways: to see whether NP can trigger an immune reaction as microbes do; and to see whether NP can interfere with the protective immune reaction against microbes. These experiments were performed either in vitro or in vivo. The experiments in humans were done with white blood cells, but PANDORA used immune cells in vitro also for sea urchins, mussels and worms. Particular care was taken in characterising the NP and their contaminants, to exclude effects due to microbial contamination or toxic ions, and in assessing the interaction of NP with the environmental agents (sea water, biological fluids, soil components), to make sure that exposure to NP in the lab was made in conditions that closely resembled the real-life exposure.
The results obtained suggest the following answers to the question:
• all living species essentially react to NP in the same way;
• the majority of NP do not induce an immune reaction in any living species (i.e. the immune system does not consider them as a danger);
• few NP types stimulate an immune reaction, which is however transient and disappears rapidly without detrimental consequences (i.e. the immune system considers them as a potential danger and mounts a normal defensive immune response);
• no NP were found capable to induce a persistent potentially detrimental response;
• few NP could partially interfere with a protective immune response (i.e. in general their presence does not affect the capacity of the organism to protect itself from infections).

2. How can we understand if a particular nanoparticle is detrimental for environmental species?
PANDORA worked at the design and optimisation of a number of realistic assays for testing the capacity of NP to trigger inflammatory responses in different living species. The PANDORA scientists have also defined a small number of parameters that one should measure to have an idea of the health risk posed by NP. The industrial partner in PANDORA has developed some of these assays and translated them into easy-to-use marketable products. Thus, the answer is as follows:
• Using the scientific knowledge for setting up realistic predictive assays that can allow the reaction to NP in real life;
• Developing such assays into easy to use marketable kits.

3. Can we design nanoparticles that do not have detrimental effects on environmental species?
The PANDORA partners include expert chemists that, in collaboration with biologists, have modified the NP chemical composition, size, shape, surface charge, and have assessed the effects of such changes on the NP capacity to affect immune responses. Essentially, the chemical composition of NP defines whether toxic ions are released or not in aqueous environments, the NP surface charge dictates the composition of the biological coating that forms on the NP surface within a specific environment, while the shape and size determine the way NP are taken up by immune phagocytic cells and their intracellular fate/destruction. In addition, the health conditions of the organism can make a difference: the same NP in the same environment may have no effect on an healthy animal and show some toxicity for an infected or wounded animal. Thus, we can answer as follows:
• there is no way of designing safe NP, because their detrimental effects depend not only on the NP characteristics but also on the environment and the conditions of the animal exposed to them;
• a number of modifications can be made on NP that change their interaction with the external environment and with the immune system and, consequently, modulate their overall immune effects;
• we can certainly design “safer” NP.

During their studies, PANDORA’s fellows and mentors were very active in communication and outreach, having already published 48 scientific papers, and participated to over 150 science communication events targeting the scientific community, the general public and industrial and regulatory stakeholders. PANDORA was one the H2020 MSCA success stories in 2019 (https://ec.europa.eu/research/infocentre/article_en.cfm?artid=49934) and was featured in the H2020 Results in Brief in 2020 (https://cordis.europa.eu/article/id/418359-nanoparticle-safety-time-to-reconsider).
PANDORA was successful in bringing about a comprehensive investigation approach to the interaction of NP with the immune system that encompassed living species across evolution, from plants to man, thereby providing information useful for both environmental and human health. The major progress in knowledge generated by PANDORA’s studies is the finding that NP are generally unable to trigger an immune reaction and, in the few cases in which this occurs, they induce a transient reaction that is not detrimental for the organism. Impressively, the effects of NP on immunity is very reproducible across species. Thus, the potential impact of PANDORA’s results lies in the acknowledgement that NP are generally non-toxic and that their potential immuno-risk can be monitored and limited with appropriate engineering. An additional impact can come from the notion that NP can have beneficial effects for plants (increasing their growth and fitness) and in human beings in modulating their immune reactivities in therapeutic approaches (e.g. against cancer) and in preventive strategies (e.g. increasing vaccine efficacy). But the best PANDORA’s result by far is the successful training of eleven young scientists along the principles of RRI. The adoption of principles of responsible and sustainable research and innovation occurred since the very beginning of their PhD studies and is now embedded in their approach to research. This is truly a new generation of scientists that work with and for the society.
LOGO PANDORA