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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - PANDORA (Probing safety of nano-objects by defining immune responses of environmental organisms)

Teaser

Summary

PANDORA aims at identifying the effects of nanoparticles on the immune responses of environmental organisms.
The rapid development of nanotechnologies worldwide has fostered intense studies regarding the safety of engineered nanoparticles (NP), which enter in an increasingly larger number of consumersâ€™ 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.
PANDORA aims at merging immunology, environmental sciences and nanotoxicology into a broader approach to environmental nanosafety that is expected to attain a deeper vision of the problem, and to propose valid tools and realistic solutions.

Work performed

The work performed in the first 24 months and the results achieved so far are detailed below:
â€¢ Assessing the capacity of selected NP to induce innate defence reactions in environmental organisms.
During this reporting period, we have set up and implemented a series of in vivo and in vitro models of innate immunity in various living species, including plants (A. thaliana), worms (E. foetida, E. andrei), isopods (P. scaber), marine bivalves (M. galloprovincialis), sea urchins (P. lividus) and humans (H. sapiens). A number of endpoints were identified that, in each species and model, could reliably represent the innate reactions to exogenous danger signals/agents. In all models, the effects of NP were already preliminarily tested using prototypical metal NP provided by partner ICN2.

â€¢ Classifying the NP-induced reaction as normal (transient) or anomalous (too high or too low, persistent);
Partners have designed their in vivo and in vitro models with a two-pronged aim: the first is detecting innate reactions that are the â€œphysiologicalâ€ successful defensive response of cells/organisms to dangerous agents or events, which resolves with the elimination of the danger and re-establishment of homeostasis. The second aim is identifying innate reactions that are unsuccessful, i.e., unable to eliminate the danger and/or directly causing significant damage to the organism. The effects of NP are being evaluated in their ability to directly induce successful vs. unsuccessful types of innate immune reactions in the established models, and for their ability to indirectly modulate successful or unsuccessful innate immune reactions. More specifically, NP will be considered potentially harmful when directly able to induce an unsuccessful innate immune reaction (e.g., persistent inflammation), or when able to down-regulate a successful reaction (risk of immunosuppression) or to exacerbate a persistent/anomalous reaction (risk of autoinflammation or chronic/destructive activation).

â€¢ Identifying common pathways/markers in NP-induced defence reactions across species that can be predictive of immuno-nanorisk for environmental and human health.
Partners have started examining, in their in vivo and in vitro models, a number of parameters of innate immune activation. The goals are essentially two. First, to establish criteria, in each of the organisms examined, able to discriminate between successful and anomalous innate defensive responses. This is very important, because the difference between a normal reaction and a potentially harmful one can be subtle, since the same mechanisms are involved in both. The second objective is that of exploiting the high degree of conservation of innate immune molecules and mechanisms across living organisms for identifying some markers of immuno-nanorisk that are common across species. This would be greatly helped by notions on innate responses to pathogens, for which many markers are known that will serve as benchmarks to which NP-induced effects can be compared.

â€¢ Designing NP surface modifications that may change their impact on innate immunity.
Partner ICN2 was active in synthesizing metal NP of different size and shape, and to design different coatings, in order to assess the NP ability to differently interact with biological matrices and environmental elements (from tissue culture medium, serum and plasma, to humic acid, sea water and bacterial molecules) and to adsorb and retain them on their surface. Partners involved in the evaluation of the NP effects on innate immunity have started using such different NP to understand how differences in the NP characteristics can change their biological effects. This objective will be continuously developing, since new modifications of the NP design will be proposed by ICN2 based on the outcomes of the experiments of the other partners.

â€¢ Building and validating novel cell-based immuno-nanosafety assays for environmental and human health.
The cell-based

Final results

The development of predictive innate immunity assays for evaluating the effects of NP will allow questions about the immunological risk posed to living organisms (including human beings) to be answered in a realistic fashion, or addressed properly for the first time, a capability with significant attraction to prospective employers in academia. The exposure of fellows to different disciplines (from nanotechnology to evolution of immune responses to human immunity to safety/toxicology) and the intense exchange programme will allow them to expand the range of their scientific and technical knowledge and to learn how to work in multidisciplinary collaborations. An important issue that we wish to underline is that the PANDORA activities are all implementing an RRI strategy. A very effective course on RRI was delivered to fellows at the beginning of their PhD, and they have all adsorbed the concepts and started integrating them into their lab activities and experimental strategies. The societal impact of their studies will be most likely enhanced by their RRI-based attitude.