Current Bionanotechnology   2213-5308/16 $58.00+.00 © 2016 Bentham Science Publishers Diana Boraschi * and Paola Italiani Laboratory of Innate Immunity, Institute of Protein Biochemistry, National Research Council, Napoli, Italy  A R T I C L E H I S T O R Y Received: February 23, 2016 Revised: March 21, 2016 Accepted: March 22, 2016 DOI: 10.2174/22135294026661606011217 21 Abstract: The thorough understanding of the interaction between nanomaterials and the immune system is the starting point both for nanomaterial exploitation in nanomedicine and for the implementation of an effective regulatory framework concerning nanosafety for human health and the environment. In this context, the use of valid models, in vitro and in vivo, is central for assessing both the positive and the detrimental effects of nanomaterials, thereby predicting their possible risks for human and environmental health. Thus, predicting models are sought that allow us on one side defining hazard posed by nanomaterials, and therefore implementing safety regulation and safe-by-design nanotechnologies, and on the other side exploiting nanomaterials for more effective therapeutic and preventive medical strategies. Here, we consider the advantages and limitation of the current in vitro and in vivo human and animal models, and the appropriateness of their use for assessing the effects of nanomaterials on immunity. Keywords: Innate immunity, inflammation, nanomaterials, human, animal, in vitro, in vivo, safety. 1. INTRODUCTION The interaction of nanomaterials with the immune system is a topic of key importance both in nanotoxicology and in nanomedicine. The immune system is a complex system of cells and soluble mediators scattered throughout the body, which has the double role of maintaining tissue integrity and homeostasis, and of protecting the organism from possible dangers [1]. Immune cells and molecules at the body surface (airway and digestive mucosa, skin) are the first that come in contact with nanomaterials upon accidental exposure, whereas immune effectors in blood, muscle, liver and kidney are those that come in contact with injectable nanomedicinal products, while those in skin and lung are involved in the interaction with topical and inhaled nanodrugs/nanovaccines [2, 3]. In all cases, the first interaction is with cells and mediators of the so-called innate immune system, characterized by low specificity but immediate and potent activity of recognition and destruction of the foreign agent [4]. Interaction of nanomaterials with the immune system may result in four events (Fig. 1). 1. No recognition and tolerance . The immune system does not consider the nanomaterial as a potential danger and simply ignores it. Or, the nanoparticles are recognised and "tolerised", i.e., they induce immunological tolerance. Most *Address correspondence to this author at the Institute of Protein Biochemistry (IBP), National Research Council (CNR), Via Pietro Castellino 111, 80131 Napoli, Italy; Tel: ++39-081-613-2623; Fax: ++39-081-613-2277; E-mail: d.boraschi@ibp.cnr.it nanomaterials fall in these two categories, and are therefore eliminated as such through renal filtration and excretion with the urine. This kind of “no interaction/tolerogenic interaction” leads to no consequences for the organism. 2. Recognition and silent elimination . The immune system recognizes the nanomaterial as a potential danger and acts accordingly by eliminating it. This is mainly done by macrophages, whose role in tissue is that of taking up debris and particles, and degrade them into their phagolysosomes, thereby maintaining tissues clean and healthy. Silent elimination is an immune mechanism that takes place all the time in our body, mainly directed to eliminating endogenous senescent cells or misfolded proteins. Also this interaction is inconsequential for the organism. 3. Recognition and successful inflammatory reaction . The immune system recognizes the nanomaterial as a danger but it does not succeed in eliminating it silently and therefore it starts a defensive inflammatory reaction, in which several cell types and effector molecules are involved. Such reaction brings about the successful elimination of the foreign particles, and is followed by a phase of resolution, in which the immune system contributes to repairing possible damages to the tissue and to re-establishing homeostasis. This kind of interaction is the typical defensive response mounted by the immune system, as for instance in the case of interaction with microorganisms. It does not lead to pathology, although there might be some transient damage to the affected tissue during the reaction. 4. Recognition and unsuccessful inflammatory reaction . The immune system reacts to the nanomaterial by mounting Send Orders for Reprints to reprints@benthamscience.ae Current Bionanotechnology, 2016, 2, 71-76 71 REVIEW ARTICLE Model Validity in Nanoimmunosafety: Advantages and Disadvantages of In vivo vs In vitro Models, and Human vs Animal Models