Advanced Review Interactions of nanomaterials with the immune system Salik Hussain, 1,2† Jeroen A. J. Vanoirbeek 2 and Peter H. M. Hoet 2∗ Evaluation of the immunomodulatory potentials of nanomaterials is essential for developing safe and consumer-friendly nanotechnology. Various nanomaterials interact with the immune system, in a beneficial or deleterious way, but mechanistic details about such interactions are scarce. A lack of agreed-upon guidelines for evaluating the immunotoxicity of nanoparticles (NPs) adds to the complexity of the issue. Various review articles have summarized the immune system interactions of biodegradable NPs (with pharmaceutical uses), but such information is largely lacking for nonbiodegradable NPs. Here we give an overview of interactions of nonbiodegradable, persistent NPs with the immune system. Particular emphases include key factors that shape such interactions, cell-specific responses, allergy and immune-sensitive respiratory disorders. © 2011 Wiley Periodicals, Inc. How to cite this article: WIREs Nanomed Nanobiotechnol 2012, 4:169–183. doi: 10.1002/wnan.166 INTRODUCTION T he exploration of the immunomodulating poten- tial of nanoparticles (NPs), encompassing both immunostimulatory and immunosuppressive compo- nents, has only recently been a focus of research into the health effects of nanomaterials. However, little data are available on the mechanisms involved in such effects. An in-depth evaluation of such effects with both accidental exposure (e.g., environmental and occupational) and therapeutic exposure (vaccinations, drug delivery tools) is required. For both voluntary and involuntary exposure, knowledge is limited, and questions such as how NPs can interact with the immune system and which effects are expected in both the short- and long-term remain unanswered. Novel immunotoxicological assessments of nanomaterials were previously suggested to need stepwise validation, standardization, and demonstration of physiological relevance 1 (Box 1, Figure 1). †Present address: National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, Durham, NC, USA ∗ Correspondence to: peter.hoet@med.kuleuven.be 1 Unit of Functional and Adaptive Biology, Laboratory of Molecular and Cellular Responses to Xenobiotics, Universit´ e Paris Diderot, Paris, France 2 Research Unit for Lung Toxicology, K.U. Leuven, Leuven, Belgium BOX 1 IMMUNOTOXICOLOGY Immunotoxicity can be defined as any adverse effect on the immune system that can result from exposure (Figure 1). To determine the effects of an agent on immune function, in general five adverse event categories are studied. 1. Immunosuppression refers to impairment of any component of the immune system resulting in a decreased immune function. 2 The impairment can be observed as myelo- suppression, changes in immune system organ weights, and decreased serum glob- ulin levels. Functionally, it can result in an increased incidence of infections and/or tumors. 2. Immunogenicity is immune reactions elicited by a specific stressor (agent) and/or its metabolites, possibly resulting in an allergic response, on multiple exposure to the stressor. 3. Hypersensitivity is the immunological sen- sitization by a specific stressor (agent) and/or its metabolites, resulting in a strong adverse response; four types of hypersensitiv- ity responses have been described. 3 Volume 4, March/April 2012 © 2011 Wiley Periodicals, Inc. 169