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EDITORIAL A Quarter-Century of Immunotoxicology: Looking Back, Looking Forward
Citation:
House, R. V. AND M. SELGRADE. EDITORIAL A Quarter-Century of Immunotoxicology: Looking Back, Looking Forward. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 118(1):1-3, (2010).
Impact/Purpose:
This editorial, written to mark the occasion of the 25 th anniversary of the Immunotoxicity Specialty Section of the Society of Toxicology, provides both an historical perspective and an assessment of the challenges that lie ahead for this sub-discipline of toxicology
Description:
The Immunotoxicology Specialty Section of the Society of Toxicology celebrated its 25th anniversary at the 2010 Annual Meeting, prompting us to provide here both an historical perspective and an assessment of the challenges that lie ahead for this sub-discipline of toxicology. In 1985 immunotoxicology focused primarily on use of rodent models to evaluate suppression of adaptive immune responses (which our peers sometimes considered obscure), as well as evaluation of allergic responses to chemicals, primarily allergic contact dermatitis. Apart from a common organ system, immune suppression and allergy were considered totally separate disciplines. Innate and adaptive immunity were also viewed as independent entities, and at the time the adaptive immune system received more attention from immunotoxicologists because it was the hot area in immunology. Innate immunity was perceived as evolutionarily "ancient" and therefore less relevant. What a difference a few decades makes. Twenty-five years ago because AIDS had only recently been identified, both the scientific community and the public at large were acutely aware of the adverse results of immune suppression and the important role that T lymphocytes play in maintaining good health. Hence, these were de facto the hot topic for immunotoxicology. Polychlorinated biphenyls were the first class of chemicals studies followed shortly thereafter by halogenated hydrocarbons (dioxin and others), heavy metals, and some organotins (Moore, 1979). In the beginning testing for immune suppression relied primarily on routine histopathology and research to develop better tests focused on host resistance models and functional assays in laboratory rodents (Vos, 1977). Compatibility between rodent tests and human studies was non-existent. Through much effort and inter-laboratory collaboration the concept of "tier testing" was developed, the springboard' for much of immunotoxicology for the 90s (Luster et al., 1988). Meanwhile, tests for hypersensitivity relied mostly on skin painting guinea pigs and humans and observing dermal erythema and edema (Botham et al., 1991); other types of allergic and autoimmune responses were largely untouched. Risk assessors wondered what to make of our discipline. Twenty-five years later we are thinking much more in terms of modulation of the immune system rather than immune suppression, hypersensitivity or autoimmunity as isolated entities. Certain immune function tests have been included in harmonized test guidelines (EPA, 2003; EPA, 1998; ICHS8, 2006; GECD, 1995), specific examples of immune suppression in the human population have been found that mirror results seen in laboratory animals (Luebke et al.,2004; Selgrade, 2007) and our understanding of how to interpret results of these tests in risk assessment has vastly improved (Germolec, 2004) although consensus has yet to be reached. Guinea pig tests have given way to the more mechanistically-based local lymph node assay for predicting the likelihood that an exposure will result in allergic contact dermatitis (Gerberick et al., 2007), opening the door for more quantitative risk assessment (Griem et al., 2003). Even autoimmunity -long one of the most difficult forms of immunotoxicity to understand -is coming into better focus (Dietert et al., 2010). Much has been accomplished, but much remains to be done and the field is open for the next generation(s) of immunotoxicologists to make further advancements in the following areas: • Developmental immunotoxicology, the understanding of how xenobiotics affect neonatal and perinatal development of the immune system (Burns-Naas et al., 2008); • Wildlife immunotoxicology, understanding how ecosystems are affected by immunotoxic insults (Fairbrother et ai., 2004; Liney et ai., 2006); • In vitrolin silico immunotoxicology, in which cell culture and computer paradigms can vastly improve predictivity while limiting animal use (Corsini and Roggen, 2009); • Immunotoxicology of vaccines and other medicines specifically intended to alter the immune system (Brennan and Dougan, 2005); • Continued development and refinement of models to predict and understand the relationship between xenobiotic exposures and autoimmunity, respiratory hypersensitivity, idiosyncratic hypersensitivities, such as drug-induced liver or vascular injury, and food allergy and systemic anaphylaxis (Holsapple et al., 2006; Selgrade et ai., 2009); • Understanding innate and inflammatory processes and their contribution to toxicity in general With the rest of the toxicology community we are pushing forward to develop high throughput, in vitro molecular assays to predict immunotoxicity (Baken et ai., 2008; Germolec et al., 2009; Luebke et ai., 2006). This effort is aided by a quarter of a century of work to identify mechanisms and pathways underlying functional effects on the immune system. We are still unable to predict respiratory hypersensitivity nor do we have acceptable models for the prediction of systemic anaphylaxis or idiosyncratic hypersensitivities, and we have much to learn about the role of chemicals in autoimmune disease. Research to address these problems is ongoing. Finally, the immune system, particularly inflammation, plays a major role in many types of toxic responses. We have known since Metchnikoff that the immune system responds to tissue injury and is therefore among the first reactions to toxic insult. Inflammatory pathways are likely to be included in high throughput testing for many types of toxicity (National Academie of Sciencess, 2007), and chronic inflammation plays an important role in many diseases including type 2 diabetes, atherosclerosis, asthma, neurodegenerative diseases, and cancer (Medzhitov, 2010). The mechanisms underlying innate inflammatory responses to pathogens include receptors that recognize features common to many pathogens. The most well-known of these are the Toll-like receptors. It now appears that tissue injury, such as that produce by toxic chemicals, triggers similar pathways (Bianchi and Manfredi, 2009). One thing is certain, the discipline of immunotoxicology that began as a fledgling more than 30 years ago has grown to become a major player in the field of toxicology as more and more issues both in applied and basic toxicology involve an understanding of impacts on the immune system.
