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INTRODUCTION

Immunotoxicology can be most simply defined as the study of adverse effects on the immune system resulting from occupational, inadvertent, or therapeutic exposure to drugs, environmental chemicals, and, in some instances, biological materials. Studies in animals and humans have indicated that the immune system is comprised of potential target organs, and that damage to this system can be associated with morbidity and even mortality. Indeed, in some instances, the immune system can be compromised (decreased lymphoid cellularity, alterations in lymphocyte subpopulations, decreased host resistance, altered specific immune function responses) in the absence of observed toxicity in other organ systems. These studies coupled with tremendous advances made in immunology and molecular biology have led to a steady and exponential growth in our understanding of immunotoxicology during the past 40 years. Recognition by regulatory agencies that the immune system is an important, as well as sensitive, target organ for chemical- and drug-induced toxicity is another indication of the growth of this subdiscipline of toxicology. With the availability of sensitive, reproducible, and predictive tests, it is now apparent that the inclusion of immunotoxicity testing represents a significant adjunct to routine safety evaluations for therapeutics, biologics, and chemicals now in development.

Understanding the impact of toxic responses on the immune system requires an appreciation of its role, which may be stated succinctly as the preservation of integrity. It is a series of delicately balanced, complex, multicellular, and physiologic mechanisms that allow an individual to distinguish foreign material (i.e., “nonself”) from “self,” and to neutralize, eliminate, and/or coexist with the foreign matter. One definition of nonself is essentially anything other than that encoded in one's own germline genome (Nathan, 2006). Examples of self are all the tissues, organs, and cells of the body. Examples of nonself include a variety of opportunistic pathogens, such as bacteria and viruses, and transformed cells or tissues (i.e., tumors). Nonself might also include drugs, xenografts, or allergens, such as pollen. The immune system is characterized by a virtually infinite repertoire of specificities, highly specialized effectors, complex regulatory mechanisms, and an ability to travel throughout the body. The great complexity of the mammalian immune system is an indication of the importance, as well as the difficulty, of its role. If the immune system fails to recognize as nonself an infectious entity or neoantigens expressed by a newly arisen tumor, then the host is in danger of rapidly succumbing to the unopposed invasion. This aspect of immune competence is the reason why the immune system is often synonymous with “host defense.” Alternatively, if some integral bodily tissue is not identified as self, then the immune system is capable of turning its considerable defensive capabilities against that tissue, and elicitation of autoimmune disease may ensue. This aspect of immune competence emphasizes the tremendous destructive potential that is associated with the host defense mechanisms of the immune system. The cost to the host of these mistakes, made in either direction, may be ...

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