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What’s So Special about the Developing Immune System?Drug Safety Research and Development, Pfizer Global Research and Development, San Diego, CA 92064, California, USA
United States Food and Drug Administration, Center for Drug Evaluation Research, Office of New Drugs, Rockville, Maryland, USA
DuPont Company, Experimental Station, Wilmington, Delaware, USA
United States Environmental Protection Agency, National Center for Environmental Assessment, Washington, DC, USA
WIL-Biotechnics, Inc., Hillsborough, North Carolina, USA
ILSI Health and Environmental Sciences Institute, Washington, DC, USA Correspondence: Address correspondence to Leigh Ann Burns Naas, PhD, DABT, Drug Safety Research and Development, Pfizer Global Research and Development 10777 Science Center Drive, San Diego, CA 92064, USA. E-mail:leighann.burns{at}pfizer.com The evolution of the subdiscipline of developmental immunotoxicology (DIT) as it exists today has been shaped by significant regulatory pressures as well as key scientific advances. This review considers the role played by legislation to protect children’s health, and on the emergence of immunotoxcity and developmental immunotoxicity guidelines, as well as providing some context to the need for special attention on DIT by considering the evidence that the developing immune system may have unique susceptibilities when compared to the adult immune system. Understanding the full extent of this potential has been complicated by a paucity of data detailing the development of the immune system during critical life stages as well as by the complexities of comparisons across species. Notably, there are differences between humans and nonhuman species used in toxicity testing that include specific differences relative to the timing of the development of the immune system as well as more general anatomic differences, and these differences must be factored into the interpretation of DIT studies. Likewise, understanding how the timing of the immune development impacts on various immune parameters is critical to the design of DIT studies, parameters most extensively characterized to date in young adult animals. Other factors important to DIT, which are considered in this review, are the recognition that effects other than suppression (e.g., allergy and autoimmunity) are important; the need to improve our understanding of how to assess the potential for DIT in humans; and the role that pathology has played in DIT studies in test animals. The latter point receives special emphasis in this review because pathology evaluations have been a major component of standard nonclinical toxicology studies, and could serve an important role in studies to evaluate DIT. This possibility is very consistent with recommendations to incorporate a DIT evaluation into standard developmental and reproductive toxicology (DART) protocols. The overall objective of this review is to provide a ‘snapshot’ of the current state-of-the-science of DIT. Despite significant progress, DIT is still evolving and it is our hope that this review will advance the science.
Key Words: Developmental Immunotoxicology • DIT • Immune Development Immune System • Immune Testing • Immunopathology
International Journal of Toxicology, Vol. 27, No. 2,
223-254 (2008) |
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