Developmental immunotoxicology (DIT): windows of vulnerability, immune dysfunction and safety assessment

Developmental immunotoxicity (DIT) is an increasing health concern since DIT outcomes predispose children to those diseases that have been on the rise in recent decades (e.g., childhood asthma, allergic diseases, autoimmune conditions, childhood infections). The enhanced vulnerability of the developing immune system for environmental insult is based on unique immune maturational events that occur during critical windows of vulnerability in early life. The semi-allogeneic pregnancy state, with suppression of graft rejection and associated skewing of the fetal and neonatal immune system, also influences the specific nature of DIT outcomes. In the exposed offspring, targeted immunosuppression can co-exist with an increased risk of allergic and/or autoimmune disease. Because with DIT immune dysfunction rather than profound immunosuppression is the greater concern, testing approaches should emphasize multi-functional assessment. Beyond T-cells, dendritic cells and macrophages are sensitive targets. The last-trimester fetus and the neonate are normally depressed in TH1-dependent functions and postnatal acquisition of needed TH1 capacity is a major concern with DIT. With this in mind, assessment should include a measure of TH1-dependent cell-mediated immunity [cytotoxic T-lymphocyte (CTL) activity or delayed-type hypersensitivity (DTH) response] in conjunction with a multi-isotype T-dependent antibody response (TDAR) and evaluation of innate immunity (e.g., NK activity). Other parameters such as immune histology, immunophenotyping, cytokine responses, and organ weights can be useful when included with immune functional evaluation. A multifunctional DIT protocol using influenza challenge is presented as one example of an approach that permits dysfunction and misregulation to be evaluated.