Developmental Immunotoxicology Testing (DIT)

Abstract Interest in developmental immunotoxicity testing (DIT) has generally been based on the premise that the “developing” immune system is more susceptible to external stressors than the “developed” immune system. A critically important extension of that premise is that traditional approaches to characterize the effects of drugs and chemicals on the immune system, as assessed in young adult animals, would miss the susceptibility associated with the developing immune system. There is no question that DIT can be—and has been—conducted as “stand-alone” studies. However, the consensus is that DIT should be integrated into the protocols associated with developmental and reproductive toxicology (DART) study designs to the extent possible. The aforementioned approach is not without complications. Following an Introduction, this chapter describes pregnancy as a unique situation in which the immune system plays a major role in maternal tolerance of a semiallogenic fetus. Both local and systemic adaptations such as selective immune tolerance, immunosuppression, and immunomodulation are involved in facilitating and maintaining a successful pregnancy, while maternal immunity is protected. This phenomenon involves complicated processes including many different mechanisms working in synergy. This chapter reviews the roles of different cell types and their interactions. However, while much progress has been made in understanding the roles of different cell types and their interactions over the past few decades, the exact roles of interactions between different cell types in the environment needed for a successful pregnancy are not yet fully understood. The complexity of this situation will be increased as more immunosuppressants and immunomodulators are tested in DART study designs—a point underscored by a case study centered on cancer immunotherapeutic agents. The third section of this chapter focuses on the influence of the gut microbiome on reproductive and developmental immunology. While myriad roles have been assigned to the gastrointestinal (GI) microbes, one of the most important roles is the stimulation of appropriate immune system development. The fourth part of this chapter reviews the development of the immune system as a highly regulated process, which is not fully completed at birth. Human neonates have deficiencies in both the innate and adaptive immunity due to the immaturity of their immune system. This makes newborns more susceptible to infections than older children and adults. And, as noted above, the developing immune system can also be more vulnerable than the adult system to chemically induced immunotoxicity. In addition to a review of the developing immune systems in humans, this section of the chapter highlights some of the differences between humans and critical nonclinical species. The fifth part of this chapter focuses on some of the specific end points that have been included in DIT study designs. The final part of this chapter describes the current state of the implementation of DIT into regulatory guidelines for toxicity testing. This stage in the evolution of DIT is critical to improve hazard identification and risk assessment in preclinical studies and should ultimately shed light on the susceptibility of children, thereby providing better protection of their health.