Immune system postnatal development

A review of the literature on chemical-induced immunosuppression in rats and mice, exposed during the pre- and/or postnatal period, was compared to exposure of adults. Five known immunosuppressants (i.e., TCDD, TBTO, DES, Pb, and diazepam) were reviewed. The data revealed that the developing immune system was more sensitive to chemical exposure than the mature immune system. Based on these evaluations, the authors concluded that it was reasonable to assume that testing only in adults would not provide a sufficient level of sensitivity to define immunotoxicity in the neonate 132. In summary, this chapter provides compelling evidence that the developing, compared to the mature, immune system is more vulnerable to perturbation. 

At dosages above 30mg/kg in the diet, chlordane interfered with reproduction in rats and mice, but this effect was reversible after exposure ceased." Pre- and postnatal exposures to chlordane altered the development of the immune system in rodents. A dose-related increase in the incidence of hepatocellular carcinomas was found in male and female mice fed approximately 60mg/k chlordane for 80 weeks. In rats, increases in the incidences of thyroid follicular cell neoplasms were observed. ... 

Whereas the experimental design is quite standardized regarding maternal aspects, the duration of postnatal infant assessments is rather variable between studies, for example, from 7 days to 720 days in our experience. Evidently there is a need for standardization of the timing and type of test batteries for infants and of the time period the infant should be raised. For behavioral tests, a postnatal observation period of 9 months appears essential since these tests can only by applied from the age of 6 months onward. For evaluation of immune system development, a period of 6 months appears mandatory since from that age onward blood volume is sufficient to conduct several tests, such as the T cell dependent antibody response (TDAR), NK cell... 

The development of the mammalian immune system comprises a sequence of events that are exquisitely timed and coordinated, begin very early in fetal life, and continue through early postnatal development. The key developmental processes are the same and define the critical windows of development where the relative risks associated with exposure to inununotoxicants are likely to be different. In order to examine immune sensitivity differences across age-groups, immune development has been examined and critical windows of immune development have been defined and compared for rodents, canines, nonhuman primates, and/or humans (Dietert et al., 2000 Holladay and Smialowicz, 2000 Landreth, 2002 Holsapple et al., 2003 Dietert and Piepenbrink, 2006a Burns-Naas et al, 2008). A time-normalized comparison... 

At the time of birth, macaques and humans have a fuUy developed immune system. This contrasts with rodents that have an immature immune system at the time of birth (Holladay and Smialowicz, 2000). This difference alone does not predude the use of the rodent in developmental toxicity studies, so long as there is adequate species cross-reactivity of the test agent and the animals are dosed appropriately during critical periods in immune system development. Because a considerable amount of extrauterine immune system development occurs in the mouse versus the human or nonhuman primate, it may be necessary to dose the rodent pups during the postnatal period in order to mimic the human situation. This is not necessary for nonhuman primates where intrauterine immune system development mimics the human situation. 

Although there is considerable information on the postnatal development of the rodent immune system, much less is known about the postnatal... 

For most biotherapeutics that do not cross-react with rodents or rabbits, an embryofetal development study in macaques is generally conducted during clinical development to support the inclusion of women of childbearing potential in clinical trials. However, postnatal development studies in nonhuman primates have not routinely been conducted. Consequently, the protocols and the end points are less well established for evaluation of postnatal effects on the immune system. 

There is accumulating evidence that the interaction between the intestinal microbiota and the gut plays an important role for the postnatal development of the immune system. However, the interactions between the intestinal epithehal and immune cells and the different species of the intestinal microbiota are very complex and not fully understood. The complexity of these interactions is based on the fact that on the one hand the human defense system consists of several layers, for example, of mechanical and chemical barriers (first line of defence) as well as innate and adaptive immunity (67) all of which can be influenced by microbiota (68). 

There is increasing evidence that the interaction between the intestinal microbiota and the intestinal epithelial and immune cells plays a key role in the postnatal development of the immune system. First studies with probiotics (74) and synbio-tics (40) demonstrate effects during infancy, and studies regarding the vaccination response in the elderly (75) indicate that the prebiotics might also influence the immune system. In particular, the animal experiments with prebiotics described above allow the hypothesis that prebiotics that are able to influence the composition of the entire intestinal microbiota toward microbiota found in breastfed infants might support the development of the immune system during infancy. 

The data demonstrate a significant and biological relevant effect of dietetic prebio-tics on the postnatal development of the immune system. The most conclusive data exists for a mixture of GOS/lcFOS. The mechanism behind the immune modulatory effects of the studied prebiotic oligosaccharides is not fully understood yet. However, the finding in the human trial is in accordance with the results obtained from animal models demonstrating an active strengthening of the immune system. This indicates that these prebiotics would serve as an effective and safe tool for prevention of infection and allergies. 

More reproductive studies of a more sophisticated kind were following effects on sperm and ova, as well as on the complete reproductive process. Studies of the developing embryo and fetus reflected a more critical and reasonable attitude to thresholds and dose-response aspects of teratogenicity. Greater involvement in behavioral studies had led to combined approaches that permitted analysis of the postnatal consequences of in utero exposure. Finally, the contribution of immunotoxicology was increasing not infrequently, compounds stimulated the immune system at low levels of exposure and inhibited it at high levels. 

Nauta AJ, Amor KB, Knol J, Garssen J, Van Der Beek EM. Relevance of pre- and postnatal nutrition to development and interplay between the microbiota and metabolic and immune systems. Am J Clin Nutr. 2013 98 586S—593S. 

The intestinal flora plays a crucial physiological role in the postnatal development of most gastrointestinal functions, including the development of the gut-associated immune system. 

The intestinal flora induced by breastfeeding is effective in supporting the postnatal development of the gastrointestinal tract and the immune system. 

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