A Practical Approach, Second Edition=Ronald D. Ho.pdf

1092 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONT-cells can be demonstrated in spleen and peripheral blood by 16-18 weeks gestation (Kay et al.,1970). Similar results were reported by Mumford et al. (1978), who observed responses to Con Awith thymus cells at 13-14 weeks of gestation, and with spleen cells at approximately 18 weeksof gestation; while August et al. (1971) observed that fetal thymocytes responded to mitogenicstimulation at 12 weeks of gestation and splenic T-cells responded between 14 and 16 weeks ofgestation. Reactivity of fetal lymphocytes in the MLR has been variably reported as beginningduring weeks 10-14 (Ohama and Kaji, 1974; Loke, 1978; Royo et al., 1987), followed by functionaleffector reactivity in cell-mediated lympholysis (CML) assays subsequently, proceeding in variablefashion depending on the lymphoid tissue tested (Granberg and Hirvonen, 1980; Murgita andWigzell, 1981). Fetal thymocytes have been shown to demonstrate a positive MLR by 12 weeksgestation, and fetal splenocytes by about 19 weeks, although to a consistently-low degree until 23weeks (Granberg and Hirvonen, 1980). Lymphocytes derived from cord blood have been demonstratedto generate a positive CML response at 18-22 weeks gestation; however high individualvariability was found (Rayfield et al., 1980). The functionality of T cells from human neonates hasbeen demonstrated to be reasonably well-developed (Hayward, 1983). Thus, neonatal T cells canproliferate in MLR and in response to most mitogens, and show weak proliferation and cytokineproduction with stimulation by endogenous antigen presenting cells or anti-CD3 monoclonalantibody (representative ‘physiologic’ stimuli) (Granberg and Hirvonen, 1980; Rayfield et al., 1980;Loke and King, 1991). Furthermore, with TcR-independent stimulation, neonatal T-cells showequivalent proliferation and cytokine production to adult T cells (Splawski and Lipsky, 1991;Demeure et al., 1994; Tsuji et al., 1994). However, the cytokine profiles of the human neonateshow a deficient and/or delayed production of interleukin (IL)-2, interferon-γ, IL-4 and IL-6, thuspossibly skewed toward a Th2 phenotype (Splawski and Lipsky, 1991; Demeure et al., 1994; Tsujiet al., 1994). In some reports, the cytokine networks appear less efficient, requiring increasedstimulation and/or receptor maturation (Cairo et al., 1991; Tucci et al., 1991). T-cell reactivity canbe demonstrated in CML assays, but at lower levels than adult T cells (Granberg and Hirvonen,1980; Rayfield et al., 1980; Barret et al., 1980; Loke and King, 1991). Demonstrating in vivofunctionality, newborns can reject organ and tissue allografts, however, they remain very sensitiveto clinical immunosuppression (Demeure et al., 1994; Webber, 1996; Pietra and Boucek, 2000).Indeed, it has been demonstrated that a survival advantage of approximately 10-12% is maintainedmore than 10 years post-transplant if heart transplantation is performed within the first 30 days oflife compared to 1-6 months of age, and that this survival advantage is due to decreased immunerelatedevents (Pietra and Boucek, 2000).The development of functional NK cells in the human fetus occurs at 28 weeks of gestation,with full-term newborns displaying peripheral blood NK activity at approximately 60% of adultlevels (Toliven et al., 1981). NK cells are fewer in number at birth than later, and have been reportedto be less active and less responsive to stimulation, with diminished cytotoxicity capacity (Kohl etal., 1984; Rabatic et al., 1990). However, levels of NK cells during early fetal life have beendemonstrated to be significantly higher than during neonatal life, suggesting that certain aspectsof innate immunity may play a more important role in the fetal immune response than adaptiveimmunity (Erkellar et al., 1992; Hulstaert et al., 1994).As noted above, adult levels of B-cells bearing sIg of all classes are reached by 14-15 weeksgestation in humans (Anderson et al., 1981). Circulating B lymphocytes are generally at high levelsin the neonate, with immature markers demonstrable, and these decline with age (Tucci et al., 1991;Erkeller-Yuksle et al., 1992; Hannet et al., 1992; Peakman et al., 1992; Plebani et al., 1993; Hulstaertet al., 1994; Nahmias et al., 1994). The development of mature plasma cells in the bone marrowis incomplete at birth (Loke, 1978; Durandy et al., 1990). Isotype switching is defective, withsimultaneous surface expression of different isotypes, and immunoglobulin production is low (Loke,1978; Gathings et al., 1981; Hayward, 1983; Nahmias et al., 1994). Human neonatal B-cells arefunctionally defective in their capacity to generate antibody-producing cells in vitro, compared to© 2006 by Taylor & Francis Group, LLC