Open Access

Review

Perinatal Immune Development versus the Adult Immune System Top

Immune development has been characterized from a toxicologic perspective through a series of discrete functional changes representing critical windows of differential vulnerability to toxicants (Dietert et al. 2000; Holsapple et al. 2003; Landreth 2002; Landreth and Dodson 2005; Leibnitz 2005). These reviews have emphasized that each “window” of development likely has different immunologic risks associated with immunotoxicant exposure, and indeed, examples of differential immunotoxic outcomes among these windows do exist (Bunn et al. 2001b; Lee et al. 2001). Although it is not practical or necessary to directly evaluate the differential risk of limited exposures over different periods within perinatal development, it is important to accurately estimate immunologic risk across the entire period of immune development because of the important role of effective immune function in children’s health (Daston et al. 2004; Kimmel et al. 2005).

Table 1 draws upon the broader critical windows of immune development (Dietert et al. 2000) to illustrate a set of seven discrete events that are either unique to perinatal immune development or critical to the post-natal immune integrity while serving a different role in the adult. These immune events include those that are restricted solely to the immune system as well as some involving the role of the immune system in host organ/tissue homeostasis. In most cases, clear associations exist between exposure to specific toxicants and disruption of the perinatal event. It is not simply by chance that this set of early immune events seems to impinge primarily on the risk of atopy, autoimmune disease, and later-life immune balance (which also influences risk of cancer, etc.). In fact, the perinatal period of immune development is precisely the period in which immune balance must shift from that of an allogeneic yet full-term fetus to that of an offspring ready to meet the complete spectrum of disease challenges. At the heart of the issue is the fact that impact of a xenobiotic on that shift cannot be tested with adult exposure assessment.

Establishing and Renewing Macrophage-Derived Cells in Critical Tissues Top

One of the early events connecting the immune system to virtually all organs is the differentiation and seeding of myelomonocytic lineage macrophages and macrophage-derived cells to various sites, including the bronchial (e.g., alveolar macrophages), hepatic (Kupffer cells), neurologic (microglia), and reproductive systems (testicular macrophages). These cells provide regulatory and host defense roles in these tissues. Specific examples describe the vulnerability of these tissues during the perinatal period when exposure to toxicants impairs macrophages, including the possibility that the heavy metal lead can impair both the function and the self-renewal of testicular macrophages, which contributes to male sterility problems (Pace et al. 2005). Similarly, pulmonary and alveolar macrophages play a key role in lung development (Beyea et al. 2005), and sensitivity of the perinatal lung to some environmental agents is directly related to alterations in early-life macrophage populations (Cao et al. 2004; Li et al. 2001). In the brain, inappropriate cytokine production from microglial cells and/or astrocytes is now recognized as an early component of many postnatal neurologic diseases (Bell and Hallenbeck 2002; Cacci et al. 2005; Mesples et al. 2005; Ravizza et al. 2005). With Kupffer cells in the liver (Naito et al. 1997), researchers recently found that their capacity to develop a tolerance for lipopolysacharride (LPS) (Uhrig et al. 2005) is critical for the ability of the liver to control inflammation.

Lymphoid seeding of the thymus and thymopoiesis.

Another early immune process critical for subsequent host defense is the migration of pro–T lymphocytes to the thymus and their expansion during thymopoiesis. During the perinatal period, the thymus is central to the production of T lymphocytes. Even in children, the thymus continues to play the major role in T-lymphocyte generation (Mackall et al. 1995; Schonland et al. 2003). In contrast, the thymus has a much different role in the adult. Although the adult thymus retains some capacity for the production of cells, particularly with severe immune depletion, its role remains minor in the repopulation of T lymphocytes (Hakim et al. 2005; Petrie 2002). Instead, most T-lymphocyte production comes from the periphery in adults (Hakim et al. 2005). The ramifications of this are that the targeting of pro–T lymphocytes by chemicals or drugs and/or induction of thymus atrophy would be expected to have different consequences depending upon age. As shown in Table 1, several environmental agents appear to target either pro–T lymphocytes or the thymopoiesis process.

Negative selection in the thymus of auto-reactive T-cell clones.

A third early immune process critical for host integrity is the negative selection and removal of autoreactive T-lymphocyte clones in the thymus. This occurs during the process sometimes designated as “T-cell education.” Meylan et al. (2005) provided a clear demonstration of this process as it occurs in humans. Partially mature thymocytes undergo negative selection at the corticomedullary boundary and in the medulla of thymus (Sprent and Kishimoto 2002). This process is essential if self-reactive clones are to be eliminated before birth. Conversely, excessive loss of thymocytes during negative selection leads to T-cell depletion. Although explicit examples of chemicals or drugs blocking negative selection have yet to be determined, this perinatally unique stage of immune development would appear to be a significant factor in later-life autoimmune disease. Metals represent one category of immunotoxicants warranting examination based on the capacity of mercury and other metals to either trigger or accelerate the progression of autoimmune manifestations (Fournie et al. 2002; Lawrence and McCabe 2002; Rowley and Monestier 2005). Conversely, some chemicals are known to disrupt the negative selection process by overpromoting negative selection and inappropriate thymocyte apoptosis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an example of such a toxicant (Camacho et al. 2004; Fisher et al. 2004).

Thymic Generation of Regulatory T-Cells (CD4⁺CD25⁺ High Expression) and Acquisition of Tolerance Top

A parallel protection against self-reactivity resides in the gestational thymic production and subsequent activation of a specialized population of regulatory T lymphocytes. The specialized regulatory T-cell (Treg) population carries the phenotype FoxP3⁺CD4⁺CD25⁺ and develops during gestation (~ 12–13 weeks) in the human fetus (Cupedo et al. 2005; Darrasse-Jeze et al. 2005). Tregs are critical in the suppression of autoreactive lymphocytes that have escaped elimination through negative selection in the thymus (Cupedo et al. 2005; Kronenberg and Rudensky 2005; Sakaguchi and Sakaguchi 2005). It appears that Tregs acquire their regulatory and suppressive phenotype while within the fetal thymus and are further activated in peripheral lymphoid organs (Cupedo et al. 2005). The process through which these cells emerge and acquire the capacity to identify and suppress self-reactive lymphoid clones occurs embryonically. As with negative selection discussed previously, the active perinatal process of producing and activating Tregs is a logical stage where toxicant-induced risk of later-life autoimmune disease would be great. Evidence suggests that some doses of cyclophosphamide (Lutsiak et al. 2005) and cyclosporin A (Kawai et al. 2005) cause inhibition of Treg populations. Treg suppression is thought to be one route to increase allergic disease (Robinson et al. 2004), and the breaking of tolerance to nickel has been associated with Treg suppression (Cavani 2005).

Maturation of dendritic cells from the fetal (immature) phenotype.

Dendritic cells are known to be important in antigen presentation and in determining the nature of subsequent immune responses. A fifth perinatal process involves the maturation of immature dendritic cells to produce interleukin (IL-12) (counterbalancing IL-10 production) and acquire the capability of promoting T-helper 1 (T_H1) or type 1 responses. This does not happen in humans until parturition under normal circumstances (Holt and Jones 2000; Holt and Sly 2002).

In fact, the T_H1 response must be suppressed until after birth to protect the pregnancy from T_H1-mediated immunologic rejection (Lim et al. 2000). One of the processes for accomplishing this is the metabolism of the amino acid tryptophan by the enzyme indoleamine-2,3-dioxygenase (IDO) to produce tryptophan metabolites such as kynurenines (Fallarino et al. 2003; Gutierrez et al. 2003; Meisel et al. 2004; Mellor et al. 2002). These metabolites selectively suppress T_H1 function by inducing apoptosis in T_H1 but not T_H2 cells (Fallarino et al. 2003), thereby skewing responses toward T_H2. In the fetus, this is required to avoid allogeneically induced miscarriage (Mellor et al. 2002). But in the newborn this must be corrected to provide adequate immune balance. Not surprisingly, imbalances in IDO activity have been associated with diseases such as colitis (Gurtner et al. 2003) and inflammatory bowel disease (Wolf et al. 2004).

The perinatal system is exquisitely sensitive to these time/life-stage–dependent shifts in immune balance. For example, Malamitsi-Puchner et al. (2005) demonstrated that even the mode of birth delivery can influence the acquisition of T_H1 cytokine production capacity in humans. Newborns delivered by cesarean section remained more T_H2 skewed compared with vaginally delivered newborns. This emphasizes the potential problems in using an adult exposure assessment protocol for immunotoxicity to model the perinatal immune changes surrounding birth.

In keeping with this idea, a recent study demonstrated that human cord blood–derived dendritic cells respond completely differently than their adult counterparts when exposed to dexamethasone (Mainali and Tew 2004). Dexamethasone exposure of these immature cells prevents their maturation to promote T_H1 responses and locks in the T_H2 IgE-promoting phenotype. The T_H2 skewing effect appears to be long-lasting (Mainali et al. 2005). This type of early-life-stage–restricted immunotoxicity appears to contribute to an increased risk of atopy and asthma. Andersson et al. (2004) showed that maturation of newborn immature dendritic cells with LPS reduced the development of a T_H2-associated birch allergen response. In contrast, the lack of dendritic cell maturation from the fetal immature stage was associated with children at risk for type 1 diabetes (Skarsvik et al. 2004). In addition to dexamethasone (Mainali and Tew 2004), nicotine (Nouri-Shirazi and Guinet 2003) has been reported to block dendritic cell maturation. Again, such toxicant-induced perinatal alterations cannot be examined with adult-only exposure because extensive dendritic cell maturation would have occurred after birth and before adult exposure to the test xenobiotic.

Shifting T_H balance for later life.

Beyond dendritic cells, some xenobiotics such as the heavy metals and tryptophan metabolites may directly affect T_H cells and contribute to skewed immune responses in later life. Because mammals are born with a T_H2-skewed functional capacity (Protonotariou et al. 2003), perinatal versus adult exposure assessment actually measures two different alterations. In the perinatal case, the issue is whether a xenobiotic locks in the already existing T_H2 bias among T lymphocytes, thereby preventing the genetically influenced adult balance to be achieved postnatally. This would allow as the default an increased risk of neonatal T_H2-associated diseases (Holt and Sly 2002). In contrast, under the best circumstances adult exposure assessment could measure only whether a xenobiotic selectively impaired T_H1 cells in an already balanced system. At physiologic levels of exposure, many more environmental factors may be capable of delaying or reducing the efficiency of perinatal T_H1 maturation (thereby perpetuating the fetal imbalance) than can clinically alter adult T_H balance.

Surfactant modulation of macrophages.

Beyond the gestational seeding of macrophages to different tissues and initial maturation in situ, there is a special perinatal maturation of macrophages (particularly alveolar) that enables them to acquire increasing host defense capabilities (phagocytosis, chemotaxis, tumor necrosis factor-α production, antibody-dependent cellular cytotoxicity) with increased postnatal age (Goldman et al. 2004). Hence, perinatal exposure to chemicals and drugs would target functionally immature cells in a manner unlike the fully functional population in exposed adults. Among the critical factors in this perinatal macrophage maturation is exposure to various factors known as “collectins” (surfactant proteins).

Although collectins can be immunomodulatory for adult alveolar macrophages (Hickling et al. 2004), they seem to provide important maturational signals for perinatal macrophages that go well beyond defense of the lung (Mendelson and Condon 2005). Palaniyar et al. (2005) discussed the role of surfactant protein D in enhancing macrophage clearance of DNA and in minimizing anti-DNA antibody production. Additionally, Brinker et al. (2001) demonstrated that surfactant interactions with macrophages and dendritic cells help to shift responses from purely innate to acquired immune responses. Surfactant protein A signals amniotic fluid macrophages to migrate to the uterus and initiate the parturition process (Condon et al. 2004; Mendelson and Condon 2005). Complicating the age issue is the fact that surfactant content varies with age (Egberts et al. 1992). Obviously, such perinatal alterations in macrophage activities are difficult to evaluate using adult-only exposure to potential immunotoxicants.

Although these developmental immune events illustrate the biological problem with modeling immunotoxicologic risk using adult exposures, the resulting underestimation of perinatal sensitivity can take several forms. These are described in the following section.

Nature of Increased Perinatal Immunotoxic Sensitivity Top

Dose sensitivity.

The increased sensitivity of the developing versus the adult immune system to immunotoxic alteration can take several forms. First, early-life stages have increased dose sensitivity to most toxicants. There are several examples suggesting that the developing immune system is altered by significantly lower doses of toxicants than those required to produce effects in the adult. Such comparisons were recently reviewed in Luebke et al. (2006). Lead (Chen et al. 2004; Heo et al. 1996; McCabe et al. 1999; Miller et al. 1998; Snyder et al. 2000) appears to differ across ages for immunotoxic end points ranging from 3- to 12-fold in lowest observed adverse effect levels (LOAELS). Similarly, mercury appears to have age-based differences (Havarinasab et al. 2004; Hultman and Hansson-Georgiadis 1999; Silva et al. 2005). With TCDD the age-based range in LOAELS appears to be even greater (Gehrs and Smialowicz 1997, 1999; Gehrs et al. 1997; Smialowicz et al. 1994; Walker et al. 2004; see also Table 2).

Range and severity of effects.

A second measure of differential age-based sensitivity to immunotoxicants concerns the spectrum and severity of effects. Not surprisingly, immunotoxicants frequently produce a different and unpredictable array of alterations when the exposure occurs in utero or in the early neonate versus the adult. Among those immunotoxicants that produce different ranges or severities of outcomes depending upon age of exposure are lead (Bunn et al. 2001b; Lee et al. 2001), methoxychlor (White et al. 2005), T-2 toxin (Holladay et al. 1993b), benzo[a]pyrene (Holladay and Smith 1994; Rodriguez et al. 1999), chlordane (Barnett et al. 1985), 7,12-dimethylbenz[a]anthracene (Cooray and Jonsson 1990; Holladay and Smith 1994; Holladay et al. 1995), ethanol (Giberson and Weinberg 1995, 1997; Giberson et al. 1997), nonylphenol (Karrow et al. 2004), tributyltins (Smialowicz et al. 1989; Tryphonas et al. 2004; Vos et al. 1990), and genistein (Guo et al. 2002).

For example, with methoxychlor exposure of rats, F₁ males had significantly elevated levels of splenic antibody-forming cells, unlike their exposed mothers, whereas F₁ females had a significantly reduced percentage of CD8⁺ T cells (at all doses examined) with no corresponding effect in the exposed dams (White et al. 2005). Likewise with genistein exposure, exposed F₀ rat dams displayed altered natural killer (NK) activity, whereas their daughters exposed in utero had altered antibody-forming cell activity but no change in NK activity (Guo et al. 2002). With TCDD exposure in rats to assess persistent effects, exposed offspring had a significant reduction in contact hypersensitivity with no effect in the exposed dams (Walker et al. 2004). These examples illustrate that adult exposure assessment is inherently ineffective in predicting the range of likely immunotoxic effects after in utero exposure.

Persistence of effects.

Another feature of developmental immunotoxicity is that alterations after early exposure are frequently persistent and last long after exposure, frequently into adulthood of the exposed offspring. Examples where early xenobiotic exposure results in a greater persistence of effects than would be predicted from adult exposure assessment are found with diethylstilbestrol (DES) (Fenaux et al. 2004; Holladay et al. 1993a; Kalland and Forsberg 1978; Luster et al. 1979, 1980) and cyclosporin A (Hussain et al. 2005b).

Latency.

Finally, one of the anomalies of early exposure is that a sublethal exposure to a toxicant may produce an unrecognizable immunotoxic alteration until the postnatal immune system is placed under subsequent stress. This hidden or cryptic state is referred to as “latency.” A classic example exists for early exposure to DES (Fenaux et al. 2004). In this case, an apparently innocuous early exposure to DES alters the immune system in such a manner that it responds to a second adult estrogenic exposure (which of itself has no effect) with a completely aberrant cytokine production profile. The in utero exposure to DES primes the immune system for postnatal unpredictable responses. A similar example has been seen after low-level exposure to lead where postnatal viral infection resulted in unpredictable alterations in leukocyte mobilization (Lee et al. 2002). Obviously, adult exposure assessment affords no opportunity to examine this phenomenon of embryonic-induced immune latency.

Sex Differences in Sensitivity Outcome Top

Differential immunotoxic effects between sexes are neither universal after early exposure (Voderstrasse et al. 2004) nor unique to early-life stages. However, a surprising number of examples exist in which males and females have different immune outcomes after perinatal xenobiotic exposure. Xenobiotics can have different effects on the developing immune system based on the hormonal environment (Hussain et al. 2005a). Among the chemicals listed in Table 2, gender differences in developmental immunotoxicity have been reported for lead (Bunn et al. 2001a, 2001b, 2001c; Miller et al. 1998), mercury (Silva et al. 2005), genistein (Guo et al. 2002), nonylphenol (Karrow et al. 2004), TCDD (Gehrs and Smialowicz 1999), and methoxychlor (White et al. 2005).

Need for Nonadult Exposure Assessment Top

Table 2 lists examples of immunotoxicants where age-based comparisons exist and adult exposure assessment is not predictive of perinatal sensitivity to the xenobiotic. Although basic hazard identification could be performed on most of the toxicants listed using only adult exposure data, there would be little guidance for protecting early life stages from problematic exposure of the developing immune system. This is one reason that several recent reviews have suggested the benefit of exposure regimes that include all nonadult (conception, gestation, lactation, juvenile) stages of development (Holsapple et al. 2003; Kimmel et al. 2005; Luster et al. 2005). Recent findings of key maturation events surrounding birth and of chemical- and drug-induced disruption of those immune-associated events (Mainali and Tew 2004; Mainali et al. 2005; Shaheen et al. 2005) are further indications that adult-only exposure protocols are unlikely to accurately predict the risk of perinatal immunotoxicity. Exposure over the nonadult stages of immune development is more likely to include those age-based populations at greatest risk.

Conclusions Top

Many critical processes occurring during peri-natal immune development are either nonexistent or comparatively unimportant in the adult (e.g., Table 1). Therefore, when safety limits are established on the basis of adult immune exposure data, they likely have limited use for predicting developmental immunotoxicity and protection of the nonadult. For the chemicals and drugs compared across age groups to date, the developing immune system has a greater sensitivity than that of the fully matured adult. Because this increased sensitivity can take different forms (e.g., Table 2), use of magnitude safety factors is of limited benefit in the absence of relevant exposure data. Where adult exposure protocols are used as the only yardstick of immunotoxic safety, consideration should be given to replacing these protocols with exposure regimes extending throughout the nonadult period of development. Given the specific pattern of perinatal immune alterations, it is likely that they explain, in part, the increased incidence of such human diseases as atopy, asthma, and certain autoimmune manifestations.

Figures and Tables Top

Table 1.

Immune toxicant targets associated with perinatal development.

Table 2.

Examples of perinatal-induced immune outcomes not predicted by standard adult-exposure assessment.

References Top

1. Andersson AC, Seppala U, Rudin A 2004. Activation of human neonatal monocyte-derived dendritic cells by lipopolysaccharide down-regulate birch allergen-induced Th2 differentiation Eur J Immunol 34:3516–3524.15517608 Find this article online
2. Barnett JB, Soderberg LSF, Menna JH 1985. The effect of pre-natal chlordane exposure on the delayed hypersensitivity response of Balb/c mice Toxicol Lett 25:173–183.3159128 Find this article online
3. Bell MJ, Hallenbeck JM 2002. Effects of intrauterine inflammation on developing rat brain J Neurosci Res 70:570–579.12404511 Find this article online
4. Beyea JA, Olson DM, Harvey S 2005. Growth hormone expression in the perinatal and postnatal rat lung Dev Dyn 232:1037–1046.15736201 Find this article online
5. Blaylock BL, Soderberg LSF, Gandy J, Menna JH, Denton R, Barnett JB 1990. Cytotoxic T-lymphocyte and NK responses in mice treated prenatally with chlordane Toxicol Lett 51:41–49.2315958 Find this article online
6. Brinker KG, Martin E, Borron P, Mostaghel E, Doyle C, Harding CV, et al. 2001. Surfactant protein d enhances bacterial antigen presentation by bone marrow derived dendritic cells Am J Physiol Lung Cell Mol Physiol 281:1253–1563. Find this article online
7. Bunn TL, Ladics GS, Holsapple MP, Dietert RR 2001a. Developmental immunotoxicology assessment in the rat: age, gender and strain comparisons after exposure to Pb Toxicol Methods 11:41–58. Find this article online
8. Bunn TL, Parsons PJ, Kao E, Dietert RR 2001b. Exposure to lead during critical windows of embryonic development: differential immunotoxic outcome based on stage of exposure and gender Toxicol Sci 64:57–66. Find this article online
9. Bunn TL, Parsons PJ, Kao E, Dietert RR 2001c. Gender-based profiles of developmental immunotoxicity to lead in the rat: assessment in juveniles and adults J Toxicol Environ Health A 64:101–118. Find this article online
10. Cacci E, Claasen JH, Kokaia Z 2005. Microglia-derived tumor necrosis factor-alpha exaggerates death of newborn hippocampal progenitor cells in vitro J Neurosci Res 80:789–797.15884015 Find this article online
11. Camacho IA, Nagarkatti M, Nagarkatti PS 2004. Evidence for the induction of apoptotsis in T cells from murine fetal thymus following perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Toxicol Sci 78:96–106.14718643 Find this article online
12. Cao L, Liu C, Cai B, Jia X, Kang L, Speer CP, et al. 2004. Nuclear factor-kappa B expression in aveolar macrophage of mechanically ventilated neonate with respiratory distress syndrome Biol Neonate 86:116–123.15205540 Find this article online
13. Cavani A 2005. Breaking tolerance to nickel Toxicology 209:119–121.15767023 Find this article online
14. Chen S, Golemboski KA, Piepenbrink M, Dietert RR 2004. Developmental immunotoxicity of lead in the rat: influence of maternal diet J Toxicol Environ Health A 67:495–511.14742095 Find this article online
15. Condon JC, Jeyasuria P, Faust JM, Mendelson CR 2004. Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition Proc Natl Acad Sci USA 101:4978–4983.15044702 Find this article online
16. Cooray R, Jonsson P 1990. Modulation of resistance to mastitis pathogens by pretreatment of mice with T-2 toxin Food Chem Toxicol 28:687–692.2276697 Find this article online
17. Cupedo T, Nagasawa M, Weijer K, Blom B, Spits H 2005. Development and activation of regulatory T cells in the human fetus Eur J Immunol 35:383–390.15682453 Find this article online
18. Darrasse-Jeze G, Marodon G, Salomon BL, Catala M, Klatzmann D 2005. Ontogeny of CD4⁺CD25⁺ regulatory/suppressor T cells in human fetuses Blood 105:4715–4721.15731180 Find this article online
19. Daston G, Faustman E, Ginsberg G, Fenner-Crisp P, Olin S, Sonawane B, et al. 2004. A framework for assessing risks to children from exposure to environmental agents Environ Health Perspect 112:238–256.14754580 Find this article online
20. Descotes J, Tedone R, Evreux JC 1982. Suppression of humoral and cellular immunity in normal mice by diazepam Immunol Lett 5:41–43.7118185 Find this article online
21. De Wit D, Tonon S, Olislagers V, Goriely S, Boutriaux M, Goldman M, et al. 2003. Impaired responses to toll-like receptor and toll-like receptor 3 ligands in human cord blood J Autoimmunity 21:277–281.14599853 Find this article online
22. Dietert RR 2005. New developments in the assessment of developmental immunotoxicology J Immunotoxicol 2:185–190. Find this article online
23. Dietert RR, Etzel RA, Chen D, Halonen M, Holladay SD, Jarabek AM, et al. 2000. Workshop to identify critical windows of exposure for children’s health: immune and respiratory systems work groups summary Environ Health Perspect 108(suppl 3):483–490.10852848 Find this article online
24. Dietert RR, Lee J-E, Bunn TL 2002. Developmental immunotoxicology: emerging issues Hum Exp Toxicol 21:479–485.12458904 Find this article online
25. Dietert RR, Lee J-E, Olsen J, Fitch K, Marsh JA 2003. Developmental immunotoxicity of dexamethasone: comparison of fetal versus adult exposures Toxicology 196:163–176. Find this article online
26. Egberts J, Sprengers BM, Sietaram MA 1992. Comparison of pumonary surfactant content in alveolar macrophages of newborn, young and adult rats Exp Lung Res 18:275–285.1572333 Find this article online
27. Faith RE, Luster MI, Kimmel CA 1979. Effect of chronic developmental lead exposure on cell-mediated immune functions Clin Exp Immunol 35:413–420.455779 Find this article online
28. Fallarino F, Grohmann U, Vacca C, Orabona C, Spreca A, Fioretti MC, et al. 2003. T cell apoptosis by kynurenines Adv Exp Med Biol 527:183–190.15206731 Find this article online
29. Fenaux JB, Gogal RM Jr, Ahmed SA 2004. Diethylstilbesterol exposure during fetal development affects thymus: studies in fourteen-month-old mice J Reprod Immunol 64:75–90.15596228 Find this article online
30. Fisher MT, Nagarkatti M, Nagarkatti PS 2004. Combined screening of thymocytes using apoptosis-specific cDNA array and promoter analysis yields novel gene targets mediating TCDD-induced toxicity Toxicol Sci 78:116–124.14718646 Find this article online
31. Fournie GJ, Saoudi A, Druet P, Pelletier L 2002. Th-2 type immunopathological manifestations induced by mecuric chloride or gold salts in the rat: signal transduction pathways, cellular mechanisms and genetic control Autoimmun Rev 1:205–212.12848997 Find this article online
32. Gauthier TW, Ping XD, Harris FL, El Bahesh H, Brown LA 2005. Fetal alcohol exposure impairs alveolar macrophage function via decreased glutathione availability Pediatr Res 57:76–81.15531743 Find this article online
33. Gehrs BC, Riddle MM, Williams WC, Smialowicz RJ 1997. Alterations in the developing immune system of the F344 rat after perinatal exposure to 2,3,7,8-tetraclorobenzo-p-dioxin. II. Effects on the pup and the adult Toxicology 122:229–240.9328223 Find this article online
34. Gehrs BC, Smialowicz RJ 1997. Alteration in the developing immune system of the F344 rat after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-doxin. I. Effects on the fetus and the neonate Toxicology 122:219–228.9328222 Find this article online
35. Gehrs BC, Smialowicz RJ 1999. Persistent suppression of delayed-type hypersensitivity in adult F344 rats after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin Toxicology 134:70–88. Find this article online
36. Giberson PK, Kim CK, Hutchison S, Yu W, Junker A, Weinberg J 1997. The effect of cold stress on lymphocyte proliferation in fetal ethanol-exposed rats Alcohol Clin Exp Res 21:1440–1447.9394116 Find this article online
37. Giberson PK, Weinberg J 1995. Effects of prenatal ethanol exposure and stress in adulthood on lymphocyte populations in rats Alcohol Clin Exp Res 19:1286–1294.8561303 Find this article online
38. Giberson PK, Weinberg J 1997. Effect of surrogate fostering on splenic lymphocytes in fetal ethanol exposed rats Alcohol Clin Exp Res 21:44–55.9046372 Find this article online
39. Goldman A, Rubin C, Gomez S, Palermo MS, Tasat DR 2004. Functional age-dependent changes in bronchoalveolar lavage rat cells Cell Mol Biol 50:649–655. Find this article online
40. Guo TL, White KL Jr, Brown RD, Declos KB, Newbold RR, Weis C, et al. 2002. Genistein modulates splenic natural killer cell activity, antibody forming cell response, and phenotypic marker expression in F₀ and F₁ generations of Sprague-Dawley rats Toxicol Appl Pharmacol 181:219–227.12079431 Find this article online
41. Gurtner GJ, Newberry RD, Schloemann SR, McDonald KG, Stenson WF 2003. Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice Gastroenterology 125:1762–1773.14724829 Find this article online
42. Gutierrez G, Fitzgerald JS, Pohlmann T, Hoppe I, Markert UR 2003. Comparative effects of L-tryptophan and 1-methyl-trytophan on immunoregulation induced by sperm, human pre-implantation embryo and trophoblast supernatants Am J Reprod Immunol 50:309–315.14672333 Find this article online
43. Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. 2005. Age-dependent incidence, time course, and consequences of thymic renewal in adults J Clin Invest 115:930–039.15776111 Find this article online
44. Hao AJ, Dheen ST, Ling EA 2001. Response of amoeboid microglia/brain macrophages in fetal rat brain exposed to a teratogen J Neurosci Res 64:79–93.11276054 Find this article online
45. Havarinasab S, Lambertsson L, Qvarnstrom J, Hultman P 2004. Dose-reponse study of thimerosal-induced murein systemic autoimmunity Toxicol Appl Pharmacol 194:169–179.14736497 Find this article online
46. Heo Y, Parsons PJ, Lawrence DA 1996. Lead differentially modifies cytokine production in vitro and in vivo Toxicol Appl Pharmacol 138:149–157.8658504 Find this article online
47. Hickling TP, Clark H, Mahotra R, Sim RB 2004. Collectins and their role in lung immunity J Leuk Biol 75:27–33. Find this article online
48. Hinton DM 2000. US FDA “Redbook II” immunotoxicity testing guidelines and research in immunotoxicity evaluations of food chemicals and new food proteins Toxicol Pathol 28:467–478.10862567 Find this article online
49. Holladay SD 1999. Prenatal immunotoxicant exposure and postnatal autoimmune disease Environ Health Perspect 107:687–691.10502532 Find this article online
50. Holladay SD, Blaylock BL, Comment CE, Heindel JJ, Fox WM, Korach KS, et al. 1993a. Selective prothymocyte targeting by prenatal diethylstilbesterol exposure Cell Immunol 152:131–142. Find this article online
51. Holladay SD, Blaylock BL, Comment CE, Heindel JJ, Luster MI 1993b. Fetal thymic atrophy after exposure to T-2 toxin: selectivity for lymphoid progenitor cells Toxiol Appl Pharmacol 121:8–14. Find this article online
52. Holladay SD, Smialowicz RJ 2000. Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure Environ Health Perspect 108:463–473.10852846 Find this article online
53. Holladay SD, Smith BJ 1994. Fetal hematopoietic alterations after maternal exposure to benzo[a]pyrene: a cytometric evaluation J Toxicol Environ Health 42:259–273.8021962 Find this article online
54. Holladay SD, Smith BJ 1995. Alterations in murine fetal thymus and liver hematopoietic cell populations following developmental exposure to 7,12-dimethylbenz[a]anthracene Environ Res 68:106–113.7601071 Find this article online
55. Holladay SD, Smith BJ, Luster MI 1995. B lymphocyte precursor cells represent sensitive targets of T-2 mycotoxin exposure Toxicol Appl Pharmacol 131:309–315.7716771 Find this article online
56. Holsapple MP, Burn-Naas LA, Hastings KL, Ladics GS, Lavin GS, Makris SL, et al. 2005. A proposed testing framework for developmental immunotoxicology (DIT) Toxicol Sci 83:18–24.15456913 Find this article online
57. Holsapple MP, West LJ, Landreth KS 2003. Species comparison of anatomical and functional immune system development Birth Defects Res B 68:321–334. Find this article online
58. Holt PG, Jones CA 2000. The development of the immune system during pregnancy and early life Allergy 55:688–697.10955693 Find this article online
59. Holt PG, Sly PD 2002. Interactions between RSV infections, asthma, and atopy: unravelling the complexities J Exp Med 196:1271–1275.12438419 Find this article online
60. Hultman P, Hansson-Georgiadis H 1999. Methyl mercury-induced autoimmunity in mice Toxicol Appl Pharmacol 154:203–211.9931279 Find this article online
61. Hussain I, Piepenbrink MS, Dietert RR 2005a. Impact of in ovo-administered lead and testosterone on developing female thymocytes J Toxicol Environ Health A 68:1309–1319. Find this article online
62. Hussain I, Piepenbrink MS, Fitch KJ, Marsh JA, Dietert RR 2005b. Developmental immunotoxicity of cyclosporin-A in rats: age-associated differential effects Toxicology 206:273–284. Find this article online
63. Janossy G, Bofill M, Poulter LW, Rawlings E, Burford GD, Navarrete C, et al. 1986. Separate ontogeny of two macrophage-like accessory cell populations in the human fetus J Immunol 136:4354–4361.3711660 Find this article online
64. Kalland T, Forsberg JG 1978. Delayed hypersensitivity response to oxazolone in neonatally estrogenized mice Cancer Lett 4:141–146.647657 Find this article online
65. Kaneko K, Shimizu H, Arakawa H, Ogawa Y 2001. Pulmonary surfactant protein A in sera for assessing neonatal lung maturation Early Hum Dev 62:11–21.11245991 Find this article online
66. Karrow NA, Guo TL, Declos KB, Newbold RR, Weis C, Germolec DR, et al. 2004. Nonylphenol alters the activity of splenic NK cells and the number of leukocyte subpopulations in Sprague-Dawley rats: a two generation feeding study Toxicology 196:237–245.15036750 Find this article online
67. Kawai M, Kitade H, Mathieu C, Waer M, Pirenne J 2005. Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo Transplantation 79:1073–1077.15880046 Find this article online
68. Kimmel CA, King MD, Makris SL 2005. Risk assessment perspectives for developmental immunotoxicology. In: Developmental Immunotoxicology (Holladay SD, ed). Boca Raton, FL:CRC Press, 45–63
69. Kimmel GL 2005. An overview of children as a special population-relevance to predictive biomarkers Toxicol Appl Pharmacol 206:215–218.15967211 Find this article online
70. Kronenberg M, Rudensky A 2005. Regulation of immunity by self reactive T cells Nature 435:598–604.15931212 Find this article online
71. Krumbiegel D, Rohr J, Schmidtke P, Knuf M, Zepp F, Meyer CU 2005. Efficient maturation and cytokine production of neonatal DCs requires combined proinflammatory cytokine signals Clin Dev Immunol 12:99–105.16050140 Find this article online
72. Ladics GS, Chapin RE, Hastings KL, Holsapple MP, Makris SL, Sheet LP, et al. 2005. Developmental toxicology evaluations—issues including neurotoxicology and immunotoxicology assessments in reproductive toxicology studies Toxicol Sci 88:24–29.16120748 Find this article online
73. Landreth KS 2002. Critical windows in development of the rodent immune system Hum Exp Toxicol 21:493–498.12458906 Find this article online
74. Landreth KS, Dodson SVM 2005. Development of the rodent immune system. In: Developmental Immunotoxicology (Hollday SD, ed). Boca Raton, FL:CRC Press, 3–19
75. Landrigan PL, Kimmel CA, Correa A, Eskenazi B 2004. Children’s health and the environment: public health issues and challenges for risk assessment Environ Health Perspect 112:257–265.14754581 Find this article online
76. Lawrence DA, McCabe MJ Jr 2002. Immunomodulation by metals Int Immunopharmacol 2:293–302.11811932 Find this article online
77. Lee J-E, Chen S, Golemboski KA, Parsons PJ, Dietert RR 2001. Developmental windows of differential lead-induced immunotoxicity in chickens Toxicology 156:161–170.11164618 Find this article online
78. Lee J-E, Naqi SA, Kao E, Dietert RR 2002. Embryonic exposure to lead: comparison of immune and cellular responses in unchallenged and virally stressed chickens Arch Toxicol 75:717–724.11876505 Find this article online
79. Leibnitz R 2005. Development of the human immune system. In: Developmental Immunotoxicology (Hollday SD, ed). Boca Raton, FL:CRC Press, 21–42
80. Li YH, Yan ZQ, Brauner A, Tullus K 2001. Meconium undces expression of inducible no synthase and activation of NF-kappaB in rat alveolar macrophages Pediatr Res 49:820–825.11385144 Find this article online
81. Lim KJ, Odukoya OA, Ajjan RA, Li TC, Weetman AP, Cooke ID 2000. The role of T-helper cytokines in human reproduction Fertil Steril 73:136–142.10632428 Find this article online
82. Luebke RW, Chen DH, Dietert RR, Yang Y, King M 2006. The comparative immunotoxicity of five selected compounds following developmental or adult exposure J Toxicol Environ Health B Crit Rev 9:1–26.16393867 Find this article online
83. Lummus ZL, Henningsen G 1995. Modulation of T-cell ontogeny by transplacental benzo(a)pyrene Int J Immunopharmacol 17:339–350.7672884 Find this article online
84. Luster MI, Boorman GA, Dean JH, Luebke RW, Lawson LD 1980. The effect of adult exposure to diethylstilbesterol in the mouse: alterations in imunological functions J Reticuloendothel Soc 28:561–569.6450833 Find this article online
85. Luster MI, Faith RE, McLauchlan JA, Clark GC 1979. Effect of in utero exposure to diethylstilbesterol on the immune response in mice Toxicol Appl Pharmacol 47:279–285.377565 Find this article online
86. Luster MI, Johnson VJ, Yucesoy B, Simeonova P 2005. Biomarkers to assess potential developmental immunotoxicity in children Toxicol Appl Pharmacol 206:229–236.15967213 Find this article online
87. Luster MI, Portier C, Pait DG, White KLJ, Gennings C, Munson AE, et al. 1992. Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests Fundam Appl Toxicol 18:200–210.1534777 Find this article online
88. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H 2005. Inhibition of CD4⁺CD25⁺ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide Blood 105:2862–2868.15591121 Find this article online
89. MacKall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. 1995. Age, thymopoiesis, and CD4⁺ T lymphocyte regeneration after intensive chemotherapy N Engl J Med 332:143–149.7800006 Find this article online
90. Mainali ES, KiKuchi T, Tew JG 2005. Dexamethasone inhibits maturation and alters function of monocyte-derived dendritic cells from cord blood Pediatr Res 58:125–131.15774840 Find this article online
91. Mainali ES, Tew JG 2004. Dexamethasone selectively inhibits differentiation of cord blood stem cell derived-dendritic cells (DC) precursors into mature DCs Cell Immunol 232:127–136.15922722 Find this article online
92. Malamitsi-Puchner A, Protonotariou E, Boutsikou T, Makrakis E, Sarandakou A, Creatas G 2005. The influence of the mode of delivery on circulating cytokine concentration in the perinatal period Early Hum Dev 81:387–392.15814224 Find this article online
93. McCabe MJ Jr, Singh KP, Reiners JJ Jr 1999. Lead intoxication impairs the generation of a delayed type hypersensitivity response Toxicology 139:255–264.10647925 Find this article online
94. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D 2004. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation Blood 103:4619–4623.15001472 Find this article online
95. Mellor AL, Chandler P, Lee GK, Johnson T, Keskin DB, Lee J, et al. 2002. Indoleamine 2,3,-dioxygenase, immunosuppression and pregnancy J Reprod Immunol 57:143–150.12385839 Find this article online
96. Mendelson CR, Condon JC 2005. New insights into the molecular endocrinology of parturition J Steroid Biochem Mol Biol 93:113–119.15860253 Find this article online
97. Mesples B, Plaisant F, Fontaine RH, Gressens P 2005. Pathophysiology of neonatal brain lesions: lesson from animal models of excitotoxicity Acta Paediatr 94:185–190.15981752 Find this article online
98. Meylan F, De Smedt M, LeClercq G, Plum J, Leupin O, Marguerat S, et al. 2005. Negative thymocyte selection to HERV-K18 superantigens in humans Blood 105:4377–4382.15644416 Find this article online
99. Miller TE, Golemboski KA, Ha RS, Bunn T, Sanders FS, Dietert RR 1998. Developmental exposure to lead causes persistent immunotoxicity in Fischer 344 rats Toxicol Sci 42:129–135.9579025 Find this article online
100. Naito M, Hasegawa G, Takahashi K 1997. Development, differentiation, and maturation of Kupffer cells Microsc Res Tech 39:350–364.9407545 Find this article online
101. Nouri-Shirazi M, Guinet E 2003. Evidence for the immunosuppressive role nicotine has on human dendritic cell function Immunology 109:365–273.12807482 Find this article online
102. Pace BM, Lawrence DA, Behr MJ, Parsons PJ, Dias JA 2005. Neonatal lead exposure changes quality of sperm and number of macrophages in testes of BALB/c mice Toxicology 210:247–256.15840438 Find this article online
103. Palaniyar N, Clark H, Nadesalingam J, Shih MJ, Hawgood S, Reid KB 2005. Innate immune collectin surfactant protein D enhances the clearance of DNA by macrophages and minimizes anti-DNA antibody generation J Immunol 174:7352–7358.15905582 Find this article online
104. Petrie HT 2002. Role of thymic organ structure and stromal composition in steady-state postnatal T-cell production Immunologic Rev 189:8–19. Find this article online
105. Protonotariou E, Malamitsi-Puchner A, Rizos D, Sarandakou A, Makrakis E, Salamolekis E 2003. Alterations in T_H1/T_H2 cytokine concentrations in early neonatal life J Matern Fetal Neonatal Med 14:407–410.15061321 Find this article online
106. Pryhuber GS, Hull WM, Fink I, McMahan MJ, Whitsett JA 1991. Ontogeny of surfactant proteins A and B in human amniotic fluid as indices of fetal lung maturity Pediatr Res 30:597–605.1805157 Find this article online
107. Ravizza T, Rizzi M, Perego C, Richichi C, Veliskova J, Moshe SL, et al. 2005. Inflammatory response and glia activation in developing rat hippocampus after status epilepticus Epilepsia 46:113–117.15987264 Find this article online
108. Renkl AC, Wussler J, Ahrens T, Thoma K, Kon S, Uede T, et al. 2005. Osteoponin functionally activates dendritic cells and induces their differentiation toward a T_h1-polarizing pheno type Blood 106:946–955.15855273 Find this article online
109. Robinson DS, Larche M, Durham SR 2004. Tregs and allergic disease J Clin Invest 114:1389–1397.15545986 Find this article online
110. Rodriguez JW, Kirlin WG, Wirsiy YG, Matheravidathu S, Hodge TW, Urso P 1999. Maternal exposure to benzo[a]-pyrene alters development of T lymphocytes in offspring Immunopharmacol Immunotoxicol 21:379–396.10319287 Find this article online
111. Rowley B, Monestier M 2005. Mechanisms of heavy metal-induced autoimmunity Mol Immunol 42:833–838.15829271 Find this article online
112. Sakaguchi S, Sakaguchi N 2005. Regulatory T cells in immunologic self-tolerance and autoimmune disease Int Rev Immunol 24:3–4. Find this article online
113. Schlumpf M, Ramseier H, Lichtensteiger W 1989. Prenatal diazepam induced persisting depression of cellular immune responses Life Sci 44:493–501.2538699 Find this article online
114. Schonland SO, Zimmer JK, Lopez-Benitez CM, Widmann T, Ramin KD, Goronzy JJ, et al. 2003. Homeostatic control of T cell generation in neonates Blood 102:1428–1434.12714521 Find this article online
115. Selevan SG, Kimmel CA, Mendola P 2000. Identifying critical windows of exposure for children’s health Environ Health Perspect 108:451–455.10852844 Find this article online
116. Seppanen O, Glumoff V, Paananen R, Rounioja S, Hallman M 2005. Transcription factors NF-kappaC and C/EBPdelta and IL-1-induced expression of surfactant protein a in lung explants during perinatal period Biol Neonate 87:152–159.15564781 Find this article online
117. Shaheen SO, Newson RB, Henderson AJ, Headley JE, Stratton FD, Jones RW, et al. 2005. Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood Clin Exp Allergy 35:18–25.15649261 Find this article online
118. Silva IA, El Nabawi M, Hoover D, Silbergeld EK 2005. Prenatal HgCl2 exposure in BALB/c mice: gender specific effects on the ontogeny of the immune system Dev Comp Immunol 29:171–183.15450757 Find this article online
119. Skarsvik S, Tittanen M, Lindstrom A, Casas R, Ludvigsson J, Vaarala O 2004. Poor in vitro maturation and pro-inflammatory cytokine response of dendritic cells in children at genetic risk of type 1 diabetes Scan J Immunol 60:647–652. Find this article online
120. Smialowicz RJ, Riddle MM, Rogers RR, Luebke RW, Copeland CB 1989. Immunotoxicity of tributyltin oxide in rats exposed as adults or pre-weanlings Toxicology 57:97–111.2749744 Find this article online
121. Smialowicz RJ, Riddle MM, Williams WC, Dilberto JJ 1994. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on humoral immunity and lymphocyte subpopulations: difference between mice and rats Toxicol Appl Pharmacol 124:248–256.8122270 Find this article online
122. Snyder JE, Filipov NM, Parsons PJ, Lawrence DA 2000. The efficiency of maternal transfer of lead and its influence on plasma IgE and splenic cellularity of mice Toxicol Sci 57:87–94.10966514 Find this article online
123. Sprent J, Kishimoto H 2002. The thymus and negative selection Immunol Rev 185:126–135.12190927 Find this article online
124. Spyker-Cranmer JM, Barnett JB, Avery DL, Cranmer MF 1982. Immunoteratology of chlordane: cell-mediated and humoral immune responses in adult mice exposed in utero Toxicol Appl Pharmacol 62:402–408.7041330 Find this article online
125. Theus SA, Lau KA, Tabor DR, Soderberg LSF, Barnett JB 1992. In vivo prenatal chlordane exposure induces development of endogenous inflammatory macrophages. J Leukoc Biol 51:366–372.1564400 Find this article online
126. Tryphonas H, Cooke G, Caldwell D, Bondy G, Parenteau M, Hayward S, et al. 2004. Oral (gavage), in utero and postnatal exposure of Sprague-Dawley rats to low doses of tributyltin chloride. Part II: Effects on the immune system Food Chem Toxicol 42:221–235.14667469 Find this article online
127. Uhrig A, Banafsche R, Kremer M, Hengenbarth S, Hamann A, Neurath M, et al. 2005. Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver J Leukoc Biol 77:626–633.15860798 Find this article online
128. U.S. Food and Drug Administration 1999. Guidance for Industry and FDA Reviewers—Immunotoxicity Testing Guidance. Washington, DC:Center for Devices and Radiological Health, U.S. Food and Drug Administration
129. U.S. Food and Drug Administration 2004. S8 Immunotoxicity Studies for Human Pharmaceuticals. Draft Guidance. November 18 2004. Washington, DC:U.S. Food and Drug Administration
130. Valmori D, Merlo A, Souleimanian NE, Hesdorffer CS, Ayyoub M 2005. A peripheral circulating compartment of naive CD4 Tregs J Clin Invest 115:1953–1962.16007258 Find this article online
131. Van Loveren H, Piersma A 2004. Immunotoxicological consequences of perinatal chemical exposures Toxicol Lett 149:141–145.15093259 Find this article online
132. Voderstrasse B, Cundiff J, Lawrence B 2004. Developmental exposure to aryl hydrocarbon receptor agonist 2,3,7,8-tetra-chkorodibenzo-p-doxin impairs the cell-mediated immune response to infection with influenza A virus, but enhances elements of innate immunity J Immunotoxicol 1:103–112. Find this article online
133. Vos JG, De Klerk A, Krajnc EI, Van Loveren H, Rozing J 1990. Immunotoxicity of bis (tri-n-butyltin) oxide in the rat: effect on thymus-dependent immunity and on nonspecific resistance following long-term exposure in young versus aged rats Toxicol Appl Pharmacol 105:144–155.2118283 Find this article online
134. Walker DB, Williams WC, Copeland CB, Smialowicz RJ 2004. Persistent suppression of contact hypersensitivity, and altered T-cell parameters in F344 rats exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Toxicology 197:57–66.15003334 Find this article online
135. White KL Jr, Germolec DR, Booker CD, Hernendez DM, McCay JA, Declos KB, et al. 2005. Dietary methoxychlor exposure modulates splenic natural killer cell activity, antibody-forming cell response and phenotypic marker expression in F₀ and F₁ generations of Sprague Dawley rats Toxicology 207:271–281.15596257 Find this article online
136. Wolf AM, Wolf D, Rumpold H, Moschen AR, Kaser A, Obrist P, et al. 2004. Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease Clin Immunol 113:47–55.15380529 Find this article online
137. Wolisi GO, Majekodunmi J, Bailey GB, Urso P 2001. Immunomodulation in progeny from thymectomized primiparous mice exposed to benzo[a]pyrene during mid-pregnancy Immunopharmacol Immunotoxicol 23:267–280.11417853 Find this article online
138. Zimmerman LJI, Janssen DJMT, Tibboel D, Hamvas A, Carnielli VP 2005. Surfactant metabolism in the neonate Biol Neonate 87:296–307.15985752 Find this article online