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The Immunity Crisis in America

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

Immunity Crisis Overview

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Down Regulation of the Immune Response

Many different mechanisms are involved in the down-regulation of the immune response. Extreme situations of down-regulation may very well be indistinguishable from tolerance. This similarity between activation of suppressor circuits and clonal anergy is made more obvious by the fact that the experimental protocols used to induce one or the other were virtually identical. Several mechanisms have been proposed to explain the down-regulation of the immune response (Weiner et al. 1994). Two types of mononuclear cells (MNCs) seem to be capable of suppressor activity lymphocytes and monocytes. Recently, CD4+ cells, which express CD25 on the surface, have been shown to act as regulators (suppressors) of the immune response in a variety of experimental conditions (Groux and Powerie 1999).

Cells of the Innate Immune System

The cellular components of innate immunity consist of macrophages, neutrophils, Mast cells, eosinophils, and natural killer (NK) cells. The primary phagocytic cells, macrophages and neutrophils, have receptors on their surface for carbohydrate moieties such as lipopolysaccharide and mannose receptor that are not usually expressed by vertebrate cells. Phagocytic cells also have CR1 receptors for C3b and Fc receptors for antibodies on their surface. These carbohydrate and complement receptors allow phagocytic cells to attack antigens without assistance from the acquired immune system. These receptors allow the phagocytic cell to bind an antigen when complementary carbohydrate moieties or C3b is near one of the receptors Carbohydrate and complement receptors bind in a zipper-like fashion until the antigen is completely enclosed by a membrane-bound vesicle called a phagosome. The phagosome then fuses with another vesicle filled with degradative enzymes known as a lysosome. This fusion...

Postnatal Development Of The Immune System

It is during the immediate postnatal period that acquired immune function is first detectable in mammals (Ghia et al. 1998). Functional B and T lymphocytes are produced in the bone marrow and thymus, respectively, and migrate to the spleen, lymph nodes, and mucosal associated lymphoid tissues (MALT) as functional end cells (Osmond 1985). However, a mature pattern of immune response to antigens is not achieved until approximately one month of age in rodents. During the first month of postnatal life in mice, the immune system remains immature, fails to produce antibodies to carbohydrate antigens, and the humoral immune response to antigens is dominated by the production of IgM (Mosier et al. 1979 Dorshkind 1986). After this period of perinatal immunodeficiency, mice mount mature immune responses to protein and carbohydrate antigens and respond to intracellular pathogens, and the immune response can be assumed to accurately portray mature postnatal immune function (Raff et al. 1970).

Induction of Immune Responses Introduction

The immune system is composed both functionally and anatomically of cellular and humoral compartments. The cellular component of immunity relies most heavily on lymphocytes dependent on the thymus for their development and maturation (T cells), while the humoral component consists of a class of soluble molecules found in the serum (antibodies) that are characterized by enormous diversity as well as specificity. These antibodies are synthesized by non-thymic cells derived from bone marrow precursors (B cells). Current research provides considerable evidence for the interdependence of the two arms of the immune response and the methods of modern immunology exploit an extensive understanding of both the cellular and humoral reactions. Although it is far beyond the scope of this book to convey even superficially the excitement that has permeated research into the cellular and molecular mechanisms that underlay the immune response, two books can be strongly recommended one by Silverstein...

Critical Developmental Windows For The Immune System In Rodents

The developmental progression of cells, sequential migration of immature cells to a series of embryonic tissue sites, and differences in hematopoietic microenvironments in each of these tissue sites (Figure 1.3) strongly suggests that different periods of embryonic development may be differentially susceptible to immunotoxic insult. For that reason, a hypothetical sequence of windows of vulnerability for the developing immune system was recently proposed (Dietert et al. 2000). Details of this scheme as they apply to rodent development are presented in Figure 1.4 of this chapter and include five critical windows of potential vulnerability. Embryonic development does not proceed in lock-step sequence, and these windows of vulnerability are clearly not discrete. However, even though there is a considerable overlap of these developmental windows, they are based on a set of unique developmental events that can be followed in temporal sequence and describe the initial appearance of specific...

Tumor Necrosis Family Apoptosis and Immune Surveillance

Apoptotic tumor-infiltrating lymphocytes (TIL).199,201 The ability of tumor-expressed FasL to suppress the immune response has been extensively verified experimentally.202 In addition, increased FasL expression accompanies disease progression in colorectal carcinoma and has been significantly associated with the probability of breast and cervical carcinomas to form lymph node metastasis.197,203 In an analogous fashion, upregulation of TRAIL has been observed in hepatocellular carcinoma, and its expression in gastric carcinoma is correlated with metastasis and the presence of

Development Of The Newborn Immune System

Upon parturition, the immune system of the neonate becomes abruptly released from the immunosuppressive intrauterine environment (Holt 2003 Janeway Jr. et al. 1997b West 2002) and is concomitantly exposed to a world of antigens. Unlike the situation in rodents, the human neonatal immune system has achieved a significant level of maturity (Holt and Jones 2000 Peakman et al. 1992 West 2002). However, in comparison with the human adult immune system and with respect to the antigenic challenges facing the neonate, the neonatal immune system is considered immature (Holt and Jones 2000 Miller 1978). The neonate's susceptibility to infection has sparked the term immunodeficiency of immaturity (Schelonka and Infante 1998). In general, the neonate has an insignificant inflammatory response (Holladay and Smialowicz 2000), low levels of antibody (Holt and Jones, 2000), and reduced T cell reactivity (Holt et al. 1992 Pirenne et al. 1992). Moreover, the percentages of gd T cells (Peakman et al....

The Adult Immune System

Once the cells and organs of the immune system have established adult levels or function, few studies ascertain maturation of these compartments beyond the formative years (Kincade et al. 2002). Several studies indicate that adult patterns of lymphopoiesis are remarkably stable even into the eighth decade of life (Hao et al. 2001 Nunez et al. 1996 Rossi et al. 2003). A notable exception is the thymus, which gradually involutes after puberty (Kendall 1991). Few new T cells are exported after the thymic cortex fills with adipose tissue, and immunity to new antigens depends on cross-reactions with previously encountered antigens (Nossal 2003). The thymus plays an important role in the development of sex organs, and infants with little or no thymus at birth (e.g., ataxia telangectesia and DiGeorge and cri du chat syndromes) fail to develop normal gonads (Kendall 1991). Although steroid hormones have been called the gatekeepers of entry into and progression within lymphoid lineages...

Manipulators Of The Developing Immune System

The immune system matures according to developmental pathways but also in response to the environment. Four manipulators impact many facets of the immune system and deserve attention. First and foremost, nutrition plays a vital role in the ability of the body to defend against pathogens (Bardare et al. 1993 Devereux et al. 2002). The majority of immunocompromised individuals in the world simply lack nourishment (Janeway Jr. et al. 1997a). Studies implicate maternal diet in development of atopic disease (Bardare et al. 1993 Devereux et al. 2002). Other maternal behaviors such as breastfeeding can decrease risk of allergy, asthma, and autoimmune disease (Bjorksten 1999a Hanson 1998). The benefits of breastfeeding indicate that the neonate's diet plays a significant role in maturation of immune system function. Second, maternal disease and vaccination can impact immune development in the fetus. This maternal influence can be harmful to the fetus (for example, the association of fetal and...

Principles of the Immune System

The immune system is the organ that fights infection by pathogenic organisms such as bacteria, viruses, protozoa, or even worms. It also protects against toxins, for instance those from bacteria. The defense system of invertebrates against pathogens is simple, relying mostly on macrophages and bactericidal substances. In vertebrates, however, highly specialized cells have evolved, capable of producing cells with receptors of high binding specifity against literally billions of molecules, be they peptides, lipids, sugars, metal salts, or other chemical classes. The vertebrate immune system is a unique organ in that it is composed of a multitude of cells, molecules, and organized tissue structures, found distributed over the entire body as its field of action (Table 1). Immune cells are mobile and capable of communicating directly with each other by cell surface structures, or over considerable distances via lymphokines and chemokines. Close cell-cell contact is often necessary to...

Vulnerability Of The Developing Immune System

Development of the immune system begins in the early embryo and continues well into postnatal life, the greatest difference between humans and rodents being the stage of development at birth. Studies have demonstrated susceptibility of the immune system to environmental exposures at several developmental stages (Hol-laday and Luster 1994 Luster et al. 2002). Laboratory mice have been the most extensively used animal models for demonstrating postnatal immune effects following perinatal exposure to agents that affect the immune system. Fetal thymus development has been well characterized in mice, in which thymic colonization occurs in the latter portion of gestation. In humans, the first trimester is a period when both thymic colonization and early T-cell development are found. The limited data available indicate that early stages of T-lymphocyte development may be similar in the two species. Because of the early timing of thymic colonization in humans and involution by the time of...

Analyses of Immune Responses to Ontogeny Specific Antigens Using an Inbred Strain of Xenopus laevis J Strain

In this chapter, the procedures for specific detection of ontogenic emerging antigens during animal development are described. Anuran metamorphosis has provided us with a good experimental model for investigation of the mechanisms of tissue remodeling. The establishment of a syngeneic strain of Xenopus laevis described in this chapter has enabled us to perform a unique experiment to develop antibodies that specifically react to ontogenic antigens by immunizing syngeneic animals. This strategy was successful because the antibody repertoires produced in the adult frog serum were well subtracted by a number of common antigens expressed in syngeneic larvae. Here we show, using results of immuno-histochemical and T-cell proliferation analyses that adult frogs exhibit humoral and cellmediated immune responses to larva- or metamorphosis-specific antigen molecules in epidermal cells. Key Words Larval antigens epidermal cells skin metamorphosis tissue remodeling transformation antiserum...

UVR Light Causes Exposure of Autoantigens to the Immune System

The exact function of Ro SSA is unknown, but a recent study demonstrated that it may have a role in cytokine production by activated T cells (Ishii et al. 2003). Recently, a Ro SSA knockout mouse was developed that was characterized by the development of an autoimmune syndrome with increased sensitivity to light. This suggests that Ro SSA antibodies may actually contribute to the development of the autoimmune response by allowing cryptic epitopes to be presented to the immune system in response to UV apoptosis (Xue et al. 2003).

Immune System Teratogenicity

Several well-known teratogenic agents have been shown to have an adverse effect on the developing immune system, including the early thymus in macaques and baboons. Zinc is an essential nutrient critical for the normal development and function of the immune system. Studies in our Primate Center have been directed toward developing the rhesus macaque model to define the influence of zinc deficiency on reproductive outcome and early postnatal development (Golub et al. 1984 Haynes et al. 1987), and to demonstrate that cell-mediated immunity is affected in these animals (Haynes et al. 1987). Experimentally induced zinc deficiency (4 mg Zn g in experimental cases compared to 100 g Zn g in controls) from conception until 1 year postnatal in rhesus macaques results in severe alterations in immunocompetence (Haynes et al. 1985 Vruwink et al. 1991). The adverse effects include depressed peripheral blood lymphocyte mitogenesis, reduced polymorphonuclear leukocyte function, alterations in IgM...

Acquired Immune Deficiency Syndrome AIDS

While we now understand the basic structure of the protein viral capsid, we have been unable to find a lasting cure, since the virus continues to evolve. The basic action of the rhinovirus is similar to that of HIV, but less deadly for most. The virus attaches itself to the cell surface, and its RNA enters the human cell, which then directs the cell to replicate the virus. Unlike HIV, which focuses on the immune system, rhinoviruses mainly attack the respiratory tract. Figure 7 illustrates one such capsid of the rhinovirus. The capsid itself is made up of 60 individual building blocks arranged in an icosohedral arrangement. Figure 7a53 illustrates a rhinovirus bound to a receptor protein on the cell surface, shown in blue. In Figure 7b,54 antibodies against the infection can attach themselves to the virus in the same position to prevent the virus from binding to the cell surface and causing infection. Work toward finding pharmaceutical agents effective against the common cold...

Relationship Between Dosing Regimens And Immune System Development

The time required for full development of the immune system varies from species to species. For the human, the various elements of the immune system are fully formed early in the second trimester (around 13 to 20 weeks of gestation) (reviewed in Barnett 1995 Holladay and Smialowicz 2000, chap. 1). It is generally accepted that exposure to xenobiotics during the formative stages of immune development, i.e., prior to 20 weeks gestation in humans, could lead to either a more detrimental or permanent result. Although there is firm evidence to support this conclusion in experimental animal studies, it is difficult to obtain definitive data to support this conclusion for humans because of the large number of uncontrollable variables inherent in human studies. All of the reported developmental immunotoxicological studies on chlordane were performed using the mouse model. As the obvious reason for conducting experimental immunotoxicological studies is to determine an approximate risk...

Effect Of Prenatal Chlordane Exposure On The Immune System Of The Offspring

Initial studies on the acute toxic effects of chlordane dealt primarily with its effects on the nervous system, liver, and kidneys. However, the focus of more recent toxicological studies on chlordane have centered on its effects on the immune system. One of the earliest indicators of chlordane's immunotoxicity is a 1976 report of significant hematological changes and reoccurring fevers in a human after docu Spyker-Cranmer et al. (1982) report that the female offspring of dams treated with chlordane throughout gestation show a profound deficit in contact hypersensi-tivity response (CHR) to a contact allergen, oxazolone, at both 0.16 and 8.0 mg kg doses, while male offspring show a significant decrease at the 8.0 mg kg dose at 100 days of age. Thus, females appear to be sensitive to lower doses of chlordane. Only after recent reanalysis of the CHR data (Spyker-Cranmer et al. 1982), in light of the gender effects noted in more recent studies (Blyler et al. 1994), were these dose-gender...

Postnatal Immune System

Continued maturation of the macaque immune system has been provided by evaluation of various serum parameters during the postnatal period. Longitudinal measurements of CD4 CD8 T cell ratios have been reported in colony-bred rhesus (Dykhuizen et al. 2000) and cynomolgus (Bleavins et al. 1993 Baroncelli et al. 1997) macaques using flow cytometry. In both macaques, the CD4 CD8 ratios slowly decline with age, predominantly due to decreasing CD4+ T cell counts (Table 7.7). The CD4 CD8 values between 6 months and 1 year of age in these macaques (approximately 1.4 to 1.8) are in the same range as reported for humans between 4 to 5 years of age (Heldrup et al. 1992).

Molecular Control of Lineage Segregation A Paradigm from the Immune System

Relatively little is known in the neural crest field about the downstream effects of transcription factors associated with particular neural crest lineages. The best characterized examples of the molecular control of lineage segregation from multipotent precursors are found in the immune system, for example, the transcriptional control of B-cell development from hematopoietic stem cells (reviewed in Schebesta et al., 2002). Results from this field provide a paradigm for thinking about how lineage segregation might occur at the molecular level within the neural crest.

The Pigs Intestinal Immune System During Postnatal Development

The early postnatal development of the gut immune system is important for effective immunological responses towards nutritional and microbial antigens in the intestinal lumen. Adaptation to the commensal flora, defense against pathogens, and the development of oral tolerance to food components are essential immunological processes. Depending on the food composition and on the presence of oral food components, the morphology of both the intestinal mucosa and the intestinal immune cells changes (Ganessunker et al. 1999 Park et al. 1998 Shulman et al. 1988 Shulman 1988). In humans, it has been reported that the maturity of the child at birth and the feeding pattern in the early postnatal period influences health later on (Saarinen and Savilahti 2000 Siltanen et al. 2001). The pig may well represent an animal model suitable for studying these observations in more detail, as, for example, the development of the B lymphocyte subsets in the intestinal mucosa is comparable in humans and pigs...

Assessment Of Progression Of Infection And Immune Response To T Gondii

Progression of T. gondii infection and immune response to the parasite can be monitored by the following parameters signs of illness and time until death histopathology to assess inflammatory changes induced by the infection and to establish the presence of the parasite in tissues (immunohistochemistry) tissue levels of mRNA for genes expressed specifically in the tachyzoite stage (parasite load) tissue levels of cytokine mRNA cytokine levels in serum and other body fluids serum titers of T. gondii antibodies lymphocyte proliferation and cytokine secretion after in vitro stimulation with T. gondii and flow cytometry to detect changes in the phenotypic composition of leukocytes in different organs. Depending on the purpose of the experiment, the investigator should choose one or more of these parameters as appropriate, as well as the timing of evaluation after infection (see Anticipated Results).

Evaluation Of Specific And Innate Immune Responses To L Monocytogenes In Mice

The severity of L. monocytogenes infection can also be monitored in unimmunized mice. In normal mice, L. monocytogenes infection induces a nonspecific inflammatory response involving neutrophils, natural killer cells, and macrophages during the first 24 to 72 hr of infection. This response substantially decreases the infectious burden and is essential for the survival of infected mice. The specific immune response to L. monocytogenes occurs 5 to 7 days after infection and ultimately clears the last bacteria from the spleen and liver of infected mice. Therefore, following infection of mice with sublethal doses of L. monocytogenes, it is possible to assess the competence of innate and specific immunity by quantifying bacteria 48 to 72 hr and 7 to 10 days after infection, respectively.

In Vivo Tumor Protection And Immunotherapy Experiments

In general, vaccine formulations can be tested either for their ability to elicit anti-tumor protection or for eradication of established tumor. Although, the latter is the more challenging task, both assays are feasible using 38c-13 and A20 lymphomas. However, use of the slower-growing lymphoma, A20, is recommended for immunotherapy experiments. Both types of in vivo experiments, tumor protection and therapy of established tumor, are described in this protocol. Moreover, the protocol starts with description of immunization strategies for tumor protection experiments using DNA (a steps), protein (b steps), and cytokine-transduced vaccines (c steps), followed by tumor challenge protocols, including a tumor challenge protocol for protection studies (d step same as tumor challenge steps in Basic Protocol 1) and a detailed experiment for immunotherapy of established A20 lymphoma (e steps). All in vivo experiments should be repeated at least three times with 10 mice per experimental group...

Fetal Sensitization and Subsequent Immune Responses in Childhood

Experimental studies have shown that peripheral blood mononuclear cell sensitivity to allergens exists at birth (Kondo et al. 1992 Prescott et al. 1998 Warner et al. 1994 reviewed in Warner and Warner 2000). In particular, specific allergen-induced responses can be measured in the peripheral blood mononuclear cells as early as 22 weeks into gestation (Jones et al. 1996). Moreover, events after birth are believed to modify the developing immune response in newborns allergens, infections, diet, and gut microbial flora have all been implicated in the development, or not, of subsequent allergy (Warner and Warner 2000). The impact of diet on the development of allergies in newborns is now being recognized. The health benefits cited for breastfeeding include a reduction in childhood asthma (Oddy et al. 2002) and may be directly tied to gut microbial flora (Bjorksten et al. 1999 Holt et al. Finally, disease due to infection affects immune system maturation. The hygiene hypothesis proposed by...

The TH2Bias of the Neonatal Immune System

Before the fetus has even a rudimentary immune system, the maternal immune response has had to adapt to permit development of a child whose paternal antigens are cause for immune rejection. Evidence exists in both murine and human studies that during pregnancy, TH2 immune responses dominate in the mother, reducing TH1 type reactions that would presumably mediate rejection of the fetus (reviewed in Donovan and Finn 1999 Warner and Warner 2000). In support of this idea, Sills and coworkers demonstrated a relationship between the TH1-associated cytokine TNF and infertility. In that report, chronic therapy for infertility using biologic agents to block TNF was associated with successful induction of ovulation, conception, and normal delivery (Sills et al. 2001). Pregnant women have been shown to have compromised cell-mediated immunity (Weinberg 1984), impaired lymphocyte proliferation (Matthiesen et al. 1996), and a loss of peripheral blood mononuclear cell proliferative responses to...

Overview of Protein Folds in the Immune System

These technological advancements have made structural biology a very effective method for studying mechanisms of signal transduction in molecular immunology. For example, the determination of high-resolution structures of antibody molecules, class I and II major histo-compatibility antigen molecules, and their T cell antigen receptors have in each case served as a milestone toward our understanding of how the immune system functions. To date, there are well over a thousand structures published and the number is growing fast. This review is not intended to enumerate all published structures rather it aims at providing a comprehensive description of structures and folds related to the function of the immune system. Many of the proteins that participate in cellular signal transduction pathways of the immune system are not included in this review, primarily because their functions are broadly implicated in cell biology as opposed to immunology. This unit is intended to focus narrowly on...

Cancer and immune responses

As pointed out in the previous chapter, the body is characterized by defense systems which can limit the growth and pathogenicity of selfish tumor cells once they have arisen by a series of mutations. The previous chapter explored how the limitation of blood supply can prevent cancers from growing beyond a very small size and from progressing. This is a mechanism which is supported very well by experimental and clinical data, and which is also studied from a therapeutic point of view. Another mechanism which can potentially counter the growth of cancer cells is the immune system. As will become apparent in this chapter, however, the role of the immune system in cancer is highly debated and uncertain. The immune system defends human beings from intruders such as pathogens which would otherwise kill them. It does so by specifically recognizing proteins derived from the pathogens (for example, viruses, bacteria, or parasites). Through complicated mechanisms which will be discussed...

Current Assessment Of The Immune System In Epa Guideline Studies

A number of guideline toxicity studies utilized in the regulation of pesticides, industrial chemicals, and environmental pollutants include assessments of immune system structure and or function. The majority of these studies are performed in adult animals. Although they were not developed to assess the developing immune system, they can provide valuable information that could indicate the necessity for further testing to evaluate effects on the immune system following developmental exposure. Figure 3.1 demonstrates the immunotoxic endpoints assessed in several typical guideline toxicology studies, in relationship to the life stage of the test animals at the time of study conduct.

Primary Immune Response To Antigens In The

Early observations relating to the persistence of tumour and tissue allografts1011 and of viruses12 when placed in the brain suggested that this organ was a site of immune privilege, in which antigens were poorly immunogenic and did not elicit an inflammatory response. To elicit an immune response, antigen must be able to leave the brain, either directly or following endocytosis by a predendritic cell, and arrive at a lymphoid organ. The character of the immune response induced, including the level and type of antibody, is highly dependent on such factors as the amount and nature of the antigen, period of exposure to the antigen, and its mode of presentation. These variables help to define the balance between CD4 CD8 positive cells and between the CD4-positive TH1 and TH2 cells.13 A primarily CD4 TH1 response is associated with the DTH type of response. There is some conflict, however, regarding the extent to which the CNS may be a site of immune privilege. Unlike the testis and the...

Immune System

The body has nonspecific (innate) immune defenses linked with specific (acquired) immune defenses that counteract bacteria, viruses, fungi, parasites and foreign (non-self) macromolecules. They all function as antigens, i.e., substances that stimulate the specific immune system, resulting in the activation of antigen-specific T lymphocytes (T cells) and B lymphocytes (B cells). In the process, Blym-phocytes differentiate into plasma cells that secrete antigen-specific antibodies (immunoglobulins, Ig) ( C). Ig function to neutralize and opsonize antigens and to activate the complement system ( p. 96). These mechanisms ensure that the respective antigen is specifically recognized, then eliminated by relatively o nonspecific means. Some of the T and B cells _o have an immunologic memory. Clonal deletion is a mechanism for eliminating lymphocytes with receptors directed against auto-logous (self) tissue. After first contact with their specific self-antigen, these lymphocytes are...

Establishment Of Immune Memory And Immune Senescence

Senescence of the immune system is well documented but poorly understood. Both innate and acquired immune responses to antigens are different in rodents in the last quartile of their life (McGlauchlen and Vogel 2003 Romanyukha and Yashin 2003). This failure of immune function is due, in part, to failure of production of newly formed cells and decreased survival of long-lived cells in lymphoid tissues.

Interuterine Environment

Reproduction of a species represents a unique immunologic challenge. Despite allogeneic differences, the maternal immune response does not reject the fetus, and this situation is maintained in humans for 40 weeks of pregnancy. A body of research has demonstrated that many levels of regulation operate in a successful pregnancy. Most significantly, the placenta serves as a physical barrier, sequestering the fetus away from the mother's immune system. The trophoblast cells that form the outer layer of the placenta in contact with maternal tissues do not express classical MHC proteins, acting as a nonimmunogenic shield. A second level of protection includes production by the placenta of immuno-modulatory molecules to actively protect the fetus. Tryptophan metabolites and IL-10 inhibit T cell activation and proliferation, and expression of FasL (CD95L) eliminates activated T cells (reviewed in Holt 2003). Moreover, the expression by placental trophoblasts of a range of molecules such as...

Macrophages and Dendritic Cells

The macrophage (mf) plays a critical role as an important effector cell of the innate immune system and as an activator of the adaptive response. This cell type plays a key tissue remodeling role during fetal organ development, scavenging the cells that are genetically programmed to die. In mice, a feature distinguishing fetal mf from adult cells is their high proliferative capacity, which may be due to their activation status (reviewed in Muramatsu 1993). In contrast to mf, dendritic cells (DC) lack phagocytic activity, but they have an extraordinary ability to stimulate na ve T cells and initiate primary immune responses. Importantly, DC induce different types of T cell immune responses depending on the type of original maturation signal therefore, DC are key regulators of the immune response (Liu 2001). Very little is known about DC in the fetal period. Cells with a DC mf morphology can be found in the yolk sac, prehematopoietic liver, and in the mesenchyme by 4 to 6 weeks of...

Fetal Liver As A Hematopoietic Organ

Mind, and such studies may reveal quite different sensitivities to toxic insult. It should also be noted that the persistence and predominance of hematopoiesis in the fetal liver throughout much of gestation has made it the organ of choice for mechanistic studies of normal and disrupted rodent blood cell development and immune function development (Cumano et al. 2000).

Chemical Suppression And Susceptibility

Chemicals often suppress the developing immune system and its functional capabilities while affecting the adult system with less severity. When given during the maturation of the immune system, several well-known chemicals (e.g., TCDD, lead) are found to be more persistent immunosuppressants than when exposure occurs in adult life. Studies conducted to examine the toxic effects of chemical exposures on the developing immune system are limited (Holladay and Luster 1994). Environmental agents can affect the immune system in various ways. Effects tend to include immunosuppression, possibly resulting in altered host resistance against infections or neoplastic agents hypersensitivity or autoimmunity and uncontrolled proliferation of immune components, i.e., lymphoma or leukemia. Quantification of T cell-dependent antibody responses is known to be an extremely reliable indicator of immunotoxicity and could very well be used to predict changes in host resistance as they develop (Luster et...

Structural Assessments in Adult Animals

Macro- and or microscopic structural anatomy of immune system organs and tissues are examined in a number of general guideline screening studies utilized by the U.S. EPA, including the acute inhalation toxicity study with histopathology (40 CFR 799.9135 USEPA 1997), the 90-day subchronic study (OPPTS 870.3100, 870.3150, 870.3250, 870.3465 USEPA 1998c-f), and the chronic carcinogenicity studies (OPPTS 870.4100, 870.4200, 870.4300 USEPA 1998i-k). In guideline subchronic and chronic carcinogenicity studies, an evaluation of macroscopic structure and general qualitative histopathology is only conducted on a few immune system tissues. In subchronic studies that include young adult animals (e.g., rats 45 days to 5 months of age), the spleen, thymus, and lymph nodes from two locations (one near to and the other distal from the site of administration) are examined, and the spleen and thymus are weighed. In chronic and carcinogenicity study guidelines, there is no specification that the thymus...

Structural Assessments Following Developmental Exposures

Only two guideline studies include an evaluation of immune system structure following developmental exposures these are the prenatal developmental toxicity study (OPPTS 870.3700 USEPA 1998g), and the two-generation reproduction study (OPPTS 870.3800 USEPA 1998h). There are a number of obvious gaps in the assessment of the immune system in immature animals in these two studies. The assessments of immune system organs conducted in immature animals in these studies consist entirely of the evaluation of macroscopic changes, with no microscopic examination. Pharmacokinetic data that characterize the exposure in the young (i.e., exposure of the fetus via the placenta or of the neonate via breast milk to the chemical or its metabolites) are not routinely required and are seldom available. Functional assessments are not addressed in these guideline studies. A developmental immunotoxicity guideline, i.e., one that evaluates potential perturbation of immune system function following early pre-...

Developmental Toxicity Risk Assessment

Although not discussed in any detail in those guidelines, developmental immu-notoxicity is considered part of developmental toxicity, as is developmental neurotoxicity or any other type of functional alteration resulting from an exposure during the developmental period (conception to sexual maturity). In the case of developmental neurotoxicity, further guidance is given in the Guidelines for Neurotoxicity Risk Assessment (USEPA 1998a), and the same approach might be considered for development of guidelines for immunotoxicity risk assessment that would include the assessment of potential effects on the immune system at multiple life stages.

The Use Of Developmental Immunotoxicity Data In Rfdrfc Derivation

Developmental immunotoxicity testing is expected to provide hazard and dose response information that can be utilized in formulating risk assessment decisions for any chemical. Adverse outcomes identified through developmental immunotoxicity testing, and their associated NOAELs or LOAELs, are considered appropriate for use in establishing endpoints and doses for risk assessment, particularly for any population group that includes fetuses, infants, or children. It is important to compare information on the immune response of adult animals with that of the immature individual, as obtained through developmental immunotoxicity testing. When the database contains evidence for concern regarding toxicity to adult immune system structure or function, and no data are available that assess developmental immuno-toxic potential, the resulting uncertainties should be accounted for in the risk assessment. A database uncertainty factor applied to RfD RfC derivation can be used to address this...

Polyhalogenated Aromatic Hydrocarbons 2378Tetrachlorodibenzop Dioxin TCDD

Exposure of experimental animals to TCDD results in a variety of toxic responses which differ in intensity among various species and strains (Poland and Knutson 1989). Of the many organs systems affected by TCDD, one of the most sensitive is the immune system (Holsapple 1995). TCDD is a highly toxic compound that produces more severe effects when exposure occurs during development. In the rat and the mouse, perinatal exposure to TCDD has been associated with teratogenicity (Couture et al. 1990), reproductive toxicity (Murray et al. 1979 Mably et al. 1992 Gray et al. 1995), neurobehavioral dysfunction (Thiel et al. 1994), and immunotoxicity (Vos and Moore 1974 Faith and Moore 1977). Perinatal TCDD exposure has been shown to alter a variety of immune functions in rodents. In rats, perinatal TCDD exposure suppresses T cell mitogen responsiveness (Vos and Moore 1974 Faith and Moore1977) skin graft rejection time (Vos and Moore 1974) graft- vs.- host activity (Vos and Moore 1974) and DTH...

The Pig As An Animal Model

The pig as an omnivorous species is of major interest for studying the development of the immune system. In comparison to rodents, the piglet is almost completely developed at birth. In terms of digestion, the pig's gastrointestinal tract can be compared in several structural aspects to that of humans. So far, the pig has been used for several experimental approaches especially in transplantation research is the pig an essential animal model. This is reflected by nearly 6000 bibliographic citations between 1997 and 2002 (between 1991 and 1996, there were approximately 1530 citations). The possible use of pigs as donors for xenotransplantation has inspired much research in this area (Davis et al. 1996 Robinson et al. 1998 Tucker et al. 2002).

Dimethoate and Methylparathion

Institoris et al. (1995) examined the developmental immunotoxic effects that exposure to 7, 9, or 14 mg DM kg or to 0.2, 0.3, or 0.4 mg MPT kg has on Wistar rats over 3 generations. Exposure to either DM or MPT in drinking water of the first generation (G1) began in 4-week-old males and females. Parental males were dosed until separation of females, and after mating the females were treated until separation, at 4 weeks old, from their G2 offspring. The G3 rats were produced in the same manner as the parental G2 rats. Selected 4-week-old males from each generation were also exposed to DM or MPT for 4 weeks. Only male offspring were evaluated for immune function. G1 males exposed to 14 mg DM kg had suppressed PFC response to SRBCs, as did G3 males exposed to 0.3 and 0.4 mg MPT kg. Peripheral blood leukocyte counts were decreased in G1 males exposed to DM, while MPT exposed G3 males had reduced thymus weights at 0.2, 0.3, and 0.4 mg MPT kg. There was no effect on the DTH response to KLH...

Proposed Content Of A Developmental Immunotoxicity Study

Although the need for developmental immunotoxicity testing has long been recognized by the scientific and regulatory communities (NRC 1993b USEPA 1999, 2002b), there is currently no formal EPA testing guideline protocol for this study. Studies have, however, been conducted in numerous laboratories to assess the developmental immunotoxic potential for a myriad of pharmaceuticals, pesticides, and environmental pollutants. Additionally, the National Toxicology Program (NTP) has devised an immunotoxicity testing battery (in adult mice) that has demonstrated the value of a combination of two or three immune system tests to achieve > 90 predictability of immunotoxic compounds in rodents (Holladay and Luster 1994). The use of multiple tests, both structural and functional, is an approach that is also applicable in assessing immunotoxicity in juvenile animals following developmental exposures. Recent scientific workshops on immunotoxicity conducted in 2001 by the International Life Science...

Polycyclic Aromatic Hydrocarbons

Exposure to these PAHs can cause cancer, and B(a)P is generally recognized as the most potent carcinogenic PAH (Urso and Gengozian 1984). In addition to being carcinogenic, PAHs can also induce immune suppression in humans and laboratory animals (Luster and Blank 1987). In coke oven workers, inhalation exposure to a mixture of PAHs lowered immunoglobulin levels, particularly IgG and IgA (Szc-zeklik et al. 1994). Suppression of cellular and humoral immune function has been demonstrated in adult mice. Adult female B6C3F1 mice were exposed to 10 different PAHs at subchronic exposures and immune response measured by antibody production to sheep red blood cells (White et al. 1985). Anthracene, chrysene, benzo(e)pyrene and perylene did not significantly suppress antibody production however, benz(a)anthracene, benzo(a)pyrene, dibenz(a,c)anthracene and dibenz(a,h)anthracene suppressed the antibody forming cell response by 55 to 91 . In another study, B6C3F1 mice demonstrated reduced antibody...

Differential Susceptibility Based On Life Stage

This chapter and book are concerned with the relative immunological risk of adults vs. nonadults following toxicant exposure. Several bases for probable differential risk are associated with the exposure of differential life stages to toxicants. First, different dose response relationships can exist where the no-observed effect levels (NOELs) may differ dramatically among life stages. Such differences could arise based on different pharmacokinetics across life stages or could be associated with differential susceptibility of the target organs (in this case the immune system) across life stages. Furthermore, it is possible that effects that are only transient following adult exposure might be permanent when exposure occurs to embryos, fetuses, or juveniles. Finally, because physiological systems such as the immune system are dynamically changing targets during early development, it is feasible that the nature of the changes to the immune system could differ based on the timing of...

Developmental Exposures and Lead Induced Immunotoxicity

The interaction between genotype and environmental exposure is coming under increased examination relative to the risk of asthma (Sengler et al. 2002). There is a strong link between the lead-induced increase in Th2 activity and the associated increases in cytokine and IgE levels. Obviously, segments of the population can vary genetically relative to Th1 vs. Th2 bias. Therefore, for a subpopulation already genetically predisposed more toward Th2 responses than Th1, even modest lead-induced elevations in Th2 cytokines could shift that population into a symptomatology range. This has led several authors to suggest that lead is a potential risk factor contributing to the rise in both childhood asthma and allergic disease (Rabinowitz et al. 1990 Dietert and Hedge 1998 Miller et al. 1998 Chen et al. 1999 Snyder et al. 2000). However, the developmental data also indicate that the risk to the immune system posed by lead exposure is likely to vary widely depending upon the specific life stage...

Developmental Immunotoxicity In Rodents Exposed To Therapeutic Immunosuppressants During Pregnancy

Tion, resulting in increased autoimmunity (i.e., syngeneic graft-vs.-host disease) in the host animals (Glazier et al. 1983). Such results raise clear questions about the ability of cyclosporine A to induce or exacerbate autoimmune disease in gestationally exposed individuals. In support of this possibility, newborn mice dosed daily with cyclosporine A for the first week of postnatal life developed organ-specific autoimmune disease (Sakaguchi and Sakaguchi 1988, 1989). Such disease elicited in rodents appeared to be related to interference by cyclosporine A with the production or expansion of self-reactive T cells in the thymus (Sakaguchi and Sakaguchi 1992). Similarly, Classen (1998) found that cyclosporine A exposure during pregnancy in mice greatly increased prevalence of autoimmune disease in the offspring. These collective observations in irradiated and perinatal rodent exposure models, where new immune systems are being established in the presence of cyclosporine A, may suggest...

Immunologic Observations In Children Of Organ Transplant Recipients

Transient neonatal leucopenia and hypoplasia of the lymphatic system were among the early observations in children exposed to cyclosporine A (Pickrell et al. 1988) or to azathioprine plus prednisolone (Lower et al. 1971 Cote et al. 1981) during gestation. Because of such reports, Takahashi et al. (1994) examined lymphocyte subpopulations in cord and peripheral blood of six infants born to mothers who had received renal transplants, compared to five control infants. All of the renal transplant mothers received cyclosporine A, azathioprine, and methylprednisolone throughout pregnancy. There were no differences between numbers of CD2+, CD4+, or CD8+ T cells in the immune-suppressant exposed offspring as compared to controls however, a significant reduction in B cells was present and sometimes severe at 1 and 3 months of age in the children from renal transplant mothers. The authors concluded that the B cell line may be more sensitive than the T cell line to the immunosuppressive therapy...

Vomitoxin Deoxynivalenol

Group B trichothecenes, such as vomitoxin (VT or deoxynivalenol) and similar metabolites 3-acetyl deoxynivalenol and nivalenol, are less toxic than the group A trichothecene T-2 toxin (Bergsj0 et al. 1993). Vomitoxin is produced by Fusarium graminearum and F. culmorum and is a common contaminate of grain used to make human and animal feed. Because it is not destroyed by milling and processing, vomitoxin could be present in human food products at ppm levels (Islam et al. 2003). Swine and other monogastrics are the most sensitive to VT while chickens and turkeys have the highest tolerance to VT (Rotter et al.1996). Ingestion of moderate to low levels can cause anorexia, decreased nutritional efficiency, and immunotox-icity manifest by reduction in natural immunity and poor production performance in food animals. Exposure to high concentrations of VT causes nausea, emesis, leukocyte apoptosis, and circulatory shock (Rotter et al. 1996). The effects of vomitoxin on immune function have...

Timing Of Immune Assays For Detecting Developmental Immunotoxicity

Development of the immune system has been more studied and better defined in the mouse than any other species (see Chapter 1). With this in mind, many immune function tests utilized in adult mouse models are not valid in perinatal mice simply because of the immaturity of their immune systems. Therefore, an adult mouse immunotoxicity risk assessment screening battery must be modified to be age-appropriate, if it is to be used for detecting postnatal immune deficits following prenatal chemical exposure. Several NTP assays are not functional assays, e.g., splenic cellularity, splenic and thymic organ to body weight ratios, leukocyte counts, and splenic lymphocyte surface antigen expression. These assays may have utility for detecting developmental immunotoxicity at very early ages, or even prior to birth (Holladay and Luster 1996). The considerable information available in the mouse as to when different arms of the immune system become functional at an adult level adds strength to the...

Therapeutic Immunosuppressant Levels In Mammary Gland Secretions

Ablactation has been recommended in women treated with cyclosporine A, cyclophosphamide, doxorubicin, and methotrexate, because these compounds have been shown to have high rates of transfer into breast milk (Wiernik and Duncan 1971 Johns et al. 1972 Amato and Niblett 1977 Flechner et al. 1985 Nyberg et al. 1998). Some drugs, including doxorubicin, concentrate beyond maternal blood levels in human milk (Egan et al. 1985). As much as 5 of an immunosuppressive dose of cyclosporine A can transfer from serum into the breast milk, with largely unknown side effects on the child's immune system being a significant concern (Behrens et al. 1989). The blood of newborns, prior to initiation of breastfeeding, can contain cyclosporine A concentrations up to 65 to 85 of maternal levels (Gunter et al. 1989). Notwithstanding, a recent case study described a 35-year-old woman who, while on cyclosporine A, breastfed her child for 10.5 months. The child showed no clinical developmental abnormalities nor...

Diethylstilbestrol And Steroid Hormones

The sensitivity of the thymus and T cell-mediated immunity to certain steroidal compounds, including glucocorticoids such as hydrocortisone, has been well established (Hendrickx et al. 1975 Kalland et al. 1978 Ways et al.1979). However, the role of other steroids such as sex hormones in the development of immunity remains poorly understood. A variety of reports have indicated that exogenously administered hormones, including testosterone (Warner et al. 1969), estrogen, and related compounds possessing estrogenic properties, can alter the normal development of the immune system (Luster et al. 1979 Kalland and Forsberg 1981 Ways et al. 1980 Blair 1981 Whitehead et al. 1981 Kalland 1982 Ford et al. 1983 Noller et al. 1988 Ways et al. 1987). The use of diethylstilbestrol (DES) from the 1940s to the 1970s to prevent threatened miscarriage in pregnant women was found to cause development of genital tract anomalies and neoplasia in a number of adult women exposed in utero (Ways et al. 1987)....

Chemical Targeting Of Immune Development

A growing literature base indicates that laboratory animals exposed in utero (during immune system development) to immunotoxic chemicals may result in severe effects on the immune system that last into adult life. For example, mice exposed to the organochlorine insecticide chlordane in utero have been found to display reduced numbers of granulocyte-macrophage colony-forming units (GM-CFU) and colony-forming units spleen (CFU-S) as early as gestational day (GD) 18 and the suppression extended to 200 days of age (Barnett et al. 1990). Previous studies with in utero chlordane exposure demonstrated long-term depression of the contact hypersensitivity response to oxazolone in mice at 101 days of age (Spyher-Cranmer et al. 1982). It is noteworthy that these immune effects are either reduced or not observed in adult mice exposed to chlordane at dose levels equal to those given to the pregnant mice (Johnson et al. 1986). Similar results have been reported in mice with in utero exposure to...

Endocrinedisrupting Compounds

A current public health issue concerns the fact that endocrine-disrupting chemicals (EDCs) may adversely affect human health in both children and adults (Colborn et al. 1993 Kavlock 1999 Landrigan et al. 2003 Longnecker et al. 2003 Rice et al. 2003). Recent experimental data suggest that EDCs affect not only the reproductive system but also the immune system, thereby raising additional concerns (Barnett and Rodgers 1994 Blake et al. 1997 Ahmed 2000). Fetal exposure to EDCs is of particular concern, since these chemicals could potentially alter critical immune developmental pathways, which may have long-lasting consequences. The development of the fetal immune system is tightly regulated to favor the selection of competent immune cells and to eliminate dangerous autoreactive lymphocytes. Any alterations in the normal fetal immune development (e.g., exposure to EDCs) may have permanent or long-lasting adverse consequences. immune abnormalities. Ahmed et al. (1999, 2000) have recently...

Tcdd The Prototypic Halogenated Aromatic Hydrocarbon

The halogenated aromatic hydrocarbon most studied for suppressive effects on the immune system is undoubtedly TCDD. However, other studies indicate that TCDD may also induce changes in immune cells and immune support cells that may potentiate development of autoimmune diseases. Greenlee et al. (1985) and Schuurman et al. (1992) described thymic epithelium as targets of TCDD. This suggests that TCDD may have the potential to alter critical epithelium-dependent selective events in the thymus that could lead to decreased or defective negative selection of developing thymocytes expressing autoreactive T cell receptors (TCR). DeWaal et al. (1992) further observed altered thymic epithelial distribution of major histocompatability complex (MHC) class II molecules in TCDD-treated mice. This effect was hypothesized as having potential to cause defective thymocyte-epithelial cell interactions. Specifically, MHC class I and class II molecules act as thymic self-antigen presenting molecules in a...

Common Effects of TCDD and CsA on T Cell Development

The developing immune system has been demonstrated to have a high sensitivity to TCDD. This, coupled with evidence that increased autoimmune disease may result following TCDD exposure in adult animals, has raised questions regarding possible relationships between prenatal exposure to TCDD and increased postnatal autoim-munity. Low-level maternal TCDD exposure results in atrophy of the developing thymus as well as inhibition of thymocyte differentiation (Table 13.2). T-progenitor cells from the fetal liver seed the developing thymus and are initially double negative (DN) with respect to CD4 and CD8 surface antigens. Subsequently, thymocytes develop sequentially through immature CD8lQ and CD4+8+ double positive stages in the thymic cortex, to mature CD4+ SP or CD8+ SP thymocytes in the thymic medulla by GD 18 to 19 (Hussman et al. 1988 Penit and Vaddeur 1989). TCDD produces a significant maturational delay in fetal thymocyte development as evidenced by these CD4 and CD8 surface...

Introduction Asthma An Allergic Response

Like an autoimmune disease or the rejection of a transplanted organ, allergic asthma is the result of an unwanted immune response. Characterized by episodes of usually reversible obstruction of the airways, bronchial hyperresponsiveness, and chronic inflammation with lung infiltration by lymphocytes, eosinophils, and mast cells, asthma is a respiratory response to a variety of stimuli. This disease is manifested by thickening of the bronchial mucosa and narrowing of airways, and most commonly results in coughing, wheezing, chest tightness, and shortness of breath (Koren and O'Neill 1998 Saltini et al. 1998).

Asthma The Role of Atopy Risk Factors and Maternal Exposures

People with atopy are genetically predisposed to produce IgE antibodies in response to common household allergens and have at least one atopic disease (i.e., asthma, allergic rhinitis, or atopic eczema) (Kay 2001). Most patients with asthma are atopic, although a minority have intrinsic, nonatopic asthma that often has a later onset and a more protracted course than atopic asthma. Recent studies indicate that there are more similarities than differences in the airway abnormalities of atopic and nonatopic asthma (Humbert et al. 1999). A large body of evidence shows that allergen exposure influences the atopic phenotype, and many studies indicate that allergen or toxicant exposure during critical windows of immune system development (in utero and early infancy) may influence a sensitization process that can lead to childhood asthma (reviewed in Landrigan 1998). Epidemiological data support the findings from these studies and highlight the role of maternal factors (Donovan and Finn 1999...

Asthma Toward a Molecular Understanding

Mechanisms related to immunotoxicants can only rarely be detailed. Nonetheless, data are available to implicate several environmental toxicants in the deviation of the immune response towards the development of asthma so that the interplay between genetics, environmental toxicants, and asthma onset can be appreciated and, in time, manipulated for better treatment or cure of this disease. The immunoregu-latory mechanisms vulnerable to alteration by the factors listed above will now be discussed, including the cells, cytokines, and signaling pathways involved in asthmatic inflammation.

Sensitization vs Triggering

Encountering any particular antigen (Ag) for the first time sensitizes, or primes, a developed immune system. This elicits a primary T cell response characterized by a relatively slow clonal expansion of antigen-specific T cells secreting a variety of cytokines of no particular biological focus. Sensitization of T cells also allows the immune system to react with a memory, or anamnestic, response upon a second exposure and all subsequent exposures to the same antigen. A memory T cell response is very different from a primary response. Thus, maturation of the immune response requires this initial exposure or sensitization. Memory T cells proliferate faster, require fewer activation signals than their na ve counterparts, and are able to migrate specifically, or home, to tissues in the body where an antigen-specific response is required (Caret et al. 1998 Carter and Swain 1998 Dutton et al. 1999 Early and Reen 1999a Hayward and Groothuis 1991). Besides these differences, memory T cells...

The Influence Of Maternalfetal Interactions On Allergen Sensitization In The Human Fetus And Neonate

Although much is known about sensitization and triggering of immune responses in human adults, a paucity of information exists regarding the normal course of these processes in fetuses. What is known about the interplay of antigens and allergens with the developing immune system in the intrauterine environment will now be presented, but much research is still required into the mechanisms of basic fetal sensitization and the neonatal triggering of normal and pathological immune responses. Developmental studies have detailed the emergence of the human fetal immune system (reviewed in Chapter 2). Although stem cells are seen in the human yolk sac at 21 days of gestation (Hayward 1981), lymphocytes do not populate the fetal thymus until 8 to 9 weeks of gestation. They then migrate to the circulation by approximately 14 to 16 weeks of gestation (Donovan and Finn 1999). B lymphocytes appear in several organs, including the lungs and gut, from 14 weeks of gestation, and by fetal week 19-20,...

Relationship between Allergens and Development of Asthma

The effect of maternal or neonatal exposure to any allergen during the development of the immune system on enhanced susceptibility to asthma must be explored further. What is known of the influence of common indoor allergens associated with asthmagenesis (asthmagens) will now be discussed.

Effects of ETS on Respiratory Health

There exists a significant body of research on the potential effects on respiratory health from exposure to environmental (passive) tobacco smoke (ETS) (reviewed in National Academy of Sciences 2000). Many components of ETS are known lung irritants. There have been direct associations shown between exposure to tobacco smoke and the development of lung cancer, obstructive airway disease, chronic bronchitis, ear infections, and asthma. It is small wonder that ETS is associated with so many disparate disorders, considering that tobacco smoke components include the carcinogens benzene, toluene, and 1,3-butadiene (Mitacek et al. 2002), toxicants such as nickel (Tobacco Research Implementation Group 1998) and polycyclic aromatic hydrocarbons (PAHs) (Besaratinia et al. 2002), and common household chemicals including ammonia, formaldehyde, and acetone (Tobacco Research Implementation Group 1998). Moreover, the effects of tobacco smoke are not limited to the active smoker but to anyone exposed...

Functional Assessments in Adult Animals

Indirect assessment of immune system function is conducted in adult animals of various ages via the evaluation of peripheral blood cells and chemistry in sub-chronic and chronic carcinogenicity studies. Specific direct functional assessments of the immune system in young adult animals are included only in the skin sensitization study (OPPTS 870.2600 USEPA 1998b) and the immunotoxicity testing guideline (OPPTS 870.7800 USEPA 1998L). These studies do not include a direct assessment of immune system function in either very young or very old animals. They incorporate only a few examples of potential immune system response (e.g., delayed hypersensitivity, humoral immunity, or nonspecific cell-mediated immunity). No assessment of autoimmune disease is conducted in any of the current guideline protocols. The skin sensitization study has been generally conducted in guinea pigs as a Guinea Pig Maximization Test (GPMT) or a Buehler test. In the future, skin sensi-tization methods will...

Signaling Pathways and Transcription Factors Involved in Asthma Pathogenesis

The biochemical signaling pathway of the IgE receptor FceRI, which includes activation of the protein-tyrosine kinase (PTK) Syk (Mackay and Rosen 2001), should also be scrutinized when assessing immunotoxicant effects on allergic asthma sensitization (Figure 14.2). Toxicants affecting Syk activity might increase FceRI-a signaling, a process central to the involvement of mast cells in the triggering of an asthmatic response. Other pathway intermediates intimately involved in allergic inflammation but yet to be investigated in the development of asthma include GATA transcription factors. Expression of GATA-1 has recently been shown to promote the development and terminal differentiation of eosino-phils, with eosinophil progenitors failing to develop in the fetal livers of GATA-1 deficient mice (Hirasawa et al. 2002). In the same report, GATA-2 was demonstrated to be able to compensate for GATA-1 deficiency in terms of eosinophil development in vivo (Figure 14.5). Recognizing that GATA-1...

Pyrethroid Insecticides Cypermethrin

A number of other neuroteratogens. including additional drugs of abuse (heroin and other opiates, cocaine, and so on), pesticides, and other toxicants, act diffusely in the brain, affecting many regions through neural pathways and neurotransmitter systems, resulting in many behavioral effects and additional peripheral organ defects. In addition, some of these agents, particularly the opioids, can act directly on immune cells. A great deal of information is available on the effects of these drugs on the immune system of adults however, their effects on the developing immune system are less well described than the examples provided above. To help address the role that the extensive sympathetic innervation of primary and secondary lymphoid organs plays in modulating immune responses, Alaniz et al. (1999) analyzed the immune response in dopamine p-hydroxylase deficient mice. These mice cannot produce norepinephrine (NE) or epinephrine (E), but can produce the precursor dopamine. Compared...

Summary

Hematopoietic and immune system development in rodents can be segmented into five critical windows based on organogenesis, cell migration, and maturation of immune function. This well-documented series of developmental events has resulted in a working hypothesis that critical windows of vulnerability to chemical exposure exist for the developing immune system, and these critical windows may be differentially susceptible to chemical exposure (Dietert et al. 2000). This hypothesis is currently being tested and will need to be considered in designing experimental protocols to determine acute and persistent immunotoxic effects of environmentally applied chemicals. It is also important to realize that renewal of immunocompetent cells in postnatal animals continues to depend on differentiation of stem cells and expansion of progenitor cells in the bone marrow. This process is fundamentally different in neonatal, young, and older animals. For that reason, developmental windows of...

Hematopoiesis

Stages of immune system development appear to be fairly conserved within mammals, so for the purposes of this review, when fundamental human data are unavailable, mouse data will be provided. A thorough review of the development of the immune system in mice is given in Chapter 1. In humans, the development of the immune system begins with HSC formation in the yolk sac from 15 to 18 days through 6 weeks of gestation, with the HSC becoming undetectable by the 10th week (Tavassoli 1991). (Definitive HSC in the mouse appear in the AGM region at 9 to 11 days postcoitus Muller et al. 1994 Nishikawa et al. 2001 Orkin and Zon 2002 ). Between the 5th and 8th weeks of human gestation, the fetal liver becomes the center of hematopoiesis (Bellanti et al. 2003 Cooper et al. 1993 Holt and Jones 2000 Tavassoli and Yoffey 1983 West 2002), with some activity persisting until shortly before birth (Cooper et al. 1993). The spleen also transiently participates in blood formation from 10 to 12 weeks post...

Microenvironments

In the bone marrow, stromal cells provide physical support as well as the growth factors and hormones important for the initiation of differentiation programs that produce the many cell lineages found there (reviewed in Chaplin 2003). Particularly significant for immune function is the development of natural killer (NK) cells, B lymphocytes, dendritic cells, and macrophages (Muramatsu 1993) in the bone marrow compartment. Moreover, precursors of T lymphocytes originate in the bone marrow but emigrate to the thymus for further differentiation.

Natural Killer Cells

Natural killler (NK) cells share a progenitor with T cells (Douagi et al. 2002 Ikawa et al. 1999 Raulet 2003 Rothenberg et al. 2003) but do not require the thymic microenvironment for maturation. Instead, strontium 89 and other agents that disrupt the bone marrow have been shown in mice to impair NK cell development (Kumar et al. 1979 Seaman et al. 1979). Moreover, a cytokine produced by bone marrow stromal cells, IL-15, plays a central role in NK cell development and survival (Kennedy et al. 2000 Lodolce et al. 1998). Administration of another factor produced by stromal cells, Flt3L, has been shown to cause expansion of NK cells (Brasel et al. 1996 Shaw et al. 1998). Very little is known about NK cell ontogeny in humans (Raulet 2003) however, Toivanen et al. (1981) reported that the development of functional NK cells in the human fetus occurs at 28 weeks of gestation. Moreover, levels of NK cells have been demonstrated to be significantly higher during fetal life than during the...

Complement

A discussion of the ontogeny of the immune system is not complete without mention of the 35+ plasma or membrane proteins that make up complement and that serve as an auxiliary defense system (Prodinger et al. 2003). The major complement component C3 appears in fetal tissues as early as 6 weeks of gestation, whereas C2 and C4 are not detected until 8 weeks of gestation (Adinolfi 1997). Regulatory proteins that protect the fetus from maternal complement such as decay-accelerating factor (DAF), membrane co-factor protein (MCP), and CD59 are expressed in the liver from at least 6 weeks of gestation (Simpson et al. 1993). Complement receptors CR1 and CR3 have been detected on monocytes and neutro-phils and on cells in the bone marrow, spleen, and thymus of 14-week-old fetuses (Adinolfi et al. 1988). Recently, Mastellos and Lambris have postulated that complement is crucial in ontogeny, not because of a role in immunity, but because of a role in modulating cellular responses and cell-cell...

Cyclosporin

Cyclosporin A (CsA), a fungal metabolite used in therapeutic immunosuppression for the prevention of human organ transplant rejection, has been found to produce autoimmunity in both rodents and humans (Holladay and Smialowicz 2000). Women who received CsA during their pregnancies often delivered prematurely or had babies that were small-for-gestational-age (SGA) and had birth defects (cataracts, cleft palate, dysmorphic facial appearance, and so on). CsA has been found to prevent activation of CD8+ cytotoxic T-cell precursors by interfering with selective events during critical periods in thymocyte differentiation and clonal deletion. CsA also interferes with deletion of autoreactive T-cells after bone marrow reconstitution which in turn induces a variety of autoimmune responses in adult rodents. After exposure to CsA, fetal thymic organ cultures demonstrated that mature T-cell generation was completely blocked. These studies support the concept that the fetal immune system could be...

Combined Studies

While a developmental immunotoxicity study could be conducted as a standalone study, there are a number of reasons to consider a combined study design, which incorporates immunotoxicity endpoints into another study protocol. A combined study avoids the conduct of a separate developmental immunotoxicity study (thereby reducing the number of animals required for testing), provides an opportunity to more efficiently utilize offspring that are already in a study, and often maximizes exposure to the developing organism. For example, immunotoxicity assessments could be incorporated into a multigeneration reproductive toxicity study. This study includes test substance exposure to developing animals during in utero and postnatal life stages, coinciding with the ontogeny of the immune system. Publications by Chapin et al. (1997) and Smialowicz et al. (2001) have demonstrated success in conducting such combined studies. Protocol adjustments that must be addressed when attempting to incorporate...

Hexachlorobenzene

The effects that HCB has on immune system development in the rat were reported in studies by Vos et al. (1979a 1983). Pregnant Wistar rats received diets containing 50 or 150 mg HCB kg starting on day 1 to 3 of pregnancy and through gestation and lactation. Pups were weaned after PND 21 and continued on the same HCB dose as their dams for an additional 2 weeks prior to testing at 5 weeks of age (Vos et al. 1979a). Either male or female offspring, but not both, were evaluated for alterations in immune endpoints. The weight of the adrenal glands and livers of female pups exposed to 150 mg HCB kg was increased, as were total serum IgM and IgG concentrations. Body, spleen, and thymus weights of females were not different from controls. In both dosage groups, males infected with Listeria mono-cytogenes displayed reduced resistance to this bacterial infection, as did a separate set of males infected with Trichinella spiralis . In both dosage groups, females had increased IgM and IgG...

Cypermethrin

Santoni et al. (1997 1998 1999) examined the effects that cypermethrin, administered by gavage in corn oil during gestation, has on the developing immune system of rats. Pregnant Wistar rats were exposed to 50 mg cypermethrin for 10 days from GD 7 to GD 16. Pups were euthanized on PND 15, 30, 60, 90, or 120 and evaluated for immune dysfunction. There was no evidence of toxicity, as demonstrated by normal pregnancies, no mortality, and no loss of body weight compared to controls in the offspring. Male and female offspring results were grouped together consequently, information relative to potential gender susceptibility to prenatal cyper-methrin exposure is not available.

Heptachlor

Rats were evaluated using a battery of immune function tests, including splenic LP responses to mitogens splenic lymphocyte flow cytometry phenotype analysis MLR assay NK cell activity DTH response to BSA CHS response to DNFB and the antibody response to SRBCs, as determined by an enzyme-linked immunosorbent assay (ELISA). persisted for up to 20 weeks after the last exposure to HEP, at all of the doses employed, including the lowest dose that resulted in HEPX concentrations in the dam's milk comparable to those detected in human milk on Oahu, Hawaii, in 1981 (Baker et al. 1991 Siegel 1988). The persistent suppression of the anti-SRBC response occurred consequent to a total exposure of approximately 1.5 mg HEP kg rat. Evaluation of the antibody response to SRBCs in HEP-exposed dams, 6 to 8 weeks after parturition, indicated no alteration in this immune response (Smialowicz 2002). Taken together, these results indicate that perinatal, but not adult, exposure to HEP results in persistent...

Acyclovir

The effect that prenatal exposure of rats to acyclovir has on immune system development was examined by Stahlmann et al. (1992). Pregnant Wistar rats were exposed to 100 mg acyclovir kg body wt either with one or three (i.e., 1x100 and 3x100, respectively) s.c. injections on GD 10. There was considerable mortality during the first week after birth of pups from dams given 3x100 mg acyclovir kg. Body weights of 12-week-old offspring born to dams exposed to 3x100 were reduced by 12.5 to 18.8 compared to controls for males and females respectively. Thymus

Dexamethasone

Dexamethasone (DEX) is a synthetic adrenocortical steroid that suppresses inflammation and normal immune responses. It is used systemically and locally to treat chronic inflammatory disorders, severe allergies, lymphomas, shock, CNS trauma, and to reduce high blood calcium levels. DEX has also been used in preterm infants to decrease morbidity and mortality associated with bronchopulmonary dysplasia and to prevent chronic lung disease consequent to neonatal respiratory distress syndrome (Mammel et al. 1983 Cummings et al. 1989). DEX therapy improved pulmonary and neurodevelopmental outcomes in very-low-birth weight infants at high risk for bronchopulmonary dysplasia (Cummings et al. 1989). DEX treatment also hastened weaning infants from mechanical ventilation however infections occurred in a substantial proportion of patients studied by Mammel et al. (1983). Peritoneal macrophages from 9- to 11-week-old neonatally exposed DEX female rats produced decreased levels of TNF-a and IL-1 a...

Postnatal Adaptation

Ovalbumin-fed animals were used to follow antigen uptake by the sow and transfer of antigen and specific antibodies to the offspring via colostrum (Telemo et al. 1991). After antigen feeding during gestation and lactation, the antigen was tolerated by the piglets however, antigen feeding during lactation alone resulted in induction of IgG antibody production and diarrhea (Bailey et al. 1994b). These experiments demonstrate the immunological competence of the porcine fetus and newborn against environmental antigens. The immune response may be tolerance or defense against the antigen. In lymph duct cannulation experiments in young pigs, the nutritional uptake of antigens was described (Kiriyama et al. 1988).

Teratology Studies

Safety assessment studies of pharmaceuticals have typically involved administration of the test compound during the embryonic period, when the organ systems form, which encompasses GD 20 to 50 in the commonly used species, the rhesus and cynomolgus macaques. With the emergence of biopharmaceuticals, the safety assessment protocols have been altered to provide for longer exposure of the con-ceptus to include a significant portion of the fetal period. This period is characterized by rapid growth of the fetus and differentiation of organ systems, including the fetal immune system. The fetal period in the macaque extends from GD 50 to term (GD 155 and 165 in the cynomolgus and rhesus, respectively). Many protocols now include administration of the test compound until GD 70 to 100 (Figure 7.7). Future protocols involving immunomodulatory agents will probably include exposure throughout pregnancy (i.e., GD 20 to term) in certain cases, exposure may include the early postnatal period (i.e.,...

Organotins

Organotins have a wide variety of industrial and commercial applications including use as wood preservatives, agricultural pesticides, chemical catalysts, plastic heat stabilizers, marine antifoulants, and curing agents (Piver 1973). Certain dialkyl-and trialkyl-substituted organotins (e.g., di-n-octyltin dichloride DOTC and di-n-butyltin dichloride DBTC , and tributyltin oxide TBTO ,) alter the structure and function of the thymus and consequently affect primarily T cell-dependent immune function in rodents. There is evidence that rat natural killer (NK) cell activity is also affected by organotins (Pennicks and Pieters1995). Early work by Seinen et al. (1977 1979) demonstrated that pre- and or postnatal exposure of Wistar-derived WAG rats to either DOTC or TBTO results in suppression of the DTH response, antibody response to SRBCs, and graft-vs.-host response. Female rats were dosed by gavage with 0, 5, or 15 mg DOTC kg body wt or with 0, 1, 3, 5, or 15 mg DBTC kg body wt starting...

Diazepam Valium

A study by Livezey et al. (1986) demonstrated that the offspring of SD pregnant rats, given daily subcutaneous (s.c.) injections of 6 mg DZP kg on GD 15-20, had lower plasma total IgG concentrations, higher numbers of leukocytes, and higher incidence of uterine, lung, and skin infections as well as tumors, compared to controls. These DZP-induced adverse effects on the developing immune system were confirmed and extensively expanded upon by Schlumpf et al. (1995). Pregnant Long Evans (LE) rats were given DZP at 1.25 mg kg in sterile olive oil, from GD 14 to GD 20, via s.c. injection. This dose resulted in drug tissue concentrations in the nanomolar range, comparable to the upper human treatment range. At birth no drug was detectable in dams or pups (Schlumpf et al. 1992). TNF-a production by spleen cells following stimulation by LPS, but not ConA, was reduced compared to control in 2- and 4-week-old males from dams exposed to DZP on GD 14 to 20. When splenic lymphocytes and macrophages...

Methoxychlor

The first pesticide examined was methoxychlor (MXC) (Chapin et al. 1997) an organochlorine pesticide which is more readily metabolized and excreted than is dichlorodiphenyltrichloroethane (DDT), and which is widely used for insect and larval control. MXC is one of only four remaining chlorinated pesticides approved for use in the U.S. because of these qualities. Timed-bred SD pregnant dams were dosed by gavage with 5, 50, or 150 mg MXC kg d starting on GD 14 through PND 8, and then their pups, normalized to four of each sex litter, were gavaged until PND 42. Immune function evaluation of the pups so exposed, which consisted of spleno-cyte mitogen LP responses, NK cell activity, PFC antibody response to SRBCs, and flow cytometry phenotypic analysis of splenic lymphocytes, occurred at 8 to 9 weeks of age. Of the immune system parameters examined only the PFC response to SRBCs was suppressed in males but not females. A 35 and 42 suppression of the PFC response was observed at 5 and 50 mg...

Lead

A variety of environmental and occupational metals have been identified that alter immune function in humans and laboratory rodents (Zelikoff and Thomas 1995). One such metal is lead, a naturally occurring element found in the earth's crust as well as throughout the biosphere. Present-day concentrations of lead in the atmosphere are due primarily to anthropogenic sources, with insignificant contribution from natural sources. Lead exposure to both humans and animals at sufficiently toxic doses results in renal, hematopoietic, and central nervous system dysfunction. Lead has also been demonstrated to be a potent immunotoxicant in mice and rats as well as a developmental immunotoxicant in rats. Early work by Luster et al. (1978) and Faith et al. (1979) examined the developmental immunotoxic effects of chronic pre- and postnatal exposure of rats to low levels of lead acetate in drinking water. Weanling (21-day-old) female Sprague-Dawley (SD) rats were exposed to lead acetate at...

Mycotoxins

Mycotoxins are compounds produced by molds, which are toxic when consumed or inhaled. They differ from other environmental chemical agents in that they are naturally occurring fungal metabolites and are found primarily on moldy grains. Mycotoxins in general are relatively heat-stable and persist as a toxin in cooked and processed foods. They are well recognized as a human health hazard, causing both acute toxicosis and carcinogenesis. Allowable mycotoxin levels in human and animal food products are regulated in most countries. A number of mycotoxins are immu-notoxic to adults and a few are immunotoxic to the developing immune system. Trichothecenes (T-2 and vomitoxin), aflatoxins, and ochratoxin are discussed here.

Trichothecenes

Trichothecenes are produced by Fusarium spp. and can be present in grains such as wheat, corn, oats, and barley. They are also present in the spoors of molds that grow on cellulose-based building materials, providing a route of human exposure through inhalation. Exposure to high doses of trichothecenes, both experimentally and accidentally, causes rapid decreases in lymphoid organ size, lymphopenia, and death from a circulatory shock-like syndrome (Bondy and Pestka 2000). Chronic exposure also seems to target the immune system and can cause either immunosuppression or immunostimulation, depending on the dose and length exposure to the toxin. Trichothecene toxins are closely related and classified into groups based on chemical structure. Group A trichothecenes include T-2 toxin, which is generally considered to be the most toxic trichothecene. Group B tricothecenes include deox-ynivalenol or vomitoxin (VT), 3-acetyl deoxynivalenol, and nivalenol, and are less toxic than T-2 toxin...

Aflatoxins

Aflatoxins are toxic metabolites of the fungi genus Aspergillus, particularly A. flavus and A. parasiticus, found predominantly on corn, cornmeal, and other plant products such as nuts. The biologically active aflatoxins are termed AFB1 and AFG1 and are found in grain products AFB1 can be metabolized to another toxic derivative, AFM1, which can be found in animal products including milk (Silvotti et al. 1997). Aflatoxins are lipophilic and disseminate in the fat and other soft tissues. Aflatoxins can depress immune function in humans, pigs, guinea pigs, lambs, chicks, and rats, with altered macrophage function and depressed cell mediated immunity resulting in decreased resistance to disease (Silvotti et al. 1997 Fern ndez et al. 2000 Qe lk et al. 2000 Doi et al. 2002 Theumer et al. 2003).

Mercury

Increase in anti-DNA antibody titer (U.S. DHHS 1999a Cardenas et al. 1993). Additionally, T cells are stimulated with increases in CD3+, CD4+ and CD8+ cells. In mice, mercury vapor and mercuric chloride both induced a syndrome similar to the autoimmune response in humans characterized by general stimulation of the immune system, hyperimmunoglobulinemia, anti-nucleolar autoantibodies, and glomerular disease accompanied by vascular immune complex deposits. Mercury stimulated or suppressed immune responses depending on genetics and susceptibility of the mouse strain. Immune hyperreactivity and autoimmunity were seen in SJL N mice, but immune responses were suppressed in B6C3Fj mice (U.S. DHHS 1999a). B6C3Fj mice exposed to 2.9 or 14.3 mg Hg kg day as mercuric chloride in the drinking water demonstrated a suppression of lymphocyte proliferation to T cell mitogens. When SJL N mice were exposed to mercuric chloride, antinucleolar antibodies were observed and deposition of granular IgG in...

Ochratoxin A

Ochratoxin A is a mycotoxin produced by Aspergillus ochraceus and Penicillium verrucosum and is found worldwide as a food contaminant. It is known to cause porcine nephropathy and may be associated with a human kidney disease endemic to the Balkan region (Bondy and Pestka 2000). Mice and rats exposed to ochratoxin A in utero had altered immune responses compared to controls. A single dose of och-ratoxin A (10 to 500 mg kg) to pregnant mice decreased thymic CD4+ and increased thymic CD4+CD8+ lymphocyte populations while suppressing splenic and thymic lymphocyte responses to mitogens in the pups (Thuvander et al. 1996a). In rat pups, thymic weights and cellularity were not affected, but splenic cell mitogen responses were suppressed with maternal exposure to ochratoxin A (Thuvander et al. 1996b).

Cadmium

There is little information available on the developmental immunotoxic effects of cadmium. Many authors have demonstrated cadmium transfer across the placenta and alterations in development of human and animal fetuses following maternal exposure to cadmium (U.S. DHHS 1999b). Even low-dose exposure to cadmium during gestation and lactation results in fetotoxicity, characterized predominantly by decreased birth weight, neurophysiologic dysfunction, and skeletal deformities (Branski 1985 Kostial et al. 1993 Nagymajtenyi et al. 1997 Desi et al. 1998). Given that cadmium exposure affects adult immune responses, and that cadmium readily crosses the placenta affecting neurophysiologic responses of the offspring, the possibility exists for immunologic deficits in neonates resulting from in utero cadmium exposure. The close association and interrelatedness in function between neurological and immunologic processes makes this possibility even greater. Further studies are warranted to determine...

Chromium

In adults, exposure to chromium by inhalation, oral or dermal contact can cause skin sensitization and eruptions, urticaria, a chromium-induced asthma, and bron-chospasms accompanied with tripling of plasma histamine levels (U.S. DHHS 2000). Cellular changes include leucocytosis or leucopenia, eosinophilia, monocytosis, and changes in the number and function of alveolar macrophages. Additionally, chromium exposure increases serum immunoglobulin levels and stimulates T cell mitogen responses (U.S. DHHS 2000). Overall, chromium causes a dysregulation of immune function resulting in immunostimulation.

Xirradiation

During organogenesis of the immune system, as well as after birth, the hemato-poietic tissues are highly susceptible to damage from irradiation. The effects of irradiation have been described as varying from abnormal immune responses to imbalances in blood cell populations and leukemias (Boniver and Janowski 1986 Miller and Benjamin 1985 Nold et al. 1987). Lymphocytes, and in particular lym-phoid progenitor cells in the bone marrow, are known to be among the most sensitive cells to radiation injury (Miller and Benjamin 1985 Nold et al. 1987 Platteau et al. 1989). Dose-response studies on the effects of prenatal exposure to single or sub-chronic low-dose X-ray exposure on subsequent development of the immune system in experimental animals or humans is, as is the case with many of the preceding developmental immunotoxic agents, extremely limited. An early study reported impaired antibody production in adult mice irradiated with a single 0.5 Gy dose of x-rays at either day 5 or between...

Section Summary

Although the cellular and molecular processes involved in allergic sensitization differ from those initiated when an asthmatic response is triggered, allergic asthma is a pathologic secondary immune response resulting from re-exposure to an allergen encountered earlier. Chronic activation of allergen-specific T cells and associated airway eosinophilia cause the remodeling of airway tissue architecture characteristic of asthmatic inflammation. Mechanistically, these processes result from the activity of B cell-derived, allergen-specific IgE molecules and the degranulation of FceRI-bearing mast cells. The subsequent release of inflammatory mediators leads to contraction of smooth muscle cells and bronchoconstriction, vasodilation and lowered blood pressure, and increased vascular permeability and edema. An important feature of the pathogenesis of asthma is the recruitment by cytokines of eosinophils and other inflammatory cells. In general, the hypersecretion of mucus, shortness of...

Fetal IgE

Several studies indicate that increased cord blood levels of IgE are associated with an increased risk of atopy or asthma (Croner and Kjellman 1990 Edenharter et al. 1998 Halonen et al. 1992 Hansen et al. 1992 Hide et al. 1991 Kjellman and Croner 1984 Michel et al. 1980 Ruiz et al. 1991). Other studies do not bear out this association (Hide et al. 1991 Martinez et al. 1995). However, a general belief is that an early and inappropriate immune response can develop toward allergens and that young children with asthma or allergic rhinitis have higher than normal levels of antibodies to inhaled allergens (Okahata et al. 1990). The evidence that fetal B cells are capable of isotype switching supports this idea (Punnonen et al. 1993 Punnonen and de Vries 1994). Furthermore, production of IgM, IgG subclasses, and IgE response to CD40 ligation and cytokines from T cells is similar in neonatal B cells and antigenically na ve adult B cells (Briere et al. 1994 Servet-Delprat et al. 1996),...

Pesticides

Exposure to pesticides has been reported to cause a number of immunotoxic effects hypersensitivity, autoimmunity, modulation of immune function, and clinical immunosuppression. Several authors have recently reviewed pesticide immunotox-icity (Banerjee 1999 Colosio et al. 1999 Thomas 1995 Vial et al. 1996 Voccia et al. 1999). The majority of studies investigating the effects of pesticides on the human immune system involve relatively high-level occupational exposures. Few studies have investigated pesticide immunotoxicity in the general population at relevant, environmental exposure levels (Thomas 1995). Several studies in animals have shown that prenatal and neonatal exposure to organochlorine pesticides, such as chlordane, toxaphene, and hexachlorobenzene, does have significant effects on the developing immune system. These effects on the immune system are persistent and occur at dose levels that do not elicit effects in adult animals. However, the endpoints assessed in the studies...

Heavy Metals

The immunotoxic effects of heavy metals, such as lead, arsenic, and mercury exposure are well recognized (Bernier et al. 1995 Schuppe et al. 1998). In comparison to most environmental toxicants, the mechanism of metal immunotoxicity is well studied (reviewed in Schuppe et al. 1998). It is currently believed that metals initially elicit a cell-mediated immune response by binding to MHC class II molecules or MHC-bound self-peptides. The metal-MHC complex is then recognized by CD4+ T cells. Additionally, metal-induced alteration of self-peptides may also cause activation of autoreactive T cells. In hypersensitivity responses, such as contact allergy, CD8+ T cells may also be involved. In addition, metals may alter the T cell repertoire and influence the TH1 TH2 ratio (see previous section The TH2-bias of the Neonatal Immune System). Results from recent in vitro studies are consistent with the hypothesis that metals, such as mercury and lead, inhibit the production of TH1 cells and...

Chapter Summary

The purpose of this chapter was to address the influence of maternal fetal immu-notoxicant exposure on the development of asthma. Deciphering exactly how developmental exposures can lead to postnatal asthma onset or affect the sensitivity to triggers of asthmatic attacks remains an elusive goal due to insufficient evidence and a lack of mechanism studies. This chapter provided a molecular overview of asthma sensitization and triggering, asthmatic inflammation, and the inter- and intracellular mediators that may be affected by toxicants and allergens during asthma pathogenesis. Following this molecular review were discussions of the influences of maternal-fetal interactions during physiologic fetal sensitization and the development of normal immune responses. The processes involved included the generation of atopy-related fetal IgE, the bias towards a TH2 phenotype in the neonatal immune system, and the genetic components of asthma sensitization. The chapter concluded with discussions...

Nicotine

Immune deficits following developmental nicotine exposure from early gestation to adolescence have also been observed (Basta et al. 2000 Navarro et al. 2001a Navarro et al.), and are suspected to be a result of a combined altered CNS peripheral nervous system input. A 2-week gestational exposure to infused nicotine was shown to induce neonatal abnormalities of both T-lymphocyte and B-lymphocyte function (Basta et al. 2000). The pattern of immune deficits was similar to the pattern of neural effects produced by gestational exposure. In both the immune and nervous system, defects were observed during the early neonatal period in the treated animals, which resolved to some extent by weaning but which reemerged during adolescence and persisted into adulthood. Therefore, just as in the brain, immune deficits were maintained well after the cessation of nicotine exposure suggesting, as before, that nicotine-induced actions on the developing immune system permanently affect the programming of...

Ethanol

Immune deficits have also been seen after gestational exposure to ethanol. Human and animal studies have frequently demonstrated a decrease in T cell number (Ewald and Walden 1988 Ewald 1989) and function (Basham et al.1998 Chang et al. 1994 Gottesfeld and Ullrich 1995 Monjan and Mandell 1980 Norman et al. 1989 Redei et al. 1989 Seelig et al. 1996 Tewari et al. 1992 Weinberg and Jerrells 1991) with gestational or neonatal exposures of varying length. The majority of these studies delivered ethanol in a chronic dosage as a component of a liquid diet or in the drinking water. This chronic-exposure regimen produced more consistent immune deficits than have binge-drinking models (Basham et al. 1998). However, just how these immune alterations are related to the produced neural defects is unclear. One potential mechanism whereby the extensive CNS changes might affect offspring immune function is via the second messenger alterations to the muscarinic cholin-ergic system. Alternatively, it...

Alcohol

A number of studies have shown that consumption of alcohol inhibits immune function in both adult humans and animals (Jerrells et al. 1986). In adults, ethanol is immunosuppressive, decreasing both the cellularity of the thymus and spleen and interfering directly with B and T-lymphocyte responses. Additionally, alcohol suppresses the phagocytic activity of macrophages and reduces NK cell activity (Seelig et al. 1996). Ethanol consumption alters cytokine production, including IL-2, IL-5, IL-6, IL-10, and reduces the capacity of T cells to use IL-2. TNF-a production was impaired as was the distribution of TNF-a receptor on alveolar macrophages (Seelig et al. 1996). Experimental animals exposed to prenatal alcohol exhibit suppressed immune function. Specifically, animals exposed during development to alcohol displayed decreased lymphocyte response to the mitogens con A and LPS, reduced serum IgM and IgG levels, reduced specific antibody production to T-dependent antigen, suppressed IL-2...