Click for next page ( 141


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 140
Induced Immunodeficiencies Small rodents are used extensively to study experimentally induced im- munosuppression and, occasionally, through a variety of circumstances, are also the unintended objects of induced immunosuppression. The following discussion will provide the reader with examples of agents that advertently or inadvertently induce suppression of immune responses in rodents. A com- plete review of this subject can be found in Immunotox~cology of Drugs and Chemicals, 2d ed. (Descotes, 19881. CHEMICAL INDUCERS A wide variety of chemicals and drugs have been used, particularly in the mouse, to study and measure immune function and suppressive effects. Te- trachlorodibenza-p-dioxin (TCDD) and polybrominated biphenyls (PBBs), for example, have been shown to generally impair immune responsiveness, and Tris depresses cell-mediated immunity (Luster et al., 19871. Diethylstilbestrol The immunosuppressive effects of diethylstilbestrol (DES) and a variety of other nonsteroidal and related estrogenic compounds have been studied in detail. DES is a recognized stimulant of the reticuloendothelial system (RES) in adult mice; however, when female mice are exposed to DES in utero or postnatally, thymic involution is induced (Luster et al., 19791. In addition, both T-cell-dependent and T-cell-independent antibody responses 140

OCR for page 140
INDUCED IMMUNODEFICIENCIES 141 are suppressed, hypersensitivity responses are delayed, lymphoproliferative responses to T-cell mitogens are increased, and the numbers of hematopoietic stem cells and granulocyte-macrophage precursors in the bone marrow are depressed. Male mice exposed to DES in utero respond with an enhanced T-cell-dependent antibody response. Heavy Metals Heavy metals such as lead and cadmium can impair immune responsive- ness. Although accidental exposure to toxic amounts of heavy metals in the laboratory environment would be unusual, the investigator should be aware of the influence that heavy metals can have on the immune system. Lead Lead has been shown to increase the susceptibility of rats and mice to bacterial, viral, and protozoa! challenge (Koller, 19811. Lead-treated animals express decreased PMN phagocytic activity, and immunoglobulin and com- plement responses are reduced when lead-treated animals are subjected to active immunization regimens. Lead appears to block complement receptors on B lymphocytes (Koller and Brauner, 19771; however, lead does not sig- nificantly alter MLC responsiveness (Koller and Roan, 1980) or lymphocyte transformation by ConA and LPS (Koller et al., 19791. Lead also inhibits mitogenic responsiveness to PHA and pokeweed mitogen (PWM) and impairs the delayed-type hypersensitivity response. Cadmium Acute exposure to cadmium appears to produce mixed immunorespon- siveness in mice and rats; however, chronic exposure results in a suppression of antibody responsiveness that lasts for several weeks after exposure ceases (Koller et al., 19751. IgG is most affected, but Th cells can also be involved. E-rosette formation of alveolar macrophages and cytotoxicity of phagocytic cells have also been demonstrated (Hadley et al., 1977; Loose et al., 1978b). Cell-mediated immune responses to cadmium are mixed: The LPS response is enhanced, PHA and PWM responses are suppressed, and the MLC response is not affected (Koller, 19811. Phenols Archer et al. (1981) have summarized the effects of selected phenols on the immune system of mice. Butylatedhydroxyanisole (BHA), garlic acid (GA), and propylgallate (PG) suppress the primary anti-SRBC PFC response

OCR for page 140
142 IMMUNODEFICIENT RODENTS of mouse spleen cells. GA and PG also reduce the secondary response, but BHA does not. BHA, but not GA, suppresses the thymus-independent an- tibody response of nude mice. Alkylating Agents Alkylating agents are potent immunosuppressants in animals and humans. It is unlikely that accidental exposure would occur in experimental animals; however, these agents have been used extensively to study immune system function, particularly in mice. Alkylating agents suppress primary T-cell- dependent antibody responses when they are given prior to antigenic exposure (Ghaffer et al., 1981) or shortly after priming. They do not affect secondary responses unless the agent is administered after exposure to the antigen. Glucocorticoids Glucocorticoids are potent immunosuppressants in small rodents and are sometimes used as diagnostic aids to potentiate the expression of subclinical infections such as mouse hepatitis virus (MHV) and Pneumocystis car~nii. An immunoinhibitory role of glucocorticoids has been suggested from the observations that in rodents, thymic atrophy results from the administration of exogenous glucocorticoids or from prolonged stress (Stein, 19851. Al- though the effect of glucocorticoids on murine and guinea pig lymphocytes is much greater than that seen in humans, there is ample evidence that glucocorticoids have some inhibitory activity in all mammalian species stud- ied (Claman, 1972; Calvano, 19861. In rodents, the administration of glucocorticoids appears to have opposing effects, resulting in both the enhancement of antibody production (Bradley and Mishell, 1981 ~ and T-cell depletion (Durant, 19861. Recently, in vitro studies have demonstrated that human CD8 + T cells are more sensitive than Th cells to the effects of glucocorticoids (Paavonen, 19851. Other immu- nologic changes resulting from the administration of glucocorticoids include a depression in NK cell function (Fernandes et al., 1 975), T-cell blastogenesis (Blomgren and Andersson, 1976), graft-versus-host reactions (Medawar and Sparrow, 1956), and delayed-type hypersensitivity (Gabrielsen and Good, 19671. It has also been postulated that glucocorticoids affect immune cells by modulating the activity of macrophages. Warren and Vogel (1985) have shown that the gamma-interferon-induced increase in murine macrophage Fc-mediated phagocytosis is enhanced by glucocorticoids, while the levels of Ia antigen are decreased. Besedovsky et al. (1985) have provided evidence that stimulated rat mononuclear cells produce the hormone glucocorticoid increasing factor (GIF), which increases adrenal glucocorticoid output by a

OCR for page 140
IND UCED IMMUNODEFICIENCIES 143 mechanism that requires the pituitary gland. One candidate for this GIF activity is IL-1, which has been shown to possess corticotropin-releasing activity (Woloski et al., 19851. Exogenously administered glucocorticoids can profoundly affect the sus- ceptibility of rodents to several infectious agents (Robinson et al., 19741. Glucocorticoids compromise the ability of rodents to combat infections caused by Salmonella typhimurium and Babesia rodhaini (Plant et al., 1983; Ziv- kovic et al., 1985) and make them susceptible to clinical illness caused by Pneumocystis carinii and Bacillis piliformis, which generally are not asso- ciated with overt disease (Hughes et al., 19831. A review of the action of glucocorticoids, cyclophosphamide, and other immunosuppressive drugs has been published recently (Sternberg and Parker, 19881. INFECTIOUS AGENTS Infectious agents and their products can be potent modifiers of the immune response through a number of mechanisms, including antigenic competition, preemption of antigen-reactive cells, activation of suppressor cells and gen- eration of suppressive factors, lymphocytotoxicity, RES blockade, and al- terations in lymphocyte interactions (Weidanz et al., 19781. Small rodents have been used extensively to study many aspects of infec- tion-regulated immunosuppression and are frequently victims of adventitious infections in the experimental laboratory. Considerable variation in response can be expressed by different rodent strains to such agents as Sendai virus (Parker et al., 1 978J, ectromelia virus (Bhatt and Jacoby, 1 986; Wallace and Butler, 1986), and MHV (Levy et al., 19811; however, specific immunologic perturbations caused by these agents are not always well identified. Levy et al. (1981) have related MHV susceptibility directly to an increased coagu- lation protease activity by host monocytes following T-cell instruction. Boor- man et al. (1982) have demonstrated peritoneal macrophage activation in C57BL/6 x C3H F~ hybrids accidentally infected with MHV. These mac- rophages expressed increased tumor cell killing activity and had highly con- voluted cell membranes. Mouse thymic virus, an uncommon herpesvirus that attacks the thymus gland of neonates causing severe thymocyte necrosis, diminishes the reactivity of spleen cells to T-cell mitogens and allogeneic cells. Thymocytes express a marked reduction in graft-versus-host reactivity during a period of several weeks after infection. Spleen cells are similarly affected, but lymph node cells are not (Cross et al., 19761. Conversely, induced immunosuppression can lead to activation of latent or persistent murine infections such as parvoviruses (Tattersall and Cotmore, 1986), K virus (Greenlee, 1981), mouse adenovirus (Hashimoto et al., 1973), cytomegalovirus (CMV) (Osborn, 1986), and others that interfere with ex- perimental results by causing mortality or shifts in baseline values. Elimi

OCR for page 140
144 IMMUNODEFICIENT RODENTS nation of adventitious infections by using sound colony management procedures and reliable suppliers is considered to be an important method for refining animal experimentation. NUTRITION Malnutrition is associated with atrophy of the thymus, Peyer's patches, Hassall's corpuscles, and T-cell-dependent pericortical and periarterial areas of lymph nodes and the spleen, respectively. There is also a reduction in primary follicles and in delayed-type cutaneous hypersensitivity. Humoral responses are less affected. Chronic restriction of protein results in depressed production of antibodies, and severe protein restriction depresses both hu- moral and cellular immunity (Jose and Good, 1973a,b). Calorie restriction can also reduce humoral response and increase T-cell suppressor activity (Fernandes et al., 1975; Fernandes, 1984~. An increase in dietary polyun- saturated fatty acids (PUFAs) inhibits the cell-mediated immune (CMI) re- sponse and cytotoxicity in the in vitro 5iCr release assay (Merlin, 19761. Protein calorie malnutrition can reduce antibody affinity for antigens (Katz, 1978~. The lymphocytes of malnourished individuals have a reduced in vitro response to PHA stimulation. This might reflect deficient T-cell function or reduced numbers of T cells. Dietary deficiencies of certain trace elements can have a profound sup- pressive effect on immunity in rodents. Rats fed magnesium-deficient diets develop thymomas, leading to an immunodeficient state (Bois et al., 1969; Hass et al., 1981; Averdunk et al., 19821. Moreover, magnesium-deficient diets lead to a reduction of serum immunoglobulins in the rat (Alcock and Shils, 1974; Rayssiguier et al., 19771. Deficiency of dietary zinc results in thymic atrophy and reduced Th cell function in mice (Fraker et al., 19771. Inadvertent general malnutrition in laboratory rodents is rare, provided that standard commercial diets are fed. Impaired immunity caused by the accidental exclusion of specific nutrients also appears to be rare. The role of diet on immune function in rodents has been reviewed recently (ICLAS, 1987~. IONIZING AND ULTRAVIOLET RADIATION Ionizing radiation serves as the classic example of a method for experi- mentally inducing immunosuppression in rodents, particularly the mouse. Radiation biologists who used this technique soon found that lethally or sublethally irradiated mice died more quickly than expected if Pseudomonas aeruginosa was present in the oral cavity or gastrointestinal tract. Further- more, mice maintained under conventional conditions exhibited a wide var- iation in morbidity and mortality when they were exposed to total lymphoid

OCR for page 140
INDUCED IMMUNODEFICIENCIES 145 irradiation (TLI) with specific shielding to protect bone marrow. This was apparently due to the presence in the holding rooms of endemic viral and bacterial organisms. Following TLI, B-lymphocyte numbers begin to rise in about 2 weeks; however, T lymphocytes remain completely suppressed for about 2 months, and T lymphocytopenia persists in the mouse for about 1 year (Slavin et al., 1977~. TLI modifies the MLR by heightening the response of peripheral blood lymphocytes (PBLs) to allogeneic lymphocytes while suppressing the re- sponse to syngeneic lymphocytes. The response of PBLs to ConA is initially suppressed but soon exceeds control values; the response to PHA is impaired for prolonged periods (Strober et al., 19791. Although most subpopulations of spleen cells are at normal values by 1 month after TLI, TL+ (immature T) cells in spleen and lymph node populations are elevated. The reason for this is not entirely clear. Allograft survival approaches five times the control value following TLI, is about two times the control value if the thymus is shielded during irradiation, and is lower still if only the thymus is irradiated (Slavin et al., 19771. Antibody response to SRBCs is eliminated for about 1 month following TLI. Subsequently, IgM is produced, but {gG is not seen until about 7 months following TLI, and then it is produced at reduced levels. Irradiation of the thymus or subdiaphragmatic tissue has only a small effect on the response to SRBCs (Strober et al., 19791. Immunosuppression caused by ionizing radiation is a function of cell pop- ulation sensitivity to the killing effect of the radiation. Among the most sensitive populations are stem cells. Small lymphocytes are also highly ra- diosensitive (Casarett, 19801. Thus, ionizing radiation-induced immuno- suppression is broad based and profound at relatively modest whole-body dose levels. Exposure to ultraviolet radiation (UVR) also results in modifications to immunologic response. UVR reduces the density of Langerhans' cells ex- pressing Ia and membrane-bound adenosine triphosphatase (ATPase), inter- feres with the antigen-presenting capacity of epidermal cells, causes an unresponsiveness to contact allergens, and interferes with the rejection of highly antigenic UVR-induced tumors (reviewed by Breathnach and Katz, 19861. Little is known about microwave irradiation, although some of its non- thermal effects on antibody production and numbers of antibody-producing cells have been reported (Czerski et al., 19741. BIOLOGICAL INDUCERS Biological materials are commonly used as immunosuppressants in labo- ratory rodents. Among the most potent are anti-lymphocyte serum (ALS) and anti-theta serum, with or without added complement. Interferon poly(A

OCR for page 140
146 IMMUNODEFICIENT RODENTS U), transplanted tumors, and stress are also potent immunosuppressants (Chen and Goldstein, 1985; Johnson, 19851. Immunologic tolerance to specific antigens can be induced in neonatal rats and mice by transferring syngeneic spleen cells coupled with a palmitoyl derivative of protein antigens. This produces carrier-specific tolerance in mice, which is thought to be caused by the induction of T-cell tolerance and T-cell suppression and appears to decrease the T-cell help needed by specific B cells (Sherr et al., 1979~. Glucan taQ-~1,3-glucosidic polyglucose)] is a potent RES stimulant; how- ever, it depresses NK cell activity in mice and might promote tumor growth (Lotzova and Gutterman, 1979~. Neoplasms can cause immunosuppression by invading and destroying nor- mal immune system tissues, by serving as functional modulators of immune capacity (e.g., plasmacytomas or type-specific lymphocytomas), or by pro- moting uneven stimulation of immune modulators. The effects of stimulating the activity of intrinsic factors such as lymphokines, monokines, and thymic hormone are not always clear-cut; such stimulation might lead to immuno- suppression (e.g., the possible promotion of T suppressor cells by thymosin and thymopoietin) (Chen and Goldstein, 19851. THYMECTOMY Surgical extirpation has long been used as an experimental method for ablating or modulating the immune response of small rodents. Thymectomy, including neonatal thymectomy, is a valuable experimental tool for immu- nologic investigation. Surgical ablation of the thymus gland has been shown to compromise immune function in mammals and birds (Miller et al., 19629. The procedure, which has been described for both rodents and birds by Hudson and Hay (1976), must be performed within 24 hours of birth in mice for maximal T-cell depression. Neonatally thymectomized mice that are not maintained under germfree conditions develop a wasting syndrome between 1 and 3 months of age, which possibly results from their inability to combat various infectious agents (Miller et al., 19621. Male mice thymectomized on the third postnatal day develop spontaneous autoimmune prostatitis at puberty by autosensitization to antigens that are normally expressed during prostate differentiation (Taguchi et al., 19851. The study of neonatally thymectomized mice has been instrumental in delineating the T- and B-cell systems. Miller and Mitchell (1969) demon- strated that there is a reduced number of splenic PFCs when thy~nectomized mice are challenged with SRBCs. Similarly, Davies (1969) demonstrated a decreased response of humoral antibodies of the IgG (mercaptoethanol-re- sistant) class in thymectomized mice injected with horse erythrocytes. Neo- natal thymectomy has been associated with a diminished humoral response

OCR for page 140
INDUCED IMMUNODEFICIENCIES 147 to a vaccine strain of Japanese B encephalitis virus (Mori et al., 1970) and herpes simplex virus (A. C. Allison, Clinical Research Centre, Harrow, Middlesex, England, unpublished data). The ability of the thymectomized host to combat infections has also re- ceived attention. Thymectomized mice inoculated with ectromelia virus de- veloped a fatal, generalized infection (Allison, 19741. Likewise, thymectomized mice inoculated with herpes simplex virus type 1 developed fatal encephalitis (Mori et al., 1967~. It is of interest, however, that thymectomized mice did not die following experimental infection with lymphocytic choriomeningitis virus (Levey et al., 1963), which is known to be mediated by T cells. There is a decreased ability to expel Trichinella spiralis because there is no increase in intestinal mast cell numbers associated with the parasitism in neonatally thymectomized mice (Brown et al., 19811. In this model the normal function of intestinal mast cells is dependent on the presence of thymic-derived lym- phocytes. Development of the nude mouse, and more recently the nude rat, has diminished the need for thymectomy procedures. Spleen cells from thym- ectomized mice express increased lytic activity against syngeneic neoplasms in vitro. Thymectomized polyomavirus-infected mice have been shown to have higher neoplasm rates than normal controls. Splenectomy and lymphadenectomy are also used as immune system mod- ulators in small rodents, although the latter is less commonly used.