Immunological function in mice exposed to JP-8 jet fuel in utero.

Immunological parameters, host resistance, and thyroid hormones were evaluated in F1 mice exposed in utero to jet propulsion fuel-8 (JP-8). C57BL/6 pregnant dams (mated with C3H/HeJ males) were gavaged daily on gestation days 6-15 with JP-8 in a vehicle of olive oil at 0, 1000, or 2000 mg/kg. At weaning (3 weeks of age), no significant differences were observed in body, liver, spleen, or thymus weight, splenic and thymic cellularity, splenic CD4/CD8 lymphocyte subpopulations, or T-cell proliferation. Yet, lymphocytic proliferative responses to B-cell mitogens were suppressed in the 2000 mg/kg treatment group. In addition, thymic CD4-/CD8+ cells were significantly increased. By adulthood (8 weeks of age), lymphocyte proliferative responses and the alteration in thymic CD4-/CD8+ cells had returned to normal. However, splenic weight and thymic cellularity were altered, and the IgM plaque forming cell response was suppressed by 46% and 81% in the 1000 and 2000 mg/kg treatment groups, respectively. Furthermore, a 38% decrease was detected in the total T4 serum hormone level at 2000 mg/kg. In F1 adults, no significant alterations were observed in natural killer cell activity, T-cell lymphocyte proliferation, bone marrow cellularity and proliferative responses, complete blood counts, peritoneal and splenic cellularity, liver, kidney, or thymus weight, macrophage phagocytosis or nitric oxide production, splenic CD4/CD8 lymphocyte subpopulations, or total T3 serum hormone levels. Host resistance models in treated F1 adults demonstrated that immunological responses were normal after challenge with Listeria monocytogenes, but heightened susceptibility to B16F10 tumor challenge was seen at both treatment levels. This study demonstrates that prenatal exposure to JP-8 can target the developing murine fetus and result in impaired immune function and altered T4 levels in adulthood.     

Immunosuppression following 7,12-dimethylbenz[a]anthracene exposure in B6C3F1 mice. I. Effects on humoral immunity and host resistance

It has previously been demonstrated that the polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene (B[a]P), suppresses the terminal step in B-cell differentiation, resulting in a decrease in antibody production to T-dependent and B-2 T-independent antigens. The purpose of this study was to ascertain if this effect was common to carcinogenic PAHs or specific for B[a]P. The PAH 7,12-dimethylbenz[a]anthracene (DMBA) was administered to B6C3F1 female mice by ten sc injections of 0.5, 5, or 10 micrograms/g over a 2-week period (i.e., total dose of 5, 50, and 100 micrograms/g). Immune function and host resistance assays were performed 3 to 5 days following the last injection. The 10 micrograms/g dosage resulted in a marked decrease in spleen weights and spleen and bone marrow cellularity, while thymus and body weights were not significantly altered. The ability to generate B-lymphocyte colonies in vitro from spleen precursor cells was also suppressed at the 10 micrograms/g dose. Exposure to DMBA at 5 micrograms/g or greater resulted in a reduction of up to 97% in the number of IgM plaque-forming cells in response to the T-dependent antigen sheep red blood cells (SRBC). The IgG response to SRBC was similarly depressed. The IgM response to the hapten-conjugated T-independent antigens trinitrophenyl-lipopolysaccharide (TNP-LPS) (specific for B-1 cells) and trinitrophenyl (TNP)-Ficoll (specific for B-2 cells) was also depressed (88 and 97%, respectively) at 10 micrograms/g. DMBA exposure resulted in an increased susceptibility to challenge with the PYB6 transplantable sarcoma and the bacterium Listeria monocytogenes, in contrast to B[a]P exposure, which had no effect on host resistance assays. Thus, DMBA, a more potent carcinogen than B[a]P, produces a more extensive B-cell suppression than B[a]P as well as alters host resistance to tumor and bacterial challenge.     

Immunotoxicity of bis(tri-n-butyltin) oxide in the rat

Previous studies in the rat have shown that bis(tri-n-butyltin) oxide (TBTO), used as a biocide, was immunotoxic at dose levels that did not affect other organs. In order to determine a no-effect level, weanling rats were treated for at least 28 consecutive days with TBTO at 0, 0.5, 2, 5, or 50 mg/kg of diet. Studies on clinical chemistry, hematology, pathology, and immune function, that is, plaque-forming cell (PFC) assay, delayed-type hypersensitivity (DTH) response, and the splenic clearance of Listeria monocytogenes, were performed at the end of treatment. No treatment-related effects were noted on clinical chemistry and hematology parameters and on PFC and DTH response, whereas thymic atrophy and impaired clearance of L. monocytogenes were noted only at a dietary concentration of 50 mg/kg. These results confirm the thymus as a target organ of TBTO immunotoxicity. Under the conditions of these experiments the dietary concentration of 5 mg/kg, equivalent to a dose of 0.5 mg/kg body weight, represents a no observed effect level (NOEL) for immunotoxicity in the Sprague-Dawley rat.     

Modulation of cell-mediated resistance to listeriosis in mice given T-2 toxin

The modulating effect of preinoculation and postinoculation treatment with a single oral 4.0 mg/kg dosage of T-2 toxin on cell-mediated resistance was studied in mice inoculated with Listeria monocytogenes. Toxin treatment caused significant decreases in thymus and spleen weights, bone marrow cellularity, and in the total number of circulating leukocytes, lymphocytes, and neutrophils. Enhancement or suppression of resistance to listeriosis was dependent on the time of toxin administration relative to the time of Listeria challenge. Preinoculation treatment on Day 2 or 4 prior to Listeria challenge significantly enhanced resistance and decreased mortality due to listeriosis by as much as 50%. In contrast, resistance was suppressed and mortality was increased by 50% in mice that were treated with toxin after Listeria challenge. Enhanced resistance to listeriosis was accompanied by a significant increase in the influx of macrophages into Listeria-elicited peritoneal exudates. In addition, in vivo phagocytosis of sheep red blood cells by peritoneal macrophages was significantly increased in toxin-treated mice that were sensitized with sheep erythrocytes. The data indicate that T-2 toxin has a modulating effect on cell-mediated resistance and that enhancement of resistance to listeriosis in mice pretreated with T-2 toxin is associated with increased migration/activation of macrophage effector cells.     

Toxic effects of benzene and benzene metabolites on mononuclear phagocytes

Benzene is a potent bone marrow toxin in animals and man. Animal studies have shown that exposure to benzene can alter T lymphocyte functions and decrease the resistance of animals to Listeria monocytogenes and transplanted tumor cells. Mononuclear phagocytes participate in host resistance to Listeria and tumor cells. The purpose of the studies presented here was to determine the effects of benzene and benzene metabolites on macrophage functions and the ability of macrophages to be activated for functions which are important in host defense. Benzene had no effects on macrophage function or activation for any of the functions tested. Conversely, metabolites of benzene, catechol (CAT), hydroquinone (HQ), benzquinone (BQ), and 1,2,4-benzenetriol (BT) had potent and varied effects on macrophage function and activation. BQ inhibited the broadest range of functions including release of H2O2, Fc receptor-mediated phagocytosis, interferon gamma priming for tumor cell cytolysis, and bacterial lipopolysaccharide (LPS) triggering of cytolysis. BQ was also the most potent metabolite causing inhibition at lower concentrations than the other metabolites. HQ inhibited H2O2 release and priming for cytolysis and BT inhibited phagocytosis and priming for cytolysis. CAT only inhibited the release of H2O2. None of the compounds tested inhibited the induction of class II histocompatibility antigens on the cell surface. All of the effects measured occurred using concentrations of compounds which did not disrupt the cell integrity or inhibit general functions such as protein synthesis. Taken together these data suggest that benzene metabolites alter macrophage function through several mechanisms including inhibition of output enzymes and disruption of signal transduction systems.     

The pathologic and immunologic effects of inhaled acrolein in rats

Four groups of 40 male Sprague-Dawley rats each were exposed by inhalation to target concentrations of 0, 0.1, 1.0, and 3.0 ppm of acrolein 6 h/day, 5 days/week for 3 weeks. Subsequent changes in local pulmonary immunity were determined by examining the number of antibody plaque-forming cells in the lung-associated lymph nodes following intratracheal immunization with sheep red blood cells. Separate groups of rats were evaluated for blastogenic responsiveness to phytohemagglutinin-P and Salmonella typhimurium antigen using spleen- and lung-associated lymph node cells. In vivo resistance was evaluated utilizing acrolein-exposed rats subsequently challenged with intravenous Listeria monocytogenes. Local pulmonary antibody responsiveness was not affected by acrolein exposure. Lymphocyte blastogenesis and resistance to Listeria challenge were not altered. Body weights and spleen weights were decreased in the 3 ppm-exposed group only. Microscopic examination of the nasal turbinates revealed acrolein-induced exfoliation, erosion, and necrosis of the respiratory epithelium as well as squamous metaplasia, however, lung histology was not affected. Thus at environmental concentrations, acrolein toxicity appeared to be confined to local nasal pathologic changes with no alterations in lung histology or immune function.     

A predictive F344 rat immunotoxicology model: cellular parameters combined with humoral response to NP-CgammaG and KLH

The purpose of this study was to examine the predictive value of humoral and cellular immune parameters in determining the immunotoxic effects of the oral administration of azathioprine (AZA), cyclophosphamide (CY), or cyclosporin A (CsA) at doses of 25/17, 10, or 25 mg/kg per day, respectively, for 30 days in F344 female rats. The effect of these known immunosuppressive compounds on the immune response was assessed in a humoral model that consisted of the administration of nitrophenyl-chicken gamma globulin (NP-CgammaG) and keyhole limpet hemocyanin (KLH) antigens during immunosuppressive treatment and the measurement of resulting rat antigen-specific IgG and IgM, as well as total IgG, levels. Cellular assessment parameters were collected from the same groups of animals as the humoral parameters and included organ weights and cellularity, hematology, lymphocyte phenotype characteristics, spleen cell mitogen stimulation (T and B cell-dependent), splenic natural killer (NK) cell cytotoxicity, and bone marrow cellularity and lymphocyte phenotype differential. Although decreases in several of the cellular assay parameters were observed, the only functional assays to demonstrate a statistically significant immunosuppressive effect by all three immunosuppressive agents were the antigen-specific serum IgG levels. The primary (day 10; 15 days post-immunization) and secondary (day 25; 5 days post-rechallenge) nitrophenyl (NP) responses were significantly suppressed by > or =60%. The use of NP hapten provided consistent responses when analyzed with a sensitive, well developed, ELISA methodology. Absolute lymphocyte phenotyping and lymphocyte hematology were also predictive of T cell immunosuppression for all three compounds. The data presented herein suggests that these two parameters, NP-IgG humoral response and lymphocyte phenotyping, are sufficient for identifying immunosuppressive compounds.     

The Effects of Allyl Isovalerate on the Hematopoietic and Immunologic Systems in Rodents

The Effects of Allyl Isovalerate on the Hempatopoietic and ImmunologicSystems in Rodents. HONG, H. L., HUFF, J. E., LUSTER, M. I.,MARONPOT, R. R., DIETER, M. P., HAVES, H. T., AND BOORMAN, G.A. (1988). Fundam. Appl. Toxicol. 10, 655–663. FemaleB6C3F1 mice plus male and female Fischer 344/N rats were gavagedwith allyl isovalerate (AIV) in corn oil at 0, 31,62, or 125(mice) and 0, 31. 62, 125, or 250 (rats) mg/kg body weight forfive daily exposures per week for a 2-week period. Hematologic,immunologic, and histopathologic studies were performed 48 to72 hr following the final treatment. AIV exposure had no effecton hematology or bone marrow cellularity in mice or rats. AIVexposure at 250 mg/kg was toxic to rats causing reduced weightgain and hepatotoxicity. In vivo and in vitro studies revealedthat pluripotent hematopoietic stem cells (CFU-S) and granulocyte-macrophageprogenitors (CFU-GM) in the bone marrow were decreased in thetreated mice. Hematopoietic suppression was correlated withthe reduction in the hexose monophosphate shunt metabolism ofbone marrow cells but the Embden-Meyerhof pathway and tncarboxylicacid pathway enzymes did not appear to be affected. Examinationof host resistance following Plasmodium and Listeria challengedid not demonstrate significant differences between treatedand control mice, nor were there other effects on the immunesystem. This suggests that the myelotoxic effects were minimaland of a degree that would not alter host resistance.     

Immunological studies in B6C3F1 mice following exposure to ethylene glycol monomethyl ether and its principal metabolite methoxyacetic acid

Exposure to glycol ethers has been associated with adverse effects in laboratory animals including thymus atrophy and mild leukopenia. These effects may involve depletion of immunoresponsive cells. This study examined possible alterations in immune function and host resistance of B6C3F1 mice following exposure to ethylene glycol monomethyl ether (EGME) or its principal metabolite, methoxyacetic acid (MOAA). EGME and MOAA were administered by gavage to mice in 10 doses over a 2-week period at total dosages of 250, 500, and 1000 micrograms/g of body weight. Following exposure, immunopathology, humoral immunity, cell-mediated immunity, macrophage function, and host resistance to Listeria monocytogenes bacterial challenge were examined. A 48% reduction in thymus weight was observed at the intermediate and high doses of both chemicals. No significant alterations in immune function or host resistance to L. monocytogenes were observed in animals exposed to either EGME or MOAA.     

The effect of dimethylnitrosamine on host resistance and immunity

Adult female B6C3F1 mice were injected ip with 0.2 ml phosphate-buffered saline (PBS) only or PBS containing 1.5, 3, or 5 mg dimethylnitrosamine (DMN)/kg body wt daily for 14 days. On Day 16, mice were evaluated for changes in immune status as measured by the antibody response to sheep red blood cells (SRBCs), blastogenesis to T- and B-cell mitogens, natural killer (NK) cell function, delayed hypersensitivity, and alveolar macrophage (AM) bactericidal activity; and for changes in host resistance following challenge with various microorganisms or tumor cells. DMN-exposed animals exhibited reduced humoral antibody responses, T-cell mitogenesis, and AM bactericidal activity. B-cell mitogenesis, NK cell activity, and delayed hypersensitivity were increased. Resistance to challenge with Listeria monocytogenes, Trichinella spiralis, or Herpes simplex types 1 or 2 virus (HSV-1, HSV-2) was not significantly impaired, while that to Streptococcus zooepidemicus and influenza virus was significantly reduced. Resistance to B16-F10 tumor challenge was enhanced following DMN exposure. The data show that DMN treatment altered humoral immunity and antibody-mediated host defense mechanisms. Increased NK cell activity may account for the increased resistance to challenge with Herpes virus and B16-F10 tumor cells.     

Effect of sinomenine on antibody responses in mice

Sinomenine, an epimorphinan alkaloid, was tested for the immunosuppressive effect in mice. This compound produced a decrease of plaque-forming cells (PFC) to a T cell-dependent antigen, sheep red blood cells, in vivo. The depression of the PFC response induced with sinomenine was dose and time dependent. On the other hand, it failed to suppress the PFC response to a T cell-independent antigen, lipopolysaccharide. The immunosuppressive dose of sinomenine did not alter the cellularity of spleen, thymus, bone marrow and peripheral blood leucocytes, the DNA synthesis activity of bone marrow cells nor the proliferative responses of spleen cells induced by T cell and B cell mitogens in unprimed mice. These data suggest a selective effect of sinomenine on lymphoid cells. This compound has a potential for use in studies of immuno-deficiencies or clarifying some aspect of immunity.     

Suppression of immune response in the B6C3F1 mouse after dietary exposure to the Fusarium mycotoxins deoxynivalenol (vomitoxin) and zearalenone

The effect that dietary exposure to the naturally-occurring Fusarium graminearum toxins deoxynivalenol (DON) and zearalenone (ZEA) may have on immune function was assessed in the B6C3F1 mouse. Dietary DON depressed the plaque-forming response to sheep red blood cells, the delayed hypersensitivity response to keyhole limpet haemocyanin and the ability to resist Listeria monocytogenes. Listerial resistance was similarly decreased in control mice fed restricted diets comparable to the dietary restriction caused by DON-induced feed refusal, whereas equivalent food restriction did not decrease the plaque or delayed hypersensitivity responses. ZEA ingestion decreased resistance to L. monocytogenes but did not affect splenic plaque-forming or delayed hypersensitivity responses. Resistance to Listeria was reduced to a greater extent by co-administration of DON and ZEA than by DON alone, whereas the ability of DON to inhibit the delayed hypersensitivity response was significantly lessened in the presence of ZEA. While effects on resistance to Listeria and delayed hypersensitivity were detectable in mice ingesting the mycotoxins for 2-3 wk, these effects disappeared upon extension of the feeding period to 8 wk. In contrast, some effect on the plaque-forming response was detectable with both the 2- and the 8-wk period of mycotoxin ingestion. Immunosuppression can thus result from ingestion of F. graminearum-infected agricultural staples, the suppression being attributable to interactions between direct immunotoxic effects of DON and ZEA and nutritional effects associated with DON-induced food refusal.     

Prophylactic administration of Withania somnifera extract increases host resistance in Listeria monocytogenes infected mice

In this study, we demonstrated that Withania somnifera L. extract (WSE) protects mice from a lethal dose of Listeria monocytogenes when administered prophylactically at 100, 250 and 500 mg/kg for 10 days, with survival rates up to 30%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with L. monocytogenes, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Investigation of the production of colony-stimulating factors (CSFs) revealed increased colony-stimulating activity (CSA) in the serum of normal and infected mice pre-treated with WSE. Further studies to investigate the levels of interferon-gamma (INF-gamma) and lymphocyte cell proliferation were undertaken. We observed dose-dependent increases in cell proliferation and in the levels of INF-gamma in mice infected with L. monocytogenes and treated with WSE. All together, our results suggest that WSE indirectly modulates immune activity and probably disengages Listeria-induced suppression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow, proliferation of lymphocytes and increased INF-gamma levels.     

Early Effects of Lead on Bone Marrow Cell Responsiveness in Mice Challenged with Listeria monocytogenes

Early Effects of Lead on Bone Marrow Cell Responsiveness inMice Challenged with Listeria monocytogenes. KOWOLENKO, M.,TRACY, L., AND LAWRENCE, D. Fundam. Appl. Toxtcol. 17, 75–82.Listeria monocytogenes challenge of lead-treated mice resultsin increased mortality. Since macrophage development constitutesthe initial phase of the immune response to L. monocytogenes,bone marrow and spleens from Pb-treated mice that were infectedwith L. monocytogenes were analyzed for their ability to formcolonies when exposed to the macrophage growth factor CSF-1.Serum colony-stimulating activity also was evaluated. Data obtainedindicate the Pb exposure results in decreased responsivenessof bone marrow and spleen cells to CSF-1 while colony-stimulatingactivity in serum rises. This lack of bone marrow-derived macrophagedevelopment may contribute to the increased mortality observedwith L. monocytogenes challenged, Pb-treated mice.     

Examination of immune parameters and host resistance mechanisms in B6C3F1 mice following adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Adult female B6C3F1 mice were given a single ip dose of 0, 01, 1.0, or 10.0 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and examined for immune function and host resistance 7-10 d later. Exposure to TCDD resulted in a significant dose-related decrease in induction of both IgM and IgG antibody-forming cells. This suppression was noted for both T-dependent and T-independent antigens. TCDD at a dosage of 10 micrograms/kg was shown to suppress production of antibody to viral hemagglutinin. In contrast, TCDD exposure had no significant effect on natural killer cell function, production of interferon, or various parameters of macrophage function. Assessment of host resistance revealed a significant increase in susceptibility to fatal infection with influenza virus, but no significant alteration in susceptibility to infection with the bacterium Listeria monocytogenes.     

Effects of exposure to benzene in vivo on the murine mononuclear phagocyte system

Exposure to benzene has been shown to decrease resistance to challenges by Listeria monocytogenes or tumor cells in mice. Alterations of T-lymphocytes have been suggested as one probable cause. Macrophages are also critical participants in resistance to Listeria and to tumor cells. We have previously shown that exposure of macrophages in vitro to benzene metabolites, but not to benzene, inhibited several functions of macrophages that are critical for host resistance. The present studies were conducted to determine the effects of exposure to benzene in vivo on the murine mononuclear phagocyte system. Treated animals received daily subcutaneous injections of benzene (800 mg/kg) for 5 days. Macrophages were obtained by lavage from the peritoneal cavity after ip injection of sterile eliciting agents. Enumeration, peroxidase histochemistry, and a series of functional assays were performed. Animals exposed to benzene displayed a decreased number of macrophages elicited by peptone injection. Specific alterations of macrophage functions included a 50% decrease of Fc-receptor-mediated phagocytosis and 70% inhibition of tumor cell cytolysis but an enhancement of TPA-stimulated H2O2 release. There was no effect on interferon-gamma stimulated expression of Ia antigen. The observations that the elicited macrophage populations were composed of newly immigrated cells and that benzene treatment was terminated 3 days before the functional analyses were performed suggest that benzene was affecting monocytes in the blood and precursor cells in the bone marrow. Alterations of macrophage functions in injection controls suggested that determining the primary effect of exposure to benzene may be complicated by the inflammation induced by treatment at the site of injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of prenatal exposure of mice to cigarette smoke on offspring immune parameters

While direct exposure to cigarette smoke (CS) was shown in numerous human and animal studies to impair host immune responses, effects on the offspring following in utero CS exposure are relatively unknown. Thus, a toxicological study was performed that extended our previous investigations examining the effects of relatively low-dose CS exposure on immune tumor surveillance parameters of the prenatally exposed offspring. In the current study, pregnant B6C3F1 mice were exposed by inhalation to mainstream CS (at a concentration equivalent to smoking approximately 1 pack of cigarettes/d) for 5 d/wk, 4 h/d from gestational day 4 to parturition. Smoke-induced effects on a number of immune parameters were examined in 3- (and/or 5-), 10-, and 20-wk-old male and female offspring, including lymphoid organ weight/cellularity; blood and bronchopulmonary lavage cell numbers/profiles; splenic lymphocyte proliferation; mixed lymphocyte reactions; and, host resistance against transplanted melanoma cells. Exposure in utero to CS significantly increased circulating white blood cell and lymphocyte numbers in both sexes for up to 2.5 mo after birth (compared to their age-/sex-matched, air-exposed counterparts). In addition, 3-wk-old male and female offspring from smoke-exposed mothers had decreased mitogen-stimulated T-lymphocyte proliferation, while 5-wk-old male pups had increased mixed lymphocyte response compared to their sex-matched, air-exposed counterparts. Although effects of prenatal smoke exposure on overall offspring immunity were relatively modest, these findings could suggest that early toxic insult by CS may alter subsequent immune homeostasis in the offspring, leading, possibly, to changes in disease vulnerability.     

Immune Function and Host Defense in Rodents Exposed to 60-Hz Magnetic Fields

This study was conducted to evaluate the influence of sub-chronicexposure to pure, linearly polarized 60-Hz magnetic fields (MF)on the host immune response in mice. The experimental designwas as follows: three groups were exposed continuously (18.5hr/day) to MF at field strengths of 0.02, 2, or 10 gauss (G),one group was exposed intermittently (1 hr on/l hr off) to MFat a field strength of 10 G, and one group served as a shamcontrol. Experimental endpoints included spleen and thymus weightsand cellularity, antibody-forming cell (AFC) response, delayed-typehypersensitivity (DTH) response, splenic lymphocyte subset analysis, susceptibility to infection with Listeria monocytogenes,and natural killer (NK) cell activity. No differences in bodyweight, lymphoid organ weight, or lymphoid organ cellularitywere ob served in any MF-exposed group in comparison to shamcontrols. Likewise, no statistically significant differenceswere found in com parisons of AFC responses. Isolated statisticallysignificant differ ences from control were observed in MF-exposedmice in the DTH assay, although no clear dose-related patternof altered activity was seen. Splenic lymphocyte subset parametersexamined were within normal limits in all groups, and no differencesbetween control and MF-exposed mice were found. Host resistanceto bacterial infection was not altered at any MF exposure examinedin this study. Finally, although apparently dose-related, statisticallysignificant alterations were observed in an initial study ofNK cell function, repeat studies failed to demonstrate a consistentpattern of alteration.     

Protective effect of Nocardia rubra cell wall skeleton on experimental infection in normal and immunosuppressed mice

The protective effect of Nocardia rubra cell wall skeleton (N-CWS) on experimental infections was investigated in normal and immunosuppressed mice. Pretreatment with N-CWS provided protection against acute systemic infections due to Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Listeria monocytogenes in normal mice. N-CWS administered before or after challenge also showed protective activity against Herpes simplex virus infection in normal mice. N-CWS was the most effective against extracellular parasitic Pseudomonas aeruginosa infection when administered 1 day before challenge, but displayed the most potent protective activity against infection with Listeria monocytogenes, a facultative intracellular parasite, when administered 7 to 14 days before challenge. In mice with subcutaneous Pseudomonas aeruginosa infection, N-CWS suppressed abscess formation and decreased the viable cell count in the resultant abscess foci when administered either intraperitoneally or subcutaneously to the infected site. In addition, treatment with N-CWS markedly restored host defense ability against pseudomonal infection in mice immunosuppressed with cyclophosphamide, hydrocortisone and X-ray irradiation.     

The effect of diethylstilbestrol as measured by host resistance and tumor susceptibility assays in mice

As part of a program to develop and validate methodology to measure chemically induced immunotoxicity, the effect of DES on resistance of adult B6C3F1 female mice to various microorganisms and to challenge with syngeneic tumor cells was evaluated. The mice received sc injections of 50 microliter corn oil alone or of corn oil containing the equivalent of 0.2, 1, and 4 mg DES/kg X d for 14 d. Three days later they were challenged with Listeria monocytogenes, Streptococcus sp. influenza virus, herpes virus, Trichinella spiralis, or B16-F10 tumor cells. Host resistance parameters were mortality for the bacterial and viral systems, expulsion of adult parasites from the gut for T. spiralis, and lung weights for the B16-F10 tumor-cell model. Host resistance to L. monocytogenes, herpes virus, and T. spiralis was significantly decreased following DES exposure. Resistance to Streptococcus sp. was decreased, but not at a statistically significant level following these doses of DES. However a dose of DES at 8 mg/kg X d resulted in a highly significant decrease in resistance to the organism. Resistance to influenza virus was unaffected by the DES. In contrast to the above, host resistance to iv-administered B16-F10 tumor cells was significantly increased as a consequence of DES exposure. These model systems for measuring alterations in host resistance have been indicated to hold potential for the routine screening of drugs, chemicals, and environmental agents for their possible immune effects, both adverse and potentiating. The results indicate the importance of selecting the appropriate assay for evaluating a particular agent. They also stress the necessity for including host resistance assays along with assays to measure specific immune aspects, in order to assess in the intact animal the overall effect of complex immune interactions following exposure to a test agent.