Ethanol-induced suppression of in vivo host defense mechanisms to bacterial infection.
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Animals↗
Biomedical subjects
T R Jerrells
Publications and source records attributed to T R Jerrells.
Ethanol ingestion increases susceptibility of mice to Listeria monocytogenes.
Excessive consumption of alcohol is associated with an increase in the frequency and severity of infectious diseases. Ethanol adversely affects specific and nonspecific aspects of the immune response. We used a murine model to determine whether ethanol ingestion impairs host mechanisms of resistance to Listeria monocytogenes. Naive mice and mice immune to L. monocytogenes were pair-fed either a Leiber-DeCarli liquid diet containing 7% (v/v) ethanol or an isocaloric control diet for 7 days. Then, nonimmune mice were given a sublethal dose of L. monocytogenes and studied 2 and 5 days after infection, and immune mice were challenged with a lethal dose of L. monocytogenes and studied 5 days after infection. Multifocal liver abscesses developed in nonimmune ethanol-treated and control mice 2 days after infection. Bacterial colony counts in the spleens were similar between the two groups; however, counts in the livers were slightly higher in ethanol-treated mice as compared with those in control mice. Five days after infection the nonimmune ethanol-treated mice had large necrotizing liver granulomas and organ bacterial colony counts 100 to 1000 times higher than those in control mice. Immune ethanol-treated mice had large areas of liver necrosis and inflammation containing numerous Gram-positive bacilli, whereas immune control mice had small, well-formed granulomas and much less necrosis. Organ bacterial colony counts were about 100 times higher in immune ethanol-treated mice as compared with those in immune control mice. Liver enzyme levels and mortality were significantly higher in ethanol-treated immune and nonimmune mice as compared with those in immune and nonimmune control mice. Data support the suggestion that ethanol consumption impairs the development and expression of T cell-mediated immunity of mice to L. monocytogenes, resulting in increased susceptibility to infection with this organism.
Alcohol Drinking↗
The influence of age on blood alcohol levels and ethanol-associated immunosuppression in a murine model of ethanol consumption.
Several study findings indicate that with ethanol ingestion a number of changes occur in the immune system. We studied the effects of ethanol consumption on mice at various ages. We used a murine model in which young (age 6-8 weeks), middle-aged (age 12 months), and old (age 24 months) male C57Bl/6 mice were pair-fed either a Leiber-DeCarli liquid diet containing 7% (v/v) ethanol or an isocaloric control diet. Consumption of ethanol diet for 8 days resulted in high blood alcohol levels in young and old mice; low levels were observed in middle-aged mice. Middle-aged mice consumed more ethanol than did either young or old mice and had the lowest percent body weight loss of all three age groups. Proliferation of spleen lymphocytes to T-cell stimuli (concanavalin A and alloantigens) in both young and old mice fed ethanol was diminished. T-cell function was unchanged in middle-aged mice consuming an ethanol diet when compared with that observed in age-matched mice pair-fed control diet. No effect of ethanol on proliferation to lipopolysaccharide was noted in any group. Proliferative response of T cells to soluble anti-CD3 monoclonal antibody was also decreased in middle-aged and old pair-fed control mice when compared with young control mice. The proliferative response to soluble anti-CD3 in all three age groups of mice fed ethanol, however, was not significantly affected by ethanol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
Age Factors↗
Recent developments in alcoholism:immunological aspects.
The association between chronic ethanol use and a predisposition to infection and increased severity of infection has been recognized by clinicians for many years. Clinical studies over the last century have substantiated individual clinical observations. Numerous studies have indicated that alcoholics are more susceptible to pulmonary infections and do not respond to treatment as well as nonalcoholic patients. A diminished ability to clear bacteria after chronic or acute ethanol treatment has also been demonstrated in a variety of experimental animals. Within the last few years a number of investigators have attempted to elucidate the mechanisms responsible for the apparent impairment of the immune system by either chronic or acute ethanol treatment. Alcohol has been reported to have adverse effects on all major components of the immune system. Ethanol affects the number of immunocompetent cells as well as the function of the remaining cells. In this review the effect of acute ethanol intoxication or chronic ethanol use on leukocyte and lymphocyte numbers, alteration of cellular function, and ability of the cells to arrive at the site of infection are addressed.
Alcohol Drinking↗
Demonstration and partial characterization of antigens of Rickettsia rhipicephali that induce cross-reactive cellular and humoral immune responses to Rickettsia rickettsii.
The relatively unrelated spotted fever group rickettsia Rickettsia rhipicephali conferred on guinea pigs protective immunity against challenge with virulent R. rickettsii. Immunity was conferred at all doses of R. rhipicephali used in the study. Because of the serologic unrelatedness of these two rickettsiae, determined by the use of microimmunofluorescence and other serological assays, further studies were performed to define the nature of the immune response elicited by R. rhipicephali and the characteristics of the rickettsial antigens that evoke cross-reactive antibody responses. Animals immune to R. rhipicephali tested at the time of challenge showed a complete cross-reactive lymphocyte proliferative response to rickettsial antigens prepared from each species. In fact, spleen cells from R. rhipicephali-immune animals responded better to R. rickettsii antigens than to homologous immunizing antigens. Serum samples were obtained from R. rhipicephali-infected animals at various times after infection and tested by the use of Western immunoblot assay for antibodies that were cross-reactive with antigens of R. rickettsii. By 10 days after infection with R. rhipicephali, antibodies to antigens of both species were noted, and by 37 days after infection, sera from immune animals showed strong reactivity to antigens of R. rhipicephali with apparent molecular masses of 107 and 151 kDa. The cross-reactive antibody response to antigens of R. rickettsii was relatively strong and involved predominantly the rOmpB protein and the rickettsial lipopolysaccharide. These findings establish the presence of T-cell-dependent epitopes associated with antigens of R. rhipicephali, which confer protective immunity against challenge with R. rickettsii. Results of Western immunoblot assays support the contention that the R. rickettsii rOmpB surface antigen contains important protective epitopes.
Animals↗
Immunodeficiency associated with ethanol abuse.
A number of study findings have shown that ETOH has a profound effect on the immune system. The work from my laboratory has established in animal models that the effect of ETOH is complex. It is well established that ingestion of ETOH-containing diets results in a loss of lymphoid cells from the peripheral blood, spleen, and thymus. Some of the cell loss from the thymus is the result of corticosteroid release as a result of the withdrawal from ETOH, but the loss from the spleen and some of the thymocyte loss is independent of corticosteroids, as demonstrated by studies using ADX mice and rats. We have also established that ETOH ingestion is associated with a loss of lymphocyte function, especially T-cell-dependent immune responses. One aspect of the T-cell defect is an inability to use IL-2, an important growth factor for T cells. Similar changes in lymphocyte function have been demonstrated in animals exposed to ETOH only in utero. The inability of a person to respond immunologically in an appropriate fashion to foreign antigens has a profound effect on the survival of the person. It would be predicted that ETOH-associated immunosuppression would result in increased incidences of infections. From the data generated from my laboratory it could also be predicted that these infections would be primarily opportunistic infections that are associated with defects in T-cell function. The available literature would support these predictions. It is also likely that changes in T-cell function would alter immunosurveillance mechanisms with the end result being an increased incidence of tumors. Again, the available literature would support this prediction.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Toxicity of oleic acid anilide in rats.
In the present investigation, we have studied the toxic potential of oleic acid anilide (OAA) and heated oleic acid anilide (HOAA) in relation to the toxic oil syndrome (TOS). Male Sprague-Dawley rats were given 250 mg/kg of OAA or HOAA in mineral oil by gavage, on alternate days for 2 weeks (total 7 doses). The control rats received an equal volume of mineral oil only. The animals were sacrificed at days 1, 7, and 28 following the last dose. Ratio of organ-to-body weight showed increases in spleen and kidney of HOAA and OAA treated rats, respectively, at day 1 while this ratio for liver in HOAA treated group showed a decrease at day 1. Among blood parameters, white blood cells increased in HOAA treated group at day 1 and in both OAA and HOAA groups at day 28. Mean corpuscular hemoglobin (MCH) and mean cell volume (MCV) also showed increases in the HOAA treated rats at days 7 and 28. Serum lactate dehydrogenase (LDH) decreased in both OAA and HOAA treated rats at day 1, while at day 7 the decrease was confined only to the HOAA group. Serum glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities also decreased at most of the time points. Liver mitochondrial ATPase activity decreased in the HOAA group at day 7 and in the OAA group at day 28. Among serum immunoglobulins, IgA levels increased throughout the study but the changes were more pronounced in HOAA treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Anilides↗
Heated linoleic acid anilide: toxicity and relevance to toxic oil syndrome.
The present study was undertaken to investigate toxic potentials of linoleic acid anilide (LAA) and heated linoleic acid anilide (HLAA) and their possible role in the etiology of toxic oil syndrome (TOS). Male Sprague-Dawley rats were given 250 mg/kg of LAA or HLAA in mineral oil through gavage, on alternate days for 2 weeks (total 7 doses). Control rats received an equal volume of vehicle only. The animals were sacrificed at day 1, 7 and 28 following the last dose. Ratio of organ weight/body weight showed a significant increase in lung in LAA group at day 7 while spleen showed remarkable increases in both treatment groups at day 1 and 7. On the other hand, this ratio showed decreases in case of liver, brain and heart at some time points. Among blood parameters, red cell counts and hemoglobin content decreased at day 1 in both LAA and HLAA treated groups, while platelet counts showed an increase. Serum LDH, GOT and GPT activities significantly decreased at day 1 and 7 in both LAA and HLAA treated groups, however, these changes were more prominent in the HLAA treated group. Interestingly, at day 28, these serum enzyme levels recovered to control levels. Both LAA and HLAA treated groups showed a decrease in serum IgM levels at day 1, however, at day 7 only the LAA group showed a significant decrease. IgA levels significantly increased in both groups at all the time points studied and were more pronounced in the HLAA treated group. Similarly, IgG levels also showed increases in both the groups. In addition to serum immunoglobulin changes, alterations in the lymphocyte subpopulations were also observed. While T-cell population decreased, B-cell population remained unchanged. Among T-cell subsets, T-helper cells did not show any change while T-suppressor cells decreased significantly at day 1 in the LAA group and at day 1 and 7 in the HLAA group, but regained control levels at day 28. The biochemical and immunological alterations observed in this study as a result of LAA and HLAA exposure and more so by HLAA further support that the fatty acid anilides may play a role in the etiology of TOS.
Anilides↗
Synergistic vascular toxicity and fatty acid anilides in the toxic oil syndrome.
The underlying etiology of the toxic oil syndrome may be related to any of several toxic contaminants. The hypothesis is made that two or more toxic compounds may act synergistically to cause vascular damage in the toxic oil syndrome. To support this hypothesis, previous studies are reviewed concerning the remarkable synergistic toxic action of allylamine and beta-aminopropionitrile on the media of blood vessels. Although these toxins are not directly related to the toxic oil syndrome, this previous experimental work emphasizes the possibility that unexplored synergistic actions may be important. Furthermore, the hypothesis that contaminating fatty acid anilides in toxic oil undergo alterations during cooking is supported by high pressure liquid chromatographic analysis. The theoretic metabolism of fatty acid anilides is discussed. Recent data concerning the toxic actions of the anilides of oleic and linoleic acid are given. These data suggest that these anilides induce immunologic alterations that may be similar to those seen in the toxic oil syndrome. In addition, the heated anilides appear to have increased toxicity, supporting the concept that the use of toxic oil in cooking may increase its toxicity.
Allylamine↗
Suppression of immune responsiveness: sex differences in prenatal ethanol effects.
Exposure to ethanol in utero results in changes in the offspring's developing immune system, including thymus lymphocyte subpopulation shifts and functional lymphocyte changes that persist in adult animals. The present study was designed to define further the extent of changes in the immune system that result from fetal ethanol exposure and to compare effects in male and female offspring. In adulthood, male and female offspring from Sprague-Dawley dams fed an ethanol-containing liquid diet (alcohol, A), an isocaloric liquid control diet (pair-fed, PF), or laboratory chow and water (control, C) during pregnancy were tested for several measures of immune competency. Prenatal ethanol exposure differentially affected male and female offspring. Fetal ethanol-exposed males exhibited a decrease in thymocyte number as well as a decreased splenic lymphocyte proliferative response to the T-cell mitogen, concanavalin A (Con A), with a concomitant decrease in recoverable blast cells, when compared with PF and C males. Further, the defect in T-cell proliferation of A males was not due to an inability to produce the critical growth factor, interleukin-2 (IL-2), but to an inability of lymphoblasts to utilize exogenous IL-2. Fetal ethanol-exposed females showed some suggestion of lower thymocyte counts and decreased splenic T-cell proliferative responses to Con A compared to PF and C females. For most of the immune measures, however, no significant differences occurred among A, PF, and C females. In utero ethanol exposure did not significantly alter spleen cell counts or IL-2 production, splenic B-cell proliferation to bacterial lipopolysaccharide (LPS), or thymocyte response to IL-2 in animals of either sex.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Flow cytometric and immunohistochemical evaluation of ethanol-induced changes in splenic and thymic lymphoid cell populations.
Ethanol-induced alterations in the immune system are thought to play a major role in increasing the susceptibility of alcoholics to infections and tumors. One important change in the immune system is the noted loss of lymphoid cells from the thymus and spleen. To examine these alterations we used a model system where C57Bl/6 mice were pair-fed either a Leiber-DeCarli diet containing 7% (v/v) ethanol or an isocaloric control diet. Mice receiving ETOH for 7 days showed a loss of cells from the spleen and thymus; this loss was even more severe after withdrawal for 1 day. The most profound changes were seen after 2 weeks of ETOH. Spleen and thymus cell numbers were reduced to 36% and 6.2%, respectively compared to control mice. Staining of thymocytes with monoclonal antibodies to lymphocyte surface markers and evaluation with flow cytometry revealed that immature thymocytes (PNA+, CD4+/CD8+) were most reduced. Mature thymocytes (CD4+/CD8- or CD4-/CD8+) were depleted, and the CD4+ to CD8+ ratio was increased. Sections of thymus stained with hematoxylin and eosin or with immunohistochemical methods showed atrophy and lymphoid cell depletion. No cortex was histologically identifiable after 2 weeks of ETOH. The spleen cells most affected by ETOH were the B cells. They were reduced to 8.2 x 10(6) cells/spleen (31.5% of the lymphocytes), as compared to 38.5 x 10(6) cells/spleen (50.3% of the lymphocytes) in the control mice. The spleen was atrophic, but the immunoarchitecture was preserved. Ethanol causes a depletion of lymphocytes from the spleen and thymus with alterations in lymphocyte subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcoholism↗
Immunosuppression and lymphoid hypoplasia associated with chronic graft versus host disease is dependent upon IFN-gamma production.
We have previously shown that both IFN-gamma and IFN-beta are produced in vivo and in vitro by spleen cells obtained from mice experiencing a chronic form of graft vs host disease (GVHD). Further, we have shown that in vitro production of IFN-beta by spleen cells from GVHD mice may play a role in the suppressed in vitro mitogen responsiveness of these cells. This study was undertaken to investigate if treatment of such mice with mAb to IFN-gamma or IFN-beta could alter the immunosuppression or lymphoid hypoplasia associated with chronic GVHD. GVHD was induced across minor histocompatibilities by the i.v. injection of B10.D2 spleen cells into sublethally irradiated BALB/c mice. These mice were given daily injections for 20 days of one of the following: 1) mAb to IFN-gamma, 2) mAb to IFN-beta, or 3) control IgG. Histologic examination of these mice at 21 to 22 days post transplantation revealed that mice treated with mAb to IFN-beta or control IgG had dramatic hypoplasia of the thymus, spleen, and lymph nodes which was similar to untreated GVHD mice. Mice given mAb to IFN-gamma, however, had no lymphoid hypoplasia and had a near normal gross and histologic appearance of their thymus, spleen, and lymph node tissue when compared with syngeneic controls. In vitro mitogen-induced proliferative responses of spleen and lymph node cells obtained from GVHD mice or GVHD mice treated with mAb to IFN-beta were severely suppressed or absent. In contrast, spleen and lymph node cells from GVHD mice given mAb to IFN-gamma were capable of giving a significant in vitro proliferative response to Con A, PHA, and LPS. Further, natural suppressor cell activity and spontaneous production of IFN-beta, a characteristic of this form of GVHD, was absent in spleen cells obtained from GVHD mice treated with mAb to IFN-gamma. These results further identify the IFN as playing critical roles in the pathogenesis of GVHD.
Animals↗
Effect of adrenalectomy on ethanol-associated immunosuppression.
The alterations in lymphoid cell numbers and lymphocyte function due to administration of ethanol was found to be associated with high levels of circulating corticosteroids. The role of corticosteroids in the ethanol-induced alterations in the immune system was studied by administering ethanol to adrenalectomized rats. The results of these experiments showed that the ethanol-induced loss of cells from the thymus was not completely prevented by adrenalectomy and the ethanol-induced loss of cells from the spleen was not affected by adrenalectomy. Likewise the ethanol-induced decrease in antibody production to the T-cell-dependent antigen sheep erythrocytes were not affected by adrenalectomy. The ability of animals to produce antibodies of the T-cell-independent antigen, TNP-Ficoll, was not affected by ethanol regardless of whether the animals had adrenal glands or not. These data indicate that adrenal corticosteroids are responsible for some but not all of the thymic involution due to ethanol intoxication. Also, adrenalectomized rats did not show as much impairment in lymphocyte proliferation as sham adrenalectomized animals after ethanol administration. However, this loss of cells from peripheral lymphoid organs such as the spleen and the decreased ability to respond to T-cell-dependent antigens is not influenced by adrenalectomy indicating mechanisms other than corticosteroids mediate these effects of ethanol.
Adrenalectomy↗
Alterations in interleukin-2 utilization by T-cells from rats treated with an ethanol-containing diet.
Administration of ethanol to Sprague-Dawley rats has been shown to produce a defect in lymphocyte proliferation in response to concanavalin A. Because a critical element in T-cell proliferation is the production of interleukin-2, experiments were designed to evaluate the influence of ethanol on the production and utilization of interleukin-2 by spleen cells from ethanol-treated animals. To ensure that changes in spleen cell responses to mitogenic stimulation were not simply caused by a loss of responding T cells, we tested nylon wool-nonadherent cells. The response to concanavalin A of isolated T cells from ethanol-treated rats was consistently less than that of equivalent numbers of cells from control animals. The addition of recombinant interleukin-2 to cultures of T cells did not correct the defect in proliferation to concanavalin A noted in cells from ethanol-treated rats. Further study results demonstrated that interleukin-2 production by T cells from ethanol-treated animals was equal to or greater than that by cells from animals given control diet. Blast cells recovered from 48-hr concanavalin A-stimulated spleen cell cultures from ethanol-treated animals, however, showed a decreased ability to proliferate in response to exogenous interleukin-2. Binding of 125I-interleukin-2 to blast cells resulting from concanavalin A stimulation, under conditions that detected high-affinity binding, was similar in cells from treated and control animals. These data indicate that the deficiency in proliferation of lymphocytes from ethanol-treated animals is not caused by a lack of interleukin-2 production by the T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Alcoholism↗
Murine model of ethanol-induced immunosuppression.
Alcohol abuse has been associated with an increased susceptibility to infectious diseases and certain tumors. On the basis of these observations, an effect of ethanol on the immune system has been suggested. We have used a mouse model system in which male C57Bl/6 mice were fed either Lieber-DeCarli liquid diet containing ethanol sufficient to supply 37% of the total calories or isocaloric control diet in a pair-feeding design to examine the effect of ethanol on the immune system. The group consuming the ethanol-containing diet maintained relatively stable levels of blood ethanol for the 8 days of feeding. Consumption of ethanol for 8 days resulted in a profound loss of thymus and spleen cells, and the recovery of thymus cellularity was delayed relative to the recovery of spleen cell numbers after ethanol feeding was discontinued. Proliferation of spleen lymphocytes to T-cell stimuli (concanavalin A and alloantigens) was diminished; however, B-cell proliferation to lipopolysaccharide was relatively unchanged in mice fed ethanol-containing diet. Also in ethanol-fed mice a significant decrease in the primary antibody response to sheep red blood cells but not to the T-independent antigen trinitrophenol-ficoll occurred. These data establish the murine model system as a means to define further the effect of ethanol on the immune system and host defense mechanisms.
Alcoholism↗
Mechanisms of lymphocyte activation by nerve growth factor.
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Animals↗
Polypeptides constituting the antigenic basis for identification of Rickettsia sibirica species by the standard serotyping method for spotted fever group rickettsiae.
The antigens of Rickettsia sibirica, Rickettsia rickettsii, and Rickettsia conorii were examined by Western immunoblots and the standard immunofluorescent serotyping assay with mouse anti-Rickettsia sibirica serum that is used for determining the species identification of spotted fever group rickettsiae. Serum was employed prior to absorption and after absorption with purified native or heated Rickettsia sibirica. The unabsorbed antiserum, the antiserum absorbed with heated Rickettsia sibirica and the antibodies eluted from native Rickettsia sibirica recognized two antigenic polypeptides of Rickettsia sibirica (130 and 118 kDa), Rickettsia rickettsii (151 and 133 kDa), and Rickettsia conorii (136 and 113 kDa), respectively when examined in native state, not denatured by heat. The antiserum absorbed with native Rickettsia sibirica reacted most strongly with one polypeptide of Rickettsia sibirica (118 kDa), Rickettsia rickettsii (133 kDa), and Rickettsia conorii (136 kDa); at the endpoint of the immunofluorescence assay there was minimal reactivity with the 130 kDa polypeptide by immunoblotting. Both Western immunoblots and immunofluorescence assay showed that the antiserum absorbed with native Rickettsia sibirica reacted with homologous and heterologous antigens at a much lower titer than did the antiserum that was not absorbed. However, the titers of reaction with Rickettsia sibirica, Rickettsia rickettsii, or Rickettsia conorii were not diminished by absorption of the native antiserum with heated Rickettsia sibirica. The antibody eluted from native Rickettsia sibirica reacted by immunofluorescence with all the rickettsiae at a higher dilution than the antibody eluted from heated Rickettsia sibirica.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Mechanisms of ethanol-induced immunosuppression.
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Animals↗