Cell-mediated immunity in alcoholic liver disease. Veterans Administration Cooperative Study #275.
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Antigen-Presenting Cells↗
Biomedical subjects
C L Mendenhall
Publications and source records attributed to C L Mendenhall.
Nuclear progestin receptors in rat thymic tissue.
The thymus and its associated endothelial cells and lymphocytes act as an important immunological tissue. The endothelial cells of the thymus have been reported to synthesize cytoplasmic progestin receptor in response to estrogen priming. To measure nuclear progestin receptor, female rats were castrated and primed for 3 days with estradiol benzoate (30 micrograms/0.1 ml/d) and immediately before sacrifice injected subcutaneously with 0.2 mg of progesterone. By Scatchard plot analysis we found that specific progestin receptor (KA = 0.89 +/- 0.10 x 10(9) M-1) was present in the KCl-nuclear extract. The concentration of nuclear progestin receptor was found to be in the range of 312.6 +/- 49 fmole/g tissue (n = 9, 1 hour after progesterone injection) while the nuclear receptor was significantly reduced (approximately 44 fmol/g tissue) in the oil treated controls. This level verges on the limits of sensitivity for this assay. For cytoplasmic progestin receptor the concentration was 3.46 +/- 0.20 pmole/g tissue in oil treated controls (n = 14) and 3.36 +/- 0.20 pmole/g tissue in progesterone treated animals (n = 24). The KA of this thymic cytoplasmic progestin receptor was 1.35 +/- 0.06 x 10(9) M-1. By competition assay, the relative binding affinity of nuclear progestin receptor was: R5020 (a potent synthetic progestin) (100%), progesterone (9%), testosterone (0.56%), corticosterone (0.53%), estradiol-17 beta (0%). It is concluded that thymic reticuloepitheleal cells contain nuclear progestin receptor and this finding supports the hypothesis that progesterone, like other sex steroids may play a regulatory role in thymic cell function.
Animals↗
The interactions of insulin-like growth factor I(IGF-I) with protein-calorie malnutrition in patients with alcoholic liver disease: V.A. Cooperative Study on Alcoholic Hepatitis VI.
Plasma concentrations of insulin-like growth factor I (IGF-I) were measured in 95 alcoholic men with a spectrum of alcoholic liver injury and protein-calorie malnutrition (PCM). Circulating levels of IGF-I were depressed in the alcoholic patients (0.23 +/- 0.02 U/ml; mean +/- S.E.M.) compared to controls (1.0 +/- 0.07, P less than 0.0001). Plasma IGF-I levels declined progressively with falling indices of PCM (P less than 0.001) and correlated especially with the parameters relating to protein deficiency. While the severity of liver dysfunction and histopathologic alterations in the liver also related to plasma IGF-I concentration, partial correlation analysis showed that only PCM correlated significantly with IGF-I levels independent of the other factors. These findings indicate that IGF-I levels reflect nutritional status even in the presence of alcoholic liver disease.
Adult↗
Beef fat prevents alcoholic liver disease in the rat.
The amount and type of dietary fat is thought to be important in the pathogenesis of alcoholic liver disease (ALD). We investigated the role of different dietary fats in our rat model for ALD. Liver pathology was evaluated in rats fed ethanol and lard or tallow or corn oil over a period of 2 to 6 months. All experimental animals were pair-fed the same diet as controls except that glucose was isocalorically replaced by ethanol. Rats fed tallow and ethanol developed none of the features of ALD, those fed lard and ethanol developed minimal to moderate disease, rats fed corn oil and ethanol developed the most severe pathology. The degree of histopathological abnormality correlated with the linoleic acid content of fat in the diet (tallow 0.7%, lard 2.5%, corn oil 56.6%). We postulate that linoleic acid facilitates development of ALD and provides an explanation for our previous epidemiological observations.
Animals↗
Cell-mediated immune responses associated with short term alcohol intake: time course and dose dependency.
Using a rat model, we report here the duration of heavy drinking necessary to produce immunosuppression, the recovery time after such alcohol-induced immunosuppression, and the variations in immune response associated with varied amounts of alcohol consumption. Immune status was evaluated by means of delayed cutaneous hypersensitivity (DCH)-like responses to phytohemagglutinin. The daily consumption of 5 g of ethanol/kg body weight/d resulted in a prompt reduction in DCH-like responses which was significant by Day 3 (p = 0.03) and maximal by Day 11 (45% of baseline). These data were consistent with a similar reduction of migration inhibitory factor activity in spleen cells from ethanol fed rats. Cessation of ethanol resulted in a return to baseline within 4 days. In a second experiment ethanol was administered daily in doses ranging from 0.5 to 6.0 g/kg. Early (Day 5) low dose ethanol (0.5-2 g/kg) stimulated immune response (153-188% of baseline) while high dose (6.0 g/kg) suppressed (79% of baseline). Continued treatments resulted in a loss of stimulation at low dose and increased suppression at higher doses. The relationship of these animal studies to human binge drinking and the possible risk for infection in the alcoholic remains to be established.
Animals↗
Ethanol and soluble mediators of host response.
Lymphokines serve to modulate host inflammatory response by providing a communication link among cells involved in resistance to infection. In the alcoholic, this system may be impaired due to a combination of the direct effects of ethanol on immunocompetent cells and the soluble factors involved in cell-cell interactions. In this paper, we review the literature on this subject, describe an ethanol-related impairment of migration inhibitory factor activity in the rat, and present a possible mechanism for this alteration.
Alcoholism↗
Serum aspartate aminotransferase to alanine aminotransferase ratio in human and experimental alcoholic liver disease: relationship to histologic changes.
We studied the relationship between the ratio of serum aspartate aminotransferase (ASAT) to alanine aminotransferase (ALAT) and histologic changes in human and experimental alcoholic liver disease. The patient population included 52 hospitalized patients enrolled in a Veterans Administration Cooperative study. The experimental animal group consisted of male Wistar rats fed an ethanol-liquid diet. Of the 52 patients with alcoholic hepatitis, 33 had evidence of cirrhosis. The mean +/- SD for the ASAT/ALAT ratio in the group with alcoholic hepatitis and no cirrhosis was 1.47 +/- 0.84, the mean +/- SD in the group with hepatitis and cirrhosis was significantly higher (2.68 +/- 1.32, p less than 0.01). There was no difference in the ratio between the rats with and without liver fibrosis. The cause for the increased ASAT/ALAT ratio in serum in the presence of cirrhosis is unknown and may reflect more severe liver damage.
Alanine Transaminase↗
Phytohemagglutinin skin test responses to evaluate in vivo cellular immune function in rats.
It is often necessary to have a small animal model which permits the sequential evaluation of functional immune status over a period of time. We report here the in vivo, intradermal response to phytohemagglutinin which produces an area of induration that is histologically similar to a typical delayed cutaneous hypersensitivity response, and that provides fast, quantitative, reproducible results similar to those observed with standard but more laborious and variable in vitro tests of immune function. For small animal studies this has the advantage of permitting longitudinal evaluations over time without sacrificing the animal. Using phytohemagglutinin-microprotein (0.2 mg/0.1 ml), injected intradermally, a delayed cutaneous hypersensitivity-like response is induced which is maximal at 24 hr. When immune function was altered either by treatment with a chemical immunosuppressant (ethanol) or by hormonal manipulations (hypophysectomy and rat growth hormone), the delayed cutaneous hypersensitivity-like response (area of induration) correlated closely with both macrophage migration inhibitory factor changes (r = 0.98; P less than 0.001) and mixed lymphocyte reaction changes (r = 0.99; P less than 0.05). These observations suggest that this technique correlates well with standard in vitro measures of immune response and may thus permit an in vivo estimation of immune reactivity.
Animals↗
Age dependent alterations of host immune response in the ethanol-fed rat.
The interaction between ethanol and aging with respect to cellular immune response is unclear. For our studies, Sprague-Dawley rats were pair fed using a synthetic liquid control diet (LCD) or a diet in which ethanol was substituted for carbohydrate (LED). The special diets were started when the rats' age varied from 1-18 months and were continued for one, two, or three months. In a second set of experiments, rats were treated continuously with these diets for 24 months. At each study period blood was drawn for serum and the spleen cells removed. Immune response was assessed by the lymphocyte transformation test using combinations of cells and serum from each of the rat groups. When LCD or LED were started in aged rats (18 months), after three months, there was a significant decrease in the Concanavalin A induced lymphocyte transformation test using the serum from LCD rats compared to serum from LED rats with either cells from LCD (1,273 +/- 831 (DPM +/- SD) vs 302 +/- 139; p less than 0.04) or cells from LED animals (984 +/- 338 vs 420 +/- 196; p less than 0.02). When the diet started at younger age or for less than three months these effects were not seen. In the continuously LCD or LED fed rats, the blastogenic response peaked at three months of treatment (four months of age) and decreased at six months and remained constant over the remainder of the 24 month period. There was no difference in lymphocyte DNA synthesis comparing any of the serum or cell groups with respect to diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Longevity among ethnic groups in alcoholic liver disease.
As part of a multicenter V.A. Cooperative Study, 437 male veterans with varying stages of alcoholic liver injury were followed over a 4.5 year period. Their ethnic distribution consisted of 256 Caucasians, 109 black Afro-Americans, 63 Puerto Rican Hispanics, and 9 Native American Indians. Survival analyses revealed significant differences between groups (P = 0.0002): 66% of Afro-Americans were still living at 42 months; Caucasians were intermediate with 40% survival; and only 28% of Hispanics were alive. The number of Native American Indians enrolled was too small to draw conclusions but none of those enrolled survived beyond 24 months. Survival regression analysis of 30 clinical, laboratory, histologic and nutritional parameters, revealed the following significant risk factors: clinical severity (P less than 0.0001), histologic severity (P less than 0.0001), race (P = 0.001), age (P = 0.002), BUN (P = 0.01) and ALT (P = 0.02). These analyses indicated that ethnicity, independent of other variables, is significantly associated with outcome from the disease.
Adult↗
Alcohol and immune regulation. I. In vivo effects of ethanol on concanavalin A sensitive thymic lymphocyte function.
Alcohol is known to suppress the immune response, but the underlying mechanism to account for this immune suppression is still not clearly elucidated. In an attempt to clarify such mechanisms, experimental rats were fed for 50 days on a 36% ethanol, Lieber diet (LED) while control (LCD) rats were fed a similar diet supplying the same amount of calories but lacking ethanol. It was found that both LCD and LED animals grew at a linear rate (LCD: r = 0.981, LED: r = 0.961) but that LCD animals grew more rapidly. While thymic weights in the LED group were significantly smaller (P less than 0.05) than in the LCD group, the ratios of thymic weight/body weight between these groups were not significantly different. To identify the effects of ethanol on immune response, thymic (Th) or splenic (S) cells were prepared and incubated in culture with the mitogen, Con A and rat serum prepared from LCD or LED groups. It was found that lymphocytes prepared from thymus of LED animals appeared to be depressed in mitogen-driven blastogenic transformation when incubated in LCD serum but not LED serum. Furthermore, lymphocytes prepared from the spleen of LED animals appeared to be depressed in mitogen driven blastogenic transformation when incubated in LED serum but not LCD serum. Since lymphocytes of the thymus and spleen are undergoing maturation and replication this implies that ethanol may alter these processes.
Animals↗
Lymphocyte subset alterations in patients with alcoholic hepatitis.
Twenty-three patients with alcoholic hepatitis (AH) were entered into a study to evaluate the relationship between alcoholic hepatitis, malnutrition, and immune status. In order to quantify these variables, objective parameters of nutritional status and lymphocyte phenotype and function were used. On admission to hospital, the mean number of CD4 helper/inducer cells, CD8 suppressor/cytotoxic cells, and CD3 lymphocytes were significantly reduced compared to age matched, non-hospitalized laboratory controls. In order to ascertain whether this abnormality was reversible, 12 patients, who were willing to remain in the hospital for 30 days, were treated for this entire period with oral nutritional supplementation using a commercially available preparation high in calories, protein, and branch chain amino acids. After 30 days of this therapy and abstinence, the number of CD4 cells increased from a mean (+/- SD) of 658 +/- 428 to 815 +/- 599/mm3. There was no difference in results of the lymphocyte transformation test comparing pre- and post-therapy values using either fetal calf or autologous serum. For all groups tested, cells cultured in autologous serum exhibited a significantly decreased response to mitogen compared to cells cultured in fetal calf serum. Both the total nutritional and the protein depletion (kwashiorkor) scores improved significantly during the 30 days of nutritional supplementation (p less than 0.0009 and p less than 0.0004, respectively). Therefore, we have observed an alteration in the numbers of helper lymphocytes in patients admitted with AH. This abnormality was modifiable by abstinence and nutritional supplementation over a brief period of hospitalization.
Hepatitis, Alcoholic↗
Morphometric study of hepatic ultrastructure in alcoholic hepatitis. Veterans Administration Cooperative Study Group on Alcoholic Hepatitis.
We undertook a morphometric analysis of hepatocellular organelles in an attempt to correlate their changes with the clinical stages of patients with alcoholic hepatitis. Although hepatic ultrastructural alterations did not correlate with disease severity, we found significant differences between patient and control groups in the measured parameters of non-organelle cytoplasm, mitochondria, SER, RER, glycogen, and lipid.
Biopsy↗
Effects of mixed bacterial toxins on immune response.
Mixed bacterial toxin (MBT) is an experimental substance for treatment of certain forms of cancer. To ascertain if the cancer regression affects reported for MBT might be mediated via immunoendocrine interactions, MBT was tested in vivo in male Wistar rats or in vitro on Thymic (Tc) or Splenic (S) lymphocytes prepared from these same animals. In order to evaluate gonadal steroid effects on this process, certain groups of these rats were also castrated before treatment. Tc or S lymphocytes were prepared from these groups and cell responsiveness was monitored by in vitro blastogenic assays. Certain assay wells also contained Concanavalin A as a mitogen. The addition of MBT in vitro significantly stimulated Tc-cell responses (p less than 0.05) for all experimental groups except for certain groups of castrate MBT injected rats. Furthermore, S cells did not respond in the presence of MBT added in vitro except after castration and pretreatment with MBT where in vitro addition of MBT to cultures significantly stimulated blastogenic responses (p less than 0.02). The results of these assays are consistent with the hypothesis that the anticancer effects attributed to MBT result from the ability of MBT to act as a nonspecific mitogen-like stimulator of immature Tc-cells and mature S-cells. These results also suggest that MBT may modulate a serum factor under the control of gonadal steroids and possibly of thymic origin which can effect T-cell responsiveness.
Animals↗
False positive tests for HTLV-III antibodies in alcoholic patients with hepatitis.
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Acute Disease↗
Significance of megamitochondria in alcoholic liver disease.
The significance of megamitochondria in the alcoholic liver injury of humans was investigated as part of a large Veterans Administration cooperative study of the natural history of alcoholic hepatitis. Two hundred twenty patients were clinically stratified into the following three groups according to disease severity using serum bilirubin and prothrombin time as indicators: Group 1 (mild disease), serum bilirubin levels less than 5 mg/dl and prothrombin time prolonged for less than 4 s; group 2 (moderate disease), serum bilirubin levels greater than 5 mg/dl but prothrombin time prolonged for less than 4 s; and group 3 (severe disease), serum bilirubin levels greater than 5 mg/dl and prothrombin time prolonged for greater than 4 s. Megamitochondria were observed in 20% of the patients (45 of 220). Of these, 43 patients were in groups 1 and 2 of severity and only 1 patient belonged in group 3. The association of megamitochondria with cirrhosis was infrequent (33%, 15 of 45 patients). The differences in severity correlated with the differences in mortality: in patients with megamitochondria, only 1 had died at 6 mo compared with 40 deaths in patients without megamitochondria. By 12 mo, there were two deaths in patients with megamitochondria versus 51 deaths in those patients without. No complications were present in 72% of patients with megamitochondria versus 39% for those without. Infection, gastrointestinal bleeding, pancreatitis, hyperglycemia, azotemia, delirium tremens, seizures, and hepatic encephalopathy were all more common in patients without megamitochondria. The patients with megamitochondria appear to represent a subcategory of alcoholic hepatitis with a milder degree of clinical severity, lower incidence of cirrhosis, fewer complications, and good long-term survival.
Biopsy, Needle↗
VA cooperative study on alcoholic hepatitis. II: Prognostic significance of protein-calorie malnutrition.
Three hundred and fifty-two patients with alcoholic hepatitis were evaluated for protein-calorie malnutrition (PCM). In order to facilitate data analysis of nutritional status, a PCM score was calculated for each patient using eight nutritional parameters. The PCM score correlated significantly with mortality, clinical severity of the liver disease, and biochemical liver dysfunction. When 30 day changes in the PCM scores were compared with 30 day caloric intake (expressed as percent basal energy expenditure (BEE], a marginally significant correlation was observed (p = 0.05). However, those patients who showed improvement in their PCM score over 30 days of hospitalization also improved their 6-mo and 1-yr survival. These data indicate that nutrition, as determined by the PCM score, has prognostic significance. Additional studies are needed to establish the beneficial role for vigorous protein-calorie nutritional therapy in the management of alcoholic hepatitis.
Energy Intake↗
The ferret: a new model of oral ethanol injury involving the liver, bone marrow, and peripheral blood lymphocytes.
We have developed a model of oral ethanol ingestion in the ferret by providing a complete liquid diet in which 21% of the total caloric intake is given as ethanol. After 3 weeks of ethanol treatment, migration inhibitory factor activity from ferret lymphocytes was significantly decreased when compared to animals fed a dextrose-substituted, identical liquid diet. Lymphocyte blastogenesis in response to the mitogen, phytohemagglutinin, was also decreased after 6 weeks of ethanol ingestion. Histopathologically, hepatic cell degeneration, fat deposition, and "Mallory body-like" material were present after 11 weeks of therapy. Bone marrow aspirate cells from the iliac crest of ethanol-fed animals showed vacuolization in both erythroid and myeloid elements after 6 weeks of ethanol ingestion. Mean ferret weights were not significantly different between the ethanol and dextrose control groups; serum ethanol and acetaldehyde concentrations were somewhat higher over the study period compared to those seen in human alcoholics. Therefore, we have designed a small animal model of the toxic effects of alcohol in which multiple organ systems exhibited evidence of ethanol-related disease.
Alcoholism↗