Hepatic cirrhosis and clearance of fibrinolysis activators]

Strain differences in the antibody response to human IgG (HGG) were observed when aggregated HGG was injected intravenously. Lipopolysaccharide (LPS) administered subsequently markedly enhanced the antibody response to HGG in low responder C57BL/6 mice as compared with that in high responder DDD, C3H/He or (C57BL/6 X DDD)F1 mice. Aggregate-free preparation of HGG at a dose of 0.5 mg induced immunological tolerance in all strains of mice tested. LPS injected subsequently converted tolerogenic, aggregate-free HGG into immunogen in DDD mice but not in C57BL/6 mice. To determine the correlation between adjuvanticity and mitogenicity of LPS, spleen cells from normal mice were cultured in the presence of LPS and 3H-thymidine uptake was measured. Spleen cells of DDD mice incorporated three times as much 3H-thymidine as those of C57BL/6 mice. There seems no strong correlation between both activities of LPS. The data obtained are discussed in terms of strain differences in the macrophage function for processing the antigen.     

Pubertal growth, sexual maturation, and final height in children with IDDM. Effects of age at onset and metabolic control

The effects of free ampicillin, microencapsulated ampicillin anhydrate (MEAA) and antibiotic-free microspheres on the cell-mediated immune response in Balb/c mice were measured by lymphoproliferation assay, delayed-type hypersensitivity (DTH) and cytokine production. Injection into mice for seven consecutive days with equivalent subcutaneous doses of ampicillin, MEAA or placebo microspheres did not produce any consistent change in lymphocyte proliferation nor did it affect DTH responses or interleukin-2 production. Although the production of interleukin-4 in mice treated with ampicillin or MEAA increased compared with the control mice, this increase was not statistically significant. These results indicate that ampicillin and MEAA have similar effects on cell-mediated immunity in mice.     

Evaluation of critical orifices made from sections of hypodermic needles

Levamisole, a potentiator of cell-mediated immunity, has been reported to increase survival in patients with resectable carcinoma of the lung. Cell-mediated immunity can be measured in vitro by the leukocyte migration inhibition test. We have previously reported that this test detects cell-mediated immunity to human lung tumor antigens. In the present studies, patients with lung cancer were treated with Levamisole. Their leukocytes were evaluated in the leukocyte migration inhibition assay before, during, and following Levamisole therapy. Small increases in cell-mediated immunity were observed when patients had a high pre-existing tumor immunity. When tumor-associated reactivity was absent prior to therapy, larger increases were measured. Although Levamisole is a nonspecific immunostimulant, these data indicate that in vitro anti-tumor immune responses are enhanced by Levamisole therapy. Augmentation of cell-mediated immunity to tumor antigens may explain the clinical benefits of Levamisole therapy.     

Successful treatment of transient acquired factor X deficiency by plasmapheresis with concomitant intravenous immunoglobulin and steroid therapy

Many nontropical rodent species display seasonal changes in reproductive physiology and metabolism, as well as in immune function. Field studies of seasonal changes in immune function typically report decreased immune function in the short days of winter compared to summer; presumably, reduced immunity in winter reflects increased glucocorticoid secretion in response to environmental stressors. In contrast, laboratory studies of photoperiodic changes in immunity invariably demonstrate increased immune function in short compared to long days. Although the precise mechanisms regulating short-day enhancement of immune function are not known, it is hypothesized that increased immunity is due to the increased duration of melatonin secretion in short compared to long days. However, melatonin can act both directly (i.e, via melatonin receptors located on lymphatic tissue) and indirectly (i.e., via alterations in gonadal steroids) to affect immune function. The present study examined the effects of exogenous melatonin administration on both cell-mediated and humoral immune function in adult male deer mice (Peromyscus maniculatus), as well as the role of gonadal steroid hormones in mediating these effects. Mice either were castrated to remove circulating androgens or received sham operations and were implanted with empty capsules or capsules containing melatonin. Individual mice implanted with melatonin underwent reproductive regression and displayed enhanced splenocyte proliferation to the T-cell mitogen concanavalin A; antigen-specific serum immunoglobulin M production was unaffected by melatonin treatment. Castration had no effect on either cell-mediated or humoral immune function. Taken together, these results suggest that exogenous melatonin enhances cell-mediated, but not humoral, immune function in adult male deer mice and that this effect is independent of gonadal steroid hormones. These results are consistent with a direct effect of melatonin on immunity.     

Susceptibility to the biological effects of polyaromatic hydrocarbons is influenced by genes of the major histocompatibility complex

Polyaromatic hydrocarbons are ubiquitous environmental chemicals that are important mutagens and carcinogens. The purpose of this study was to determine whether genes within the major histocompatibility complex (MHC) influence their biological activities. Cell-mediated immunity to dimethylbenz(a)anthracene (DMBA) was investigated in congenic strains of mice. On three different backgrounds, H-2(k) and H-2(a) haplotype mice developed significantly greater contact-hypersensitivity responses to DMBA than H-2(b), H-2(d), and H-2(s) mice. In B10.A(R1) mice, which are Kk and Id, a vigorous contact-hypersensitivity response was present, indicating that the response was governed by class I, rather than class II, MHC genes. C3H/HeN (H-2(k)) and C3H.SW (H-2(s)) strains were also compared for the development of skin tumors and the persistence of DMBA-DNA adducts. When subjected to a DMBA initiation, phorbol 12-tetradecanoate 13-acetate (TPA)-promotion skin-tumorigenesis protocol, C3H/HeN mice, (which develop cell-mediated immunity to DMBA) were found to have significantly fewer tumors than C3H.SW mice (a strain that failed to develop a cell-mediated immune response to DMBA). DMBA-DNA adducts were removed more rapidly in C3H/HeN than in C3H.SW mice. The results indicate that genes within the MHC play an important role in several of the biological activities of carcinogenic polyaromatic hydrocarbons. The observations are consistent with the hypothesis that cell-mediated immunity to chemical carcinogens serves to protect individuals by removing mutant cells before they can evolve into clinically apparent neoplasms.     

Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations

A basic principle of immunology is that prior immunity results in complete protection against a homologous agent. In this study, we show that memory T cells specific to unrelated viruses may alter the host's primary immune response to a second virus. Studies with a panel of heterologous viruses, including lymphocytic choriomeningitis (LCMV), Pichinde (PV), vaccinia (VV), and murine cytomegalo (MCMV) viruses showed that prior immunity with one of these viruses in many cases enhanced clearance of a second unrelated virus early in infection. Such protective immunity was common, but it depended on the virus sequence and was not necessarily reciprocal. Cell transfer studies showed that both CD4 and CD8 T cell populations from LCMV-immune mice were required to transfer protective immunity to naive hosts challenged with PV or VV. In the case of LCMV-immune versus naive mice challenged with VV, there was an enhanced early recruitment of memory phenotype interferon (IFN) gamma-secreting CD4(+) and CD8(+) cells into the peritoneal cavity and increased IFN-gamma levels in this initial site of virus replication. Studies with IFN-gamma receptor knockout mice confirmed a role for IFN-gamma in mediating the protective effect by LCMV-immune T cell populations when mice were challenged with VV but not PV. In some virus sequences memory cell populations, although clearing the challenge virus more rapidly, elicited enhanced IFN-gamma-dependent immunopathogenesis in the form of acute fatty necrosis. These results indicate that how a host responds to an infectious agent is a function of its history of previous infections and their influence on the memory T cell pool.     

Measurement of extracellular fluid volume and blood volume in sheep

Methods are described for the simultaneous measurement of extracellular fluid volume (ECFV) and plasma volume (PV) in sheep using dilution of 82Br (as sodium bromide) and 131I-labelled ovine gamma globulin. Following injection of 82Br (100 micronCi), equilibrium in blood was reached after 3 h at which time only 4% of the injected dose was in rumen water. The ECFV was measured as the mean of the 2- and 3-h bromide space after correction for the relative water content of plasma, the Gibbs-Donnan factor and the loss of 82Br into red blood cells. 131I-labelled ovine gamma globulin (20 micronCi) was injected after the 3-h 82 Br space was obtained and blood samples were taken at 10, 20, 30 and 40 min. In 16 determinations in 11 sheep (25-47 kg body weight) the mean (+/- s.e.m.) ECFV was 9112 +/- 289 ml (or 245 +/- 9 ml/kg). The mean PV for 16 observations in 11 sheep measured together with ECFV was 1597 +/- 62 ml (or 42-8 +/- 1-8 ml/kg). Although there was no relationship between body weight and PV there was a significant correlation between ECFV and body weight and also significant negative correlations between body weight and ECFV or PV when these were expressed as a function of body weight. The variation in ECFV measured on four occasions over 7-10 days in four sheep was 3-5% (range 2-6-4-6%). For PV measured in two animals on two consecutive days at the same time as ECFV the coefficient of variation was 1-5 and 2-1%. Acute sodium depletion (250-670 mmol) by parotid duct cannulation in three sheep resulted in a fall in ECFV which would account for only 15-20% of the sodium deficit. The remainder is presumably derived from ruminal sodium stores.     

Development of immunity against antigens of the A and B blood groups during postembryogenesis in chickens

51Cr-labelled erythrocytes were injected into young chicks, F1 hybrids of the inbred chicken lines, from hatching to 2 months of age. The onset of immunity was measured by means of elimination of labelled red blood cells. It was found that with the B-locus difference between donors and recipients the immune response developed from 4 days of age to the end of the first week, whereas with the A-locus difference it developed during the second week of life. The onset of immunity is delayed in inbred chickens compared to outbred chickens, because we have used one alloantigen difference.     

Long-lived protective immunity to Listeria is conferred by immunization with particulate or soluble listerial antigen preparations coadministered with IL-12

The ability of IL-12 to promote the development of Th1-type immune responses, and thus promote cellular immunity, has been well documented. In a previous report, we showed that coadministration of IL-12 with heat-killed Listeria monocytogenes elicited intense antigen-specific T cell responses that conferred protective listerial immunity. Herein, we have extended those studies by demonstrating that multiple injections of heat-killed L. monocytogenes and IL-12 elicit memory responses that confer long-lived (> or = 3 months) protective immunity and that immunity can be transferred adoptively with cells from immunized mice injected into naive mice. These studies have also demonstrated that the powerful adjuvanticity of IL-12 is observed with soluble as well as particulate immunogens and is operative in mouse strains that have different MHC haplotypes. These findings suggest that IL-12 may be a useful adjuvant component of vaccines for a wide variety of pathogens in animal and human systems.     

Cell-mediated immunity and blocking factor in ovarian carcinoma

Lymphocyte-mediated cytotoxicity (cell-mediated immunity) to ovarian carcinoma cells and serum blocking factor were measured in 37 patients. Short-term cultures of tumor cells and a low ratio of effector to target cells were used throughout the study, minimizing nonspecific cytotoxicity. Sixteen patients were followed for long periods of time, and correlation with the course of the disease and with therapy could be obtained. Although the level of cell-mediated immunity did not always correspond to the clinical status of the patient, the presence of blocking factor was associated with clinical relapse in 14 of 16 patients. Chemotherapy with single alkylating agents or combinations of drugs caused no significant or permanent depression of cell-mediated immunity as measured in this way. In addition, blocking factor disappeared in 2 patients during remission. It appears that the chemotherapy for ovarian carcinoma may not be significantly immunosuppressive against established levels of cell-mediated immunity and may in certain instances have effects potentially beneficial to the host as evaluated by lymphocyte-mediated cytotoxicity and blocking factor studies.     

Immune system dysfunction during exposure to poult enteritis and mortality syndrome agents

Poult Enteritis and Mortality Syndrome (PEMS) is a condition of yet undefined etiology. Affected flocks may exhibit 100% morbidity with mortality up to 50% or more between 2 to 4 wk of age. The current study reports the immune status of poults experimentally infected with PEMS agent(s) in various trials. When compared with the unchallenged controls, PEMS-infected poults had significant atrophy of the bursa (up to 2-fold), thymus (up to 11-fold), and spleen (up to 2-fold) (P < or = 0.05). When challenged with SRBC, PEMS-infected poults had 1 to 2 log2 lower anti-SRBC antibody titers than the controls (P < or = 0.05). Responsiveness to a mitogenic lectin, phytohemagglutinin-P, was reduced significantly in PEMS poults (P < or = 0.05). These data show that the immune system of the poults is compromised significantly during PEMS infection in terms of lymphoid organ integrity and humoral and cell-mediated immunity. These findings imply, therefore, that immune dysfunction may contribute to the mortality observed during PEMS outbreaks.     

Acute inflammatory response to sheep red blood cell challenge in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): phenotypic and functional analysis of peritoneal exudate cells

TCDD is a widespread environmental contaminant of concern to human health because of its well-recognized immunotoxicity in laboratory animals. Suppression of the murine antibody response to xenogeneic erythrocytes has been shown to be one of the most sensitive assays for TCDD immunotoxicity. However, the cellular mechanisms underlying the suppressed immune function have not been fully elucidated. In the present studies, peritoneal macrophage recruitment, activation, and antigen-presenting function in response to sheep red blood cell (SRBC) injection were compared in C57Bl/6 mice treated with a single oral dose of 0 or 5 micrograms TCDD/kg. In vehicle-treated mice, SRBC injection induced a typical inflammatory response in the peritoneal cavity. Within 6 hr, the number of neutrophils increased and remained elevated until 40 hr. Macrophage numbers increased at 24 hr and remained elevated through 72 hr. In TCDD-treated mice, a hyperinflammatory response to SRBC was observed. The total number of peritoneal exudate cells was significantly greater at 16, 24, and 40 hr after SRBC challenge when compared to that of vehicle-treated mice. The increased number of peritoneal cells reflected significant increases in both neutrophils and macrophages. Mac-1+ peritoneal cells were examined by two-color flow cytometric analysis on Days 0-3 after SRBC injection for expression of the activation markers F4/80 and I-A. The intensity of F4/80 fluorescence significantly decreased 24-72 hr following SRBC challenge, while fluorescence associated with I-A significantly increased at 72 hr. These changes are consistent with macrophage activation. TCDD did not significantly alter F4/80 expression on Mac-1+ cells, whereas I-A expression was increased earlier on cells from TCDD-treated mice. However, TCDD treatment did not alter the antigen presentation function of peritoneal cells, assessed by their ability to induce the proliferation of SRBC-primed T cells in vitro. The antigen-presenting function of adherent spleen cells was also not altered by TCDD exposure. To test the hypothesis that an excess number of phagocytes in TCDD-treated mice were clearing the antigen more efficiently, leading to a smaller (e.g., suppressed) antibody response, we attempted to overcome TCDD suppression by increasing the amount of SRBC antigen used for challenge. However, the magnitude of the anti-SRBC response in TCDD-treated mice was not significantly altered by increasing the antigen challenge dose, suggesting that enhanced clearance of antigen by macrophage is not a mechanism for TCDD-induced suppression of the anti-SRBC response.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pertussis toxin potentiates Th1 and Th2 responses to co-injected antigen: adjuvant action is associated with enhanced regulatory cytokine production and expression of the co-stimulatory molecules B7-1, B7-2 and CD28

Pertussis toxin (PT) is a major virulence factor of Bordetella pertussis which exerts a range of effects on the immune system, including the enhancement of IgE, IgA and IgG production, delayed-type hypersensitivity reactions, and the induction of experimental autoimmune diseases. However, the mechanism by which PT mediates adjuvanticity remains to be defined. In this investigation we have shown that PT can potentiate antigen-specific T cell proliferation and the secretion of IFN-gamma, IL-2, IL-4 and IL-5 when injected with foreign antigens. A chemically detoxified PT and a genetic mutant with substitutions/deletions in the S-1 and B oligomer components that abrogate enzymatic and binding activity displayed no adjuvant properties. In contrast, a non-toxic S-1 mutant devoid of enzymatic activity but still capable of receptor binding retained its adjuvanticity, augmenting the activation of both Th1 and Th2 subpopulations of T cells. In an attempt to address the mechanism of T cell activation, we found that PT stimulated the production of IFN-gamma and IL-2 by naive T cells and IL-1 by macrophages. Therefore potentiation of distinct T cell subpopulations may have resulted in part from the positive influence of IFN-gamma on the development of Th1 cells and the co-stimulatory role of IL-1 for Th2 cells. Furthermore, PT augmented expression of the co-stimulatory molecules B7-1 and B7-2 on macrophages and B cells, and CD28 on T cells, suggesting that the adjuvant effect may also be associated with facilitation of the second signal required for maximal T cell activation. This study demonstrates that the immunopotentiating properties of PT are largely independent of ADP-ribosyltransferase activity, but are dependent on receptor binding activity and appear to involve enhanced activation of T cells.     

The cellular immune response to Bordetella pertussis in two children with whooping cough

There is increasing evidence that the cellular immune response to Bordetella pertussis plays an important role in the immune protection. Particularly in animal models, Bordetella pertussis-specific T-cells have been shown to confer immunity. In this case report, we therefore investigated the cellular immune response to whole cell Bordetella pertussis bacteria, to the pertussis antigens filamentous hemagglutinin and pertussis toxoid defined by lymphoproliferation and cytokine secretion. Two children with whooping cough were compared to three individuals vaccinated against whooping cough with a whole cell pertussis vaccine. In contrast to the vaccinated controls, the cellular immune response to Bordetella pertussis in children with whooping cough was characterized by a strong proliferation of T cells to whole pertussis bacteria as well as to filamentous hemagglutinin and pertussis toxoid. This response was defined by a marked Th-1 type T cell response with IFN-gamma secretion to all Bordetella pertussis antigens. However, in the control individuals IFN-gamma was secreted only to whole cell Bordetella pertussis bacteria and filamentous hemagglutinin but not to pertussis toxoid. A Th-2 type cytokine response could not be detected in any condition. Our observations suggest that in the immune defense of a natural Bordetella pertussis infection, the Th-1 specific T cell response to filamentous hemagglutinin and particularly to pertussis toxoid may play a major role.     

Evaluation of humoral immune responses in cattle grazing endophyte-infected or endophyte-free fescue

Anecdotal reports suggest cattle with fescue toxicosis may not respond to vaccination and thus, experience increased incidence of Bovine Respiratory Disease Complex (BRDC) when shipped to feedlots. Fescue toxicosis causes hypoprolactemia in cattle. Hypoprolactemia decreases humoral immune responses in mice. Therefore, a study was conducted to compare the magnitude of primary and secondary humoral immune responses against specific antigens in cattle grazing endophyte-infected or endophyte-free fescue. Angus steers were blocked by weight and allocated into four groups. Two groups grazed endophyte-infected (EI) fescue and the other two groups grazed endophyte-free (EF) fescue. All steers were injected IM on d 0 and 21 with lysozyme without adjuvant and concanavalin. A (Con A) with sheep red blood cells (SRBC) in incomplete adjuvant of Freund. Steers were bled on days 0, 21 and 35 post-vaccination. Average daily gains (ADG), alkaline phosphatase (ALP) activity, cholesterol concentrations, rectal temperatures, and serum prolactin concentrations were measured to confirm fescue toxicosis in steers grazing EI fescue. Antibodies to Con A and SRBC were determined by ELISA and hemagglutination assay, respectively. The ADG were decreased for the EI group during the first month. Rectal temperature were elevated and serum prolactin concentrations were decreased in the EI group. Cholesterol and ALP concentrations also were decreased in the EI group. Primary and secondary immune responses against Con A tended to be increased and were increased against SRBC in the EI group. Antibodies against lysozyme were not induced in either group. In conclusion, cattle grazing EI fescue mounted similar humoral immune responses to vaccination, despite hypoprolactemia, as cattle grazing EF fescue. Increases in bovine respiratory disease in cattle maintained on EI fescue probably is not associated with lack of humoral immune response to vaccination protocols as a result of fescue toxicosis.     

Efficacy of transfer factor in treating patients with recurrent ocular herpes infections

Recurrent ocular herpes is an insoluble problem for the clinician. As cellular immunity plays an important role in controlling herpes relapses, and other studies have shown the efficacy of HSV-specific transfer factor (TF) for the treatment of herpes patients, an open clinical trial was undertaken in 134 patients (71 keratitis, 29 kerato-uveitis, 34 uveitis) suffering from recurrent ocular herpetic infections. The mean duration of the treatment was 358 days, and the entire follow-up period 189,121 before, and 64,062 days after TF treatment. The cell-mediated immune response to the viral antigens, evaluated by the lymphocyte stimulation test (LST) and the leucocyte migration test (LMT) (P < 0.001), was significantly increased by the TF treatment. The total number of relapses was decreased significantly during/after TF treatment, dropping from 832 before, to 89 after treatment, whereas the cumulative relapse index (RI) dropped, during the same period, from 13.2 to 4.17 (P < 0.0001). No side effects were observed. It is concluded that patients with relapsing ocular herpes can benefit from treatment with HSV-specific TF.     

Antibody-coated sheep erythrocytes suppress the ability of polyclonal B-cell activators to induce plaque-forming cells against sheep erythrocytes

The primary immune response to untreated sheep erythrocytes (SRBC) in vitro was suppressed by the addition of antibody-coated SRBC. A mixture of SRBC and antibody-coated SRBC also suppressed the induction of anti-SRBC plaque-forming cells by the polyclonal B cell activators lipopolysaccharide, purified protein derivative of tuberculin, and native dextran. Injection of a mixture of SRBC and antibody-coated SRBC into mice led to an increased response to SRBC. It seems plausible from the in vitro findings that the Fc part of antibodies complexed to an antigen can exert a negative signal on antigen-specific B cells that cannot be overcome by positive signals delivered by polyclonal B cell activators.     

Defective IL-2 receptor expression in lymphocytes of patients with arsenic-induced Bowen's disease

The immune function of peripheral mononuclear cells (MNC) in patients with endemic arsenic-induced Bowen's disease (BD) was investigated. Many cytokines and immune-related factors were determined in the present study. Interleukin-1beta and TNF-alpha production was used as an indicator of monocyte/macrophage function. II-2 and sIL-2R production was used as an indicator of lymphocyte activation. The release of sCD4 and sCD8 was used as an indicator of activation of respective T-cell subpopulations. Production of IFN-gamma and IL-2 reflected the cellular effector function of helper T-cells type 1. In vivo cell-mediated immunity was also assessed by estimation of the percentage of T-cells in peripheral blood MNC and the nonspecific delayed-type hypersensitivity (DTH) response to 2,4-dinitrochlorobenzene (DNCB). Both assays revealed depressed cell-mediated immunity in BD. Compared with healthy controls, spontaneous and PHA-induced IFN-gamma and TNF-alpha production was significantly decreased in BD whereas spontaneous release of IL-2, sCD4 and sCD8 was significantly increased. Although PHA stimulation increased IL-2 release, the expression of IL-2R alpha and beta chains and the release of sIL-2R were not proportionately increased in BD. In addition, IL-2-mediated [3H]-thymidine incorporation by MNC in patients with BD was significantly decreased. These findings suggest that the defective cell-mediated immune function in BD is due to impairment of membrane IL-2R expression in lymphocytes after stimulation.