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Effect of age and degree of immune activation on cytochrome P450 3A4 activity after influenza immunization.

STUDY OBJECTIVE: To measure age- or sex-related changes in cytochrome P450 (CYP) activity secondary to influenza vaccination. DESIGN: Open-label, single-dose study. SETTING: General clinical research center at a university hospital. SUBJECTS: Fifteen healthy volunteers aged 22-51 years. INTERVENTION: Each subject was given an erythromycin breath test (ERMBT) to measure CYP3A4 activity before influenza immunization and again on day 7 after immunization. Blood was drawn before immunization and on day 28 after immunization to measure influenza antibody concentrations. MEASUREMENTS AND MAIN RESULTS: Age of subject and change in ERMBT results after influenza immunization were correlated (correlation coefficient -0.624, p < 0.015). However, no correlations could be made between antibody concentrations after influenza immunization or change in antibody concentrations from baseline and age. CONCLUSION: Decreases in CYP3A4 activity after influenza immunization are associated with increasing age. The decreases in CYP3A4 activity, however, are not associated with influenza antibody concentrations. This study bears repeating in an older cohort since the study sample did not include elderly individuals.

Adult↗

Cross-immunity between syngeneic tumors in mice immunized with gamma-irradiated ascites tumors.

C3H/He mice immunized repeatedly with irradiated (13,000 rads 60Co) MM46 or MM48, both transplantable ascites mammary carcinomas of the same strain, were subcutaneously challenged with the identical or the different tumor. In mice immunized with irradiated MM46, the growth of challenges of not only MM46 but also MM48 was inhibited. On the other hand, in mice immunized with irradiated MM48, the growth of challenges of MM48 was inhibited, but the inhibition of the growth of MM46 was not observed. Cross-immunity, therefore, was shown by immunization with MM46 but not with MM48. These findings was considered to indicate that MM46 expressed cross-immunity against MM48 because of its high resistance to the irradiation, and that MM48 did not show cross-immunity to MM46 because of its low resistance to the irradiation.

Animals↗

A polarized Th1 type immune response to Cowdria ruminantium infection is detected in immune DBA/2 mice.

Immune responses to Cowdria ruminantium, an intracellular organism that causes heartwater in domestic ruminants, were characterized in a DBA/2 mouse model. Immunity induced by infection and treatment was adoptively transferable by splenocytes and could be abrogated by in vivo depletion of T cells but not by inhibition of nitric oxide synthase using NG-monomethyl-L-arginine. IgG2a and IgG2b C. ruminantium-specific responses were detected in immune mice. Culture supernatants of splenocytes from immune DBA/2 mice, which were stimulated with crude C. ruminantium antigens or recombinant major antigenic proteins 1 or 2, contained significant levels of interferon (IFN)-gamma and interleukin (IL)-6, but insignificant levels of IL-1alpha, IL-2, IL-4, IL-5, IL-10, IL-12, tumor necrosis factor-alpha (TNF), and nitric oxide. A similar response was detected during primary infection, although IFN-gamma levels decreased significantly during clinical illness and then increased following natural or antibiotic-aided recovery. These data support the conclusion that protective immunity to C. ruminantium in DBA/2 mice is mediated by T cells and is associated with a polarized T helper 1 type of immune response. This murine model could be utilized to screen for protective C. ruminantium antigens that provoke Th1 type immune responses and for evaluation of these antigens in recombinant vaccines against heartwater.

Adoptive Transfer↗

The regional immunization registry as a public health tool for improving clinical practice and guiding immunization delivery policy.

OBJECTIVES: We assessed the distribution of immunization records among 3 health care delivery sectors and the impact of a regional immunization registry on "up to date" rates. METHODS: Immunization registry records in 2 regions were categorized as having originated in private practices, community health centers, or public health clinics. "Up to date" rates were calculated after we sequentially added immunization records from the 3 sectors. RESULTS: The percentage of children with immunizations documented in multiple sectors increased with age from 7 to 24 months, and children who were seen in multiple sectors were more likely to be up to date. There were relative increases in "up to date" rates of 50% for children aged 24 months. CONCLUSIONS: The regional immunization registry is a powerful public health tool for increasing documented "up to date" rates and providing insights into patterns of immunization delivery.

Child, Preschool↗

The effect of environmental temperature on immune response and metabolism of the young chicken. 2. Effect of the immune response to sheep red blood cells on energy metabolism.

We investigated the effect of an immune response, following injection with sheep red blood cells (SRBC) in pullets, on energy balance characteristics and on protein and far gain. Controls were sham-immunized with phosphate buffered saline (PBS). Feed intake, body weight, rate of gain, and metabolizability of gross energy were not significantly (P greater than .10) affected by SRBC-immunization. The magnitude and composition of energy gain were influenced by SRBC-immunization. The SRBC-immunized pullets retained significantly (P less than .01) more energy, deposited significantly (P less than .05) more fat, and had a significantly (P less than .01) lower maintenance requirement of metabolizable energy than PBS-injected pullets during days 1 to 5 after injection. During days 6 to 10 after injection, SRBC-immunized pullets deposited significantly (P less than .05) less fat and significantly (P less than .10) more protein than PBS-injected pullets. Effects of vaccination on metabolic rate and performance characteristics may be comparable with these effects of SRBC-immunization.

Animals↗

Effects of gonadal steroids and their antagonists on the humoral immune response of immune-selected broiler chicks.

The effects of gonadal hormones, testosterone (Te) and estrogen (E2) as factors in the development of the immune system in two lines, high response (HC) and low response (LC), of broiler chickens divergently selected for early or late immune maturation were studied. For this purpose, plasma Te and E2 levels were tested and correlated with immune response. Also, the effects of exogenous administration of gonadal steroids testosterone propionate (TP), dihydrotestosterone (DHT), and estradiol 3-benzoate (EB), and the nonsteroidal androgen antagonist flutomide (Flu) and anti-estrogen tamoxifen (Tam) on the immune system were studied. Male chicks of the LC line had a higher level of endogenous Te during first 30 d posthatch. The administration of TP or DHT had no noticeable effect on the humoral immune response, whereas DHT suppressed growth of the bursa of Fabricius of both sexes of HC line. No differences in the endogenous E2 level were observed between sexes in either line. Administration of EB inhibited comb and testicle growth and enhanced significantly the humoral immune response to Escherichia coli and sheep erythrocytes (SRBC). The anti-androgen Flu and anti-estrogen Tam strongly inhibited humoral immune response to E. coli and SRBC antigen, whereas no effects on comb and testicle growth were observed. The experimental results suggest that gonadal hormones have similar principal posthatch effects in avian as in mammals; however, the gonadal steroids prehatch effects and the genetic-physiological-environmental effects require further study.

Analysis of Variance↗

The pulmonary environment promotes Th2 cell responses after nasal-pulmonary immunization with antigen alone, but Th1 responses are induced during instances of intense immune stimulation.

The purpose of this study was to determine the nature of the CD4(+) Th cell responses induced after nasal-pulmonary immunization, especially those coinciding with previously described pulmonary inflammation associated with the use of the mucosal adjuvant, cholera toxin (CT). The major T cell population in the lungs of naive mice was CD4(+), and these cells were shown to be predominantly of Th2 type as in vitro polyclonal stimulation resulted in IL-4, but not IFN-gamma, production. After nasal immunization with influenza Ag alone, Th2 cytokine mRNA (IL-4 and IL-5) levels were increased, whereas there was no change in Th1 cytokine (IL-2 and IFN-gamma) mRNA expression. The use of the mucosal adjuvant, CT, markedly enhanced pulmonary Th2-type responses; however, there was also a Th1 component to the T cell response. Using in vitro Ag stimulation of pulmonary lymphocytes, influenza virus-specific cytokine production correlated with the mRNA cytokine results. Furthermore, there was a large increase in CD4(+) Th cell numbers in lungs after nasal immunization using CT, correlating with the pulmonary inflammatory infiltrate previously described. Coincidentally, both macrophage-inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta mRNA expression increased in the lungs after immunization with Ag plus CT, while only MIP-1beta expression increased when mice were given influenza Ag alone. Our study suggests a mechanism to foster Th1 cell recruitment into the lung, which may impact on pulmonary immune responses. Thus, while Th2 cell responses may be prevalent in modulating mucosal immunity in the lungs, Th1 cell responses contribute to pulmonary defenses during instances of intense immune stimulation.

Adjuvants, Immunologic↗

Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment.

Intensive chemotherapy is capable of reducing the viral load in HIV-1-infected individuals while infected cells are still present. A special property of DNA immunization is to induce both new CTL and Ab responses. We evaluated the possibility of inducing new immune responses in already infected individuals by means of DNA constructs encoding the nef, rev, or tat regulatory HIV-1 genes. Significant changes in viral loads and CD4+ counts were observed in four patients who started highly active antiretroviral treatment (HAART) during the immunization study. The DNA immunization induced Ag-specific T cell proliferation, which persisted up to 9 mo after the last DNA injection, and cytolytic activities but did not, by itself, reduce viral load. Increased levels of CTL precursor cells were induced in all nine DNA-immunized patients. The profile of IFN-gamma secretion observed when human PBMC were transfected with the nef, rev, and tat DNA resembled that found in the CTL activity (nef > tat > rev). Ab responses that occurred after immunizations were of a low magnitude. In accordance with the high IL-6 production induced by the nef DNA plasmid, IgG titers were highest in patients immunized with nef DNA. The initiation of HAART appears to contribute to the induction of new HIV-specific CTL responses, but by itself did not cause obvious re-induction of these activities.

AIDS Vaccines↗

Ethanol inhibition: the humoral and cellular immune response to hepatitis C virus NS5 protein after genetic immunization.

BACKGROUND: The combination of chronic hepatitis C virus (HCV) and ethanol may increase viral replication, impair cellular immunity, and result in severe and progressive liver disease. Because HCV nonstructural proteins play a major role in viral elimination, we examined the cellular and humoral immune responses after genetic immunization against NS5 in a chronic ethanol mouse model. METHODS: Mice were fed an ethanol or isocaloric pair-fed control liquid diet and were immunized with HCV NS5-expression plasmid. RESULTS: The humoral and cellular arms of the immune system were significantly impaired in ethanol-fed mice. Abstinence partially reversed the inhibitory effects on antibody levels and the CD4+ proliferative immune response but did not restore the CD8+ cytotoxic T-cell response to this HCV nonstructural protein. Furthermore, we determined whether murine interleukin-2 coadministration with the NS5 expression plasmid would reverse the inhibitory effects of chronic ethanol consumption; again, partial restoration was observed for B-cell and CD4+ T-cell activity, but not for cytotoxic T cells. CONCLUSIONS: These results suggest that the high rate of chronic HCV infection in alcoholics may be due to ethanol's effects on antiviral immune responses.

Animals↗

Immune complexes in the spleen. The difference between competitive inhibition of immune complex trapping in spleen follicles and inhibition by paratyphoid vaccine.

Paratyphoid vaccine injected between 4 days and 3 hours before injection of labelled immune complexes (125-I-labelled BGG-anti-BGG), inhibits follicular trapping of these complexes in the mouse spleen. Inhibition is maximal when paratyphoid vaccine is given 1 day before, almost no label being found in the spleen follicles. No inhibition of follicular trapping of the complexes occurred when paratyphoid vaccine was injected simultaneously with the labelled immune complexes. Competitive inhibition was found when unlabelled immune complexes were given together with labelled immune complexes. Simultaneous injection of mice with paratyphoid vaccine and labelled immune complexes resulted in an additonal form of localization of the labelled immune complexes in the white pulp, heavily labelled clumps also appearing in the periarteriolar lymphocyte sheaths and follicles. The results are discussed in relation to the mechanism of immune complex trapping in spleen follicles.

Animals↗

Production of Anti-P16 Sera by Genetic Immunization and Protein Immunization.

Genetic immmunization is a new method of producing antibody, which is different from protein immunization. In order to produce anti-P16 sera and to find out the difference between genetic immunization and protein immunization, fusion protein GST-P16 and eukaryotic expression vector pCMV-p16 were injected in rabbit respectively. Western blot analysis showed that the titer of sera from protein immunization was 1:625, which was much higher than the titer from genetic immunization sera. Our results indicate that much has to be done on the characteristics of the genetic immunization and methods for enhancing its immunization effect, before we can use it widely to produce antibody.

Journal Article↗

Cellular immune response to the antigen administered as an immune complex.

Immune complexes are specifically bound to the Fc receptors on the surface of various types of cells capable of presenting antigens. It was therefore determined if human serum albumin (HSA), bound in an immune complex, is presented more efficiently to the HSA-specific T cells than HSA alone. Primed, polyclonal murine T cells were stimulated in vitro with either HSA alone or HSA bound at equivalence to syngeneic, polyclonal anti-HSA antibodies of IgG class. The stoichiometric composition of the insoluble immune complex was AgAb2.91. The present study shows that 10(2)-10(3)-fold lower doses of HSA are sufficient for the same T-cell response in vitro, if HSA is administered to the cultures in the form of the immune complex rather than in the soluble form. The enhancement of T-cell proliferation in the presence of immune complex was blocked with monoclonal antibody (mAb) against Fc receptor. Our results indicate that binding of antigen in the immune complex could play an important role in enhancing an antigen-specific cellular immune response.

Animals↗

Immunizing California's children. Effects of current policies on immunization levels.

Data collected by the Immunization Unit of the California Department of Health Services from 1979 to 1987 were analyzed to determine the effects of changes in state policy on the immunization levels of children in California. By December 1986, 90% of all children entering kindergarten in California were adequately immunized, representing a 15% increase from 1979. Although California has shown substantial improvements, it still lags behind the national weighted average. Even with high levels of immunization at kindergarten entry, many toddlers of 7 months and 2 years old remain inadequately immunized. Children immunized solely in the private sector were more adequately immunized than those served by public health clinics; the public-private difference for infants aged 7 months was nearly twofold.

California↗

Local and systemic immune response in rabbits after intraintestinal immunization with a double-marker attenuated strain of Salmonella typhimurium.

Local and systemic immune response was studied in 3 groups of rabbits immunized and reimmunized 190 days later with S. typhimurium double-marker attenuated strain 1,771 and doses ranged from 20.10(9) to 0.2.10(9) cells. Another group of rabbits was immunized with extract (hydroxylammine) vaccine. It was found that the attenuated strain persisted for considerable time in the gut, and induced pronounced and continuous immune response as measured by the passive hemagglutination test. The serum antibody response had the character of a secondary one with switching on the synthesis of IgM to IgG already after basic immunisation. By the Coombs' technique it was shown that specific immunoglobulins demonstrated in feces were secretory antibodies of the class IgA (SIgA). The immune response developed after reimmunization was still more vigorous and prolonged pointing to an immune memory existance. It was possible to obtain well manifested immunity with the lowest dose. The extract vaccine revealed only weak and transitory serum and intestinal antibody levels without SIgA appearance. The results obtained in this setup make S. typhimurium 1771 a perspective candidate for a live vaccine.

Animals↗

Learned helplessness and immunization: sensitivity to response-reinforcer independence in immunized rats.

In experiments 1 and 2, we examined the learned helplessness and immunization effects using a test in which appetitive responding was extinguished by delivering noncontingent reinforcers. Contrary to learned helplessness theory, "immunized" animals showed performance virtually identical to that of animals exposed only to inescapable shock, and different from nonshocked controls. Experiment 2 suggests that the helplessness effect and the lack of immunization are not due to direct response suppression resulting from shock. In Experiment 3, where the immunization effect was assessed by measuring the acquisition of a response to obtain food when there was a positive response-reinforcer contingency, immunization was observed. These results cannot be explained on the basis of proactive interference, but suggest that animals exposed to the immunization procedure acquire an expectancy of response-reinforcer independence during inescapable shock. Thus, immunization effects may reflect the differential expression of expectancies, rather than their differential acquisition as learned helplessness theory postulates.

Animals↗

Immune response of pregnant cows to bovine rotavirus immunization.

Fifteen pregnant Holstein cows were freely assigned to 3 experimental groups (5 cows in each group). Cows in group I were inoculated IM and intramammarily (IMm) with Ohio Agricultural Research and Development Center (OARDC) tissue culture-propagated modified-live Nebraska calf diarrhea bovine rotavirus with added adjuvant (OARDC vaccine-immunized cows). Group II cows were given IM injections of a commercial modified-live rotavirus-coronavirus vaccine (commercial vaccine-immunized cows), and the remaining 5 cows were noninoculated controls (group III). Rotavirus antibody in colostrum and milk was mainly associated with immunoglobulin (Ig)G1, and less so with IgG2, IgA, and IgM, as analyzed by the enzyme-linked immunosorbent assay (ELISA), using monospecific anti-bovine IgG1, IgG2, IgM, and IgA sera. In serum, the rotavirus antibody was distributed almost equally between IgG1 and IgG2. The same relationships appeared in both immunized and nonvaccinated cows. All OARDC vaccine-injected cows had virus-neutralization (VN) and ELISA IgG1 rotavirus antibody titers in serum and mammary secretions at significantly increased levels (at least 100-fold; P less than 0.05) compared with the titers in groups II (commercial vaccine-immunized cows) and III (controls). Serum, colostrum, and milk antibody titers from these latter 2 groups did not differ statistically. The ELISA IgG2, IgA, and IgM rotavirus antibody titers also were significantly greater in mammary secretions from OARDC vaccine-immunized cows than in groups II and III cows. There was a high correlation between ELISA IgG1 and VN rotavirus antibody titers for all samples tested (r = 0.97, P less than 0.001), but ELISA IgG1 antibody titers were consistently higher than VN titers. The ELISA IgG1 and VN antibody titers of milk samples collected from cows 30 days after parturition were higher from the OARDC vaccine-immunized cows (ELISA IgG1, geometric mean titer (GMT) = 3,511; VN GMT = 1,689) than were titers from the group II cows (ELISA IgG1 GMT = 39; VN GMT = 33) or group III cows (ELISA IgG1 GMT = 21; VN GMT = 19). These results indicate that IM plus IMm immunization of pregnant cows, using modified-live bovine rotavirus with added adjuvant, may significantly enhance serum, colostrum, and milk rotavirus antibody titers, whereas IM vaccinal inoculation of pregnant cows with a commercial modified-live rotavirus-coronavirus vaccine may not.

Adjuvants, Immunologic↗

Some data concerning immune processes in concomitant tumor immunity experimental models. Comparative in vivo and in vitro investigation I. In vivo experiments.

Concomitant tumor immunity evinced by C57BL/6 mice, bearing a MC-induced sarcoma, was evaluated by graded challenge doses for different primary tumor sizes (2-3,4-6,8-12% tumor weight of the total body weight TW/TBW). 100% of mice bearing tumors, representing 2--6% of total body weight, rejected doses from 0.2--1 X 10(4) cells. The gradual curtailment of the concomitant tumor immunity, depending on increasing TW/TBW ratio, could be evaluated, using adequately increasing challenge doses. The immune equipotency of the whole s.c. body area, the failure to modify the concomitant tumor immunity by drainin node excision and the demonstration of its dependency upon the total challenge-dose and its independency upon fractionated multilocular inoculation of the challenge, showed clearly that the concomitant tumor immunity is a local expression of general immunity. The experimental model allows a valuable biological assessment of the tumor-beareer immune status and represents likewise an adequate tool for immunotherapeutic effects estimation.

Animals↗

Evidence for immune facilitation of breast cancer growth and for the immune promotion of oncogenesis in breast cancer.

Autoimmune diseases have been extensively studied in man and experimental animal models and salient points are reviewed, as a clear understanding of the immune mechanisms involved is essential if one is to understand the potential of immune interactions with established cancer cells or in the premalignant period of hyperplasia. Such reactions may be of benefit to the host, with down regulation of tumor growth, or unfavourable, with facilitation of oncogenesis and cancer growth. In particular, evidence is cited that supports a beneficial effect of the host response to non-small-cell lung cancer and the association of a poor prognosis in established breast cancer caused by a heightened immune response to the tumor. Histologic evidence supports these conclusions, as do studies of specific and nonspecific immune reactivity in breast cancer patients. The potential for cytokines to stimulate breast cancer growth, increase angiogenesis and decrease cell adhesion is reviewed, also recent evidence for autologous lymphocyte stimulation of breast cancer. Parallels between immune promotion of breast cancer in mice, caused by the mouse mammary tumor virus, and the development of breast cancer in women are also reviewed. If the mouse model has relevance for human breast cancer, one could predict that there would be a reduced incidence of breast cancer in a population of chronically immunosuppressed women following organ transplantation. Such is the case. This finding, plus the fact that all treatments that have shown efficacy in breast cancer have one thing in common, they are immunosuppressive, strongly support the role of immune facilitation of breast cancer growth and immune promotion of oncogenesis in breast cancer in a substantial number of growth.

Animals↗