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Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy.

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.

ADP-ribosyl Cyclase↗

Infection by different HIV-1 subtypes (B and C) results in a similar immune activation profile despite distinct immune backgrounds.

We compared the immune activation profile of 46 HIV-negative and 75 HIV-positive Israelis infected with HIV-1 subtype B, with 85 HIV-negative and 102 HIV-positive Ethiopian immigrants to Israel, who were infected with HIV subtype C. The HIV-negative Ethiopians had exceedingly high blood levels of eosinophils, immunoglobulin E (IgE), and p75s tumor-necrosis factor receptors (p75sTNFR); secretion of interleukin-4 (IL-4) and IL-10 by peripheral blood mononuclear cells (PBMC); proportion of human leukocyte antigen (HLA)-DR+ cells within CD3+, CD4+, and CD8+ T-cell subsets; and proportion of CD45RO+ CD4+ cells; while having significantly lower secretion of interferon-gamma (IFN-gamma) by PBMC and percentage of CD45RA+ CD4+ and CD28+ CD8+ cells. HIV infection in both populations was associated with reduced IL-2, IL-4, IL-10, and IL-12 secretion, number of CD28+ and CD45RA+ CD8+ cells, and increased number of HLA-DR+-CD3+, CD4+, and CD8+ cells, and CD45RO+ CD8+ cells. Thus, infection with HIV-1 subtypes B and C of studied Israelis and Ethiopians, respectively, results in a similar immune activation profile at all stages of the infection when living in the same environment, despite the striking different immune profile observed in the HIV-negative Israeli and Ethiopian populations. Together with our previous observations, this indicates that HIV subtype is not a major determinant in the natural course of HIV infection.

Antigens, CD↗

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↗

[The epidemic process in infections before and after active immunization. II. Changes in the number of susceptible individuals in the population during a natural epidemic and its control by active immunization].

Based on the long-term follow-up of the incidence of some infectious diseases in the district and calculations of the actual number of infected subjects, the authors present an estimate of the ratio of susceptible and immune subjects during the unimpaired epidemic process. The epidemic process develops from the lowest range of immune subjects and stops at the highest range. The highest range thus gives the ratio of immune subjects which must be achieved or maintained by active immunization to achieve elimination of a given infection. The authors demonstrate on the model infection the mechanism by which after immunization the shift of infections to higher age groups occurs, and during introduction of the infection not only contact infections occur, but epidemic incidence develops. The restoration of some infections after years of elimination is to a restricted extent a natural phenomenon and does not imply failure of active immunization.

Chickenpox↗

A new model of sciatic inflammatory neuritis (SIN): induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats.

Immune activation near healthy peripheral nerves may have a greater role in creating pathological pain than previously recognized. We have developed a new model of sciatic inflammatory neuritis to assess how such immune activation may influence somatosensory processing. The present series of experiments reveal that zymosan (yeast cell walls) acutely injected around the sciatic nerve of awake unrestrained rats rapidly (within 3h) produces low threshold mechanical allodynia in the absence of thermal hyperalgesia. Low (4 microg) doses of zymosan produce both territorial and extra-territorial allodynia restricted to the ipsilateral hindpaw. Higher (40-400 microg) doses of zymosan again produce both territorial and extra-territorial allodynia. However, allodynia is now expressed both in the ipsilateral as well as contralateral hindpaws. Several lines of evidence are provided that the appearance of this contralateral ('mirror') allodynia reflects local actions of zymosan on the sciatic nerve rather than spread of this immune activator to the general circulation. Since many clinical neuropathies result from inflammation/infection of peripheral nerves rather than frank physical trauma, understanding how immune activation alters pain processing may suggest novel approaches to pain control.

Acute Disease↗

Ginseng and Salviae herbs play a role as immune activators and modulate immune responses during influenza virus infection.

We have investigated the adjuvant roles of common herbal medicines (ginseng, Salviae) and their effects on early immune responses during influenza virus infection in a mouse model. Intranasal co-administration with inactivated influenza virus A (PR8) and ginseng or Salviae extract increased the levels of influenza virus specific antibodies and neutralizing activities compared to immunization with PR8 alone, and provided protective immunity. Salviae co-administration significantly enhanced IFN-gamma and IL-2 cytokine producing splenocytes while ginseng induced high levels of IL-4 and IL-5 cytokine producing cells after challenge infection. Cells expressing an early activation marker CD69 and levels of a pro-inflammatory cytokine IL-6 were highly elevated in lungs from naïve mice during challenge virus infection, which might be a mechanism in lung inflammation leading to death. In contrast, immunized mice that were co-administered ginseng or Salviae modulated CD69 expressing immune cells, did not produce IL-6, and showed significant enhancement of influenza virus specific IgA antibody in lungs after challenge virus infection. Therefore, these results indicate that both ginseng and Salviae play a role as mucosal adjuvants against influenza virus as well as immuno-modulators during influenza virus infection.

Adjuvants, Immunologic↗

[The effect of active immunization with Acanthamoeba culbertsoni in mice born to immune mother].

Acanthamoeba culbertsoni is a pathogenic free-living amoeba causing primary amoebic meningoencephalitis (PAME) in human and mouse. Several reports on the immune responses in mice with this amoebic infection have been published, but the effects of transferred passive immunity on the active immunization in offspring mice have not been demonstrated. This experiment was done to observe the effect of active immunization with Acanthamoeba culbertsoni in mice born to immune mothers. Acanthamoeba culbertsoni was cultured in the CGV medium axenically. Female BALB/c mice weighing about 20g were immunized through the intraperitoneal injection of Acanthamoeba culbertsoni trophozoites 1 x 10(6) each three times at the interval of one week. Offspring mice were immunized two times. The mice were inoculated intranasally with 1 x 10(4) trophozoites under secobarbital anesthesia. There was a statistical difference in mortality between the transferred immunity group and the active immunization group. Statistical differences were not demonstrated in antibody titer between both groups. But L3T4+ T cell/Ly2+ T cell ratio was increased in the transferred immunity group more than active immunization group of the offspring mice at the age of 5 weeks. There was no differences statistically in mortality between both groups. It was recognized that active immunization in offspring mice born to immune mother could modulate the immune status according to the time of immunization.

Acanthamoeba↗

Passive immunization reduces immunity that results from simultaneous active immunization against tick-borne encephalitis virus in a mouse model.

Concomitant administration of an antigen and antibodies of the respective specificity has been shown to result in reduced levels of actively produced antibodies. This has also recently been observed in a clinical trial on simultaneous passive and active immunization against tick-borne encephalitis virus (TBEV). In the current study the influence of simultaneous passive and active immunization on vaccine induced protective immunity against TBEV has been evaluated in a mouse model. Two immunizations with licensed whole-killed TBEV vaccines gave close to complete protection. Administration of human or mouse TBEV antibodies together with the first vaccine dose resulted in a significant reduction of vaccine induced protection against TBEV challenge. This effect was even more pronounced than that observed earlier on the levels of vaccine induced antibody.

Animals↗

Evidence for platelet-activating factor secretion during immune activation in dogs.

To elucidate the potential physiological significance of platelet-activating factor (PAF) in acute bronchoconstriction, we studied the effect of Ascaris suum antigen on the tachyphylactic response to PAF in 15 natively allergic mongrel dogs in vivo. Active bronchial tension was measured isometrically, and mediator secretion was measured as the arteriovenous difference (AVd) in plasma concentration across the lungs. Administration of PAF into the bronchial artery caused dose-related contraction in five control dogs (maximal active tension = 11.8 +/- 1.68 g/cm) that paralleled the increase in the AVd for serotonin (4,188 +/- 175 pg/ml) but not histamine (maximal AVd less than 6.0 ng/ml). The response to PAF was highly tachyphylactic. In contrast to PAF, 1:10 concentration of intra-arterial antigen caused substantial release of histamine (AVd = 308 +/- 57.1 ng/ml; P less than 0.001 vs. PAF). Diminished responsiveness (2-log shift in threshold and maximal contraction; P less than 0.001) to PAF was demonstrated in five dogs after 1:10 antigen, compatible with endogenous release of PAF during prior immune challenge in the same animals. Administration of Ascaris antigen caused a leftward shift in the dose-response curve to serotonin and only mild tachyphylaxis to the maximal response to histamine. Our data are compatible with physiological participation of PAF in eliciting bronchial smooth muscle contraction during the acute phase of immune activation caused by A. suum antigen.

Animals↗

Measles and mumps vaccination as a model to investigate the developing immune system: passive and active immunity during the first year of life.

Evaluations of neutralizing antibody responses in 6-, 9- and 12-month-old infants given measles or mumps vaccine indicated that 6-month-old infants had diminished humoral immune responses associated with passive antibody effects, but also had an intrinsic deficiency in antiviral antibody production, which was independent of passive antibody effects. In contrast, lower neutralizing antibody titers in 9-month-olds were related only to passive antibody effects. Measles and mumps-specific T-cell proliferation and interferon-gamma (IFNgamma) production were induced by vaccination at 6, 9 or 12 months, regardless of passive neutralizing antibodies or age. These observations suggest a need to refine concepts about passive antibody interference and primary vaccine failure, taking into account the sensitization of antiviral T-cells, which occurs in the presence of passive antibodies and is observed in infants who do not develop active humoral immunity. A second dose of measles vaccine given at 12-15 months enhanced antiviral T-cell responses to measles in infants who were vaccinated at 6 or 9 months, and produced higher seroconversion rates. Since T-cell immunity is elicited under the cover of passive antibodies, the youngest infants benefit from the synergistic protection mediated by maternal antibodies and their own capacity to develop sensitized antiviral T-cells, which prime for subsequent exposures to the viral antigens. Conceptually, maternal immunization approaches with vaccines that can be given to women of child-bearing age before pregnancy, or that are safe for administration during pregnancy, should enhance passive antibody protection. Rather than being detrimental to infant adaptive immune responses, maternal vaccination can be coupled effectively with vaccine regimens that elicit priming of antiviral immune responses in infants during the first year of life.

Aging↗

Testosterone metabolism in rabbits actively immunized with testosterone.

Active immunization of male rabbits results in a marked increase in plasma testosterone (T) and in the fraction of T bound to circulating proteins. In order to identify the cause of the increased T levels, the half-life of T after castration, and the metabolic clearance rate (MCR) and production rate (PR) after a single injection of tritiated T were determined in normal and immunized rabbits. In the immunized animals the half-life of T was significantly longer, the MCR showed a 10-fold decrease (10.2 +/- 3.2 1/day compared to 108 +/- 43 1/day) and the PR was increased from 0.44 +/- 0.34 mg/day to 1.20 +/- 0.36 mg/day compared with the control group. The binding of T to circulating antibodies is considered to be the direct cause of the decreased MCR and, via the diminished negative feedback at the hypothalamic-pituitary levels, the indirect cause of the increased PR in the immunized animals.

Animals↗

Active immunization against bioregulators: behavioural and catecholamine changes in albino rats immunized against sydnophen.

Active immunization of white rats against the catecholamine analogue, sydnophen, results in physiological changes extending over two months. The levels of noradrenaline in blood, and dopamine in brain, were depressed, some behavioural activities were reduced and alcohol consumption was lowered. On this basis, active immunization against various bioregulators--a method of inverse regulation--shows promise as a method for achieving long-term adjustment of physiological status.

Alcohol Drinking↗

The HIV infection and immune activation: "to fight and burn".

Immune activation, a normal immune reaction to pathogens, is now recognized as a major driving force of the CD4 T-cell depletion and immune disorders caused by HIV. By contrast, the natural hosts of its ancestor virus, simian immunodeficiency virus, have adapted to this virus by blocking immune activation and remaining healthy. This review will focus on evidence demonstrating how immune activation associated with HIV infection exhausts immune defenses to HIV as well as the immune system, thus leading to immunosenescence and immunodeficiency, and how treatment can disrupt this vicious and ultimately fatal circle.

Journal Article↗

Active immunization against tetanus in man. II. Combined active and passive prophylaxis with human tetanus immune globulin.

19 Persons were actively immunized with adsorbed tetanus toxoid and were simultaneously given tetanus immune globulin of human origin, TIG(H), in doses of 500-1500 IU. Their antitoxin titres were followed for 1 year. Seven persons were given only TIG(H), 500 IU and 1500 IU and their antitoxin titres were followed for 3 months to 1 year. For comparison, 30 military recruits were actively immunized with adsorbed tetanus toxiod according to common practice. Their antitoxin titres were followed for 1 year. The response to complete active immunization could not be demonstrated to be impaired by passive immunization, when 500 IU or 1500 IU OF TIG(H) were given simultaneously with toxoid. The titres were in accordance with those achieved by active immunization of the recruits.

Adult↗