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Induction of cellular immunity to varicella-zoster virus glycoproteins tested with pernasal coadministration of Escherichia coli enterotoxin in mice.

A mutant of Escherichia coli enterotoxin promotes the induction of cellular immunity to a live varicella vaccine (the Oka strain) as a mucosal adjuvant in mice. An investigation was carried out to determine which of the purified glycoproteins of the virus among three induced cellular immunity with a single nasal administration. Spleen cells from mice immunized nasally with the vaccine and toxin produced interleukin-2 (IL-2) at the same level on restimulation in vitro with glycoprotein H: glycoprotein L (gH:gL), gB, and gE:gI, but not IL-4. The spleen cells from mice immunized with gH:gL, gB, or gE:gI and toxin produced IL-2 on restimulation with gH:gL, gB, or gE:gI, respectively, and the vaccine, but not IL-4. Immunization with gH:gL and the toxin showed increased thymidine uptake and production of IL-2 and interferon-gamma (IFN-gamma) of the spleen cells, but not IL-4, depending on the dose of gH:gL used for immunization and restimulation in vitro. Purified gE:gI and gB have been reported to be the strongest stimulators of cellular immunity to varicella upon subcutaneous injection and are useful as a subunit vaccine. All the glycoproteins tested are excellent stimulators of cellular immunity to the virus and itself on nasal co-immunization with the toxin.

Adjuvants, Immunologic↗

Suppression of cellular immunity by surgical stress.

BACKGROUND: Suppression of cellular immunity is one of the host responses to surgical stress. In cancer patients this immunosuppression may accelerate the growth and metastasis of residual cancer cells, so it is desirable to restrict immunosuppression by surgical stress to a minimum. However, the extent and duration of immunosuppression caused by operations on gastrointestinal cancer, as well as the mechanisms involved, have not been determined. METHODS: To clarify these points, we investigated immunocyte function and measured the blood levels of hormones, cytokines, and acute phase reactants from before to after operation in 20 patients with stage I gastrointestinal cancer. RESULTS: In patients exposed to surgical stress, peripheral blood lymphocyte numbers and function were suppressed until at least 2 weeks postoperatively. This immunosuppression was mainly due to a decrease of helper-inducer T cells, cytotoxic T cells, natural killer cells, and interleukin-2 receptor-positive cells, as well as an increase of suppressor T cells. In addition, hypersecretion of cortisol and overproduction of immunosuppressive acidic protein were observed. CONCLUSIONS: Cellular immunosuppression by surgical stress was mainly due to an increase of lymphocyte subsets that depress cellular immunity coupled with a decrease of the subsets that promote it. Overproduction of cortisol and immunosuppressive acidic protein in response to surgical stress may play an important role in the development of immunosuppression.

Acute-Phase Proteins↗

Long-term persistence of cellular immunity to Oka vaccine virus induced by pernasal co-administration with Escherichia coli enterotoxin in mice.

A mutant of Escherichia coli enterotoxin induced cellular immunity to a live varicella vaccine (the Oka strain) as a mucosal adjuvant in mice. The persistence of this cellular immunity was investigated. A commercially available live Oka vaccine virus and toxin were administered once simultaneously via the nasal route, in mice. Ten or 12 months later, a delayed-type hypersensitivity to the vaccine virus was detected by footpad test, but an antibody neutralizing the varicella-zoster virus was not. When spleen cells from mice immunized with the vaccine and toxin were re-stimulated by live vaccine in vitro, their thymidine uptake and IL-2 production were higher than those from mice immunized with the vaccine alone, but lower than those of spleen cells prepared from mice 2 months after nasal administration. Production of IL-4 in these cells, however, was not induced by re-stimulation in vitro. These results suggest that although humoral immunity for Oka vaccine virus is only weakly induced by one co-administration of the vaccine and toxin, cellular immunity is induced and maintained over 1 year, though it declines with age. The nasal administration of the vaccine and toxin might be effective for maintaining cellular immunity to the varicella-zoster virus long term.

Administration, Intranasal↗

Modulation of cellular immune response against hepatitis C virus nonstructural protein 3 by cationic liposome encapsulated DNA immunization.

A vaccine strategy directed to increase Th1 cellular immune responses, particularly to hepatitis C virus (HCV) nonstructural protein 3 (NS3), has considerable potential to overcome the infection with HCV. DNA vaccination can induce both humoral and cellular immune responses, but it became apparent that the cellular uptake of naked DNA injected into muscle was not very efficient, as much of the DNA is degraded by interstitial nucleases before it reaches the nucleus for transcription. In this paper, cationic liposomes composed of different cationic lipids, such as dimethyl-dioctadecylammonium bromide (DDAB), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), or 1,2-dioleoyl-sn-glycerol-3-ethylphosphocholine (DOEPC), were used to improve DNA immunization in mice, and their efficiencies were compared. It was found that cationic liposome-mediated DNA immunization induced stronger HCV NS3-specific immune responses than immunization with naked DNA alone. Cationic liposomes composed of DDAB and equimolar of a neutral lipid, egg yolk phosphatidylcholine (EPC), induced the strongest antigen-specific Th1 type immune responses among the cationic liposome investigated, whereas the liposomes composed of 2 cationic lipids, DDAB and DOEPC, induced an antigen-specific Th2 type immune response. All cationic liposomes used in this study triggered high-level, nonspecific IL-12 production in mice, a feature important for the development of maximum Th1 immune responses. In conclusion, the cationic liposome-mediated gene delivery is a viable HCV vaccine strategy that should be further tested in the chimpanzee model.

Animals↗

Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239.

The goal of an AIDS vaccine regimen designed to induce cellular immune responses should be to reduce the viral set point and preserve memory CD4 lymphocytes. Here we investigated whether vaccine-induced cellular immunity in the absence of any Env-specific antibodies can control viral replication following multiple low-dose challenges with the highly pathogenic SIVmac239 isolate. Eight Mamu-A*01-positive Indian rhesus macaques were vaccinated with simian immunodeficiency virus (SIV) gag, tat, rev, and nef using a DNA prime-adenovirus boost strategy. Peak viremia (P = 0.007) and the chronic phase set point (P = 0.0192) were significantly decreased in the vaccinated cohort, out to 1 year postinfection. Loss of CD4(+) memory populations was also ameliorated in vaccinated animals. Interestingly, only one of the eight vaccinees developed Env-specific neutralizing antibodies after infection. The control observed was significantly improved over that observed in animals vaccinated with SIV gag only. Vaccine-induced cellular immune responses can, therefore, exert a measure of control over replication of the AIDS virus in the complete absence of neutralizing antibody and give us hope that a vaccine designed to induce cellular immune responses might control viral replication.

Animals↗

Alterations of two parameters of cellular immunity in the aged men.

There were two parameters of cellular immunity in 46 old and 34 adult (control) individuals investigated. These reactions were delayed type hypersensitivity of the skin and the in vitro leukocyte migration inhibition test. PPD was used as antigen for both reactions. According to our investigations there was no correlation between them neither in the aged nor in the control group. But the statistical analysis of data revealed a significant difference between skin responses of aged and control groups. In spite of this we consider cellular immunity unaltered in old men, because there was no difference in migration inhibition between aged and adult men and according to our earlier experiments in guinea pigs this test is much more reliable than skin response.

Adolescent↗

Cellular immunity shown in pseudorabies virus-infected pigs by leukocyte migration-inhibition procedure.

Cellular immunity in pigs inoculated with pseudorabies virus (PRV) was studied by the agarose plate technique of direct leukocyte migration-inhibition procedure. Migration of leukocytes from PRV-infected pigs was inhibited in the presence of PRV antigen, whereas migration of leukocytes from nonexposed pigs was not inhibited in the presence of the same antigen. The migration of leukocytes collected 4 days after intranasal exposure to PRV was inhibited; humoral antibodies could not be detected until 7 days after exposure. Cellular immunity was present in pigs 14 days after inoculation with inactivated PRV antigens; low concentrations of neutralizing and precipitating antibodies were present at this time. The leukocyte migration-inhibiton procedure was found to be a useful tool in studying the role of cellular immunity in PRV infections.

Animals↗

Cellular immune host response in acute cutaneous leishmaniasis.

OBJECTIVE: To evaluate cellular immune host response in various patterns of acute cutaneous leishmaniasis. DESIGN: It was a cross-sectional and comparative study. PLACE AND DURATION OF STUDY: The Armed Forces Institute of Pathology (AFIP) and Military Hospital (MH), Rawalpindi from 1996 to 1999. PATIENTS AND METHODS: Forty biopsies of active skin lesions after processing were studied for various immunophenotype cells by using monoclonal antibodies. Total as well as differential T cell counts were recorded in acute single, acute multiple and sporotrichoid lesions and in normal skin tissues. Non parametric Kruskal-Wallis Test for one way ANOVA was used to compare cell counts in these groups and p-value <0.05 was considered significant. RESULTS: No significant difference was seen in the histopathology, type of infiltrate and the ratio between the immune competent cells in acute single or multiple lesions. The results of analysis of total cell count, CD3+ cells and CD57+ (NK) cells were statistically different (p=<0.05 to p=<0.001) between acute forms of the disease and normal tissue but no difference was seen when acute forms were compared with each other. However, CD4+, CD8+ and CD19+(Plasma cells) counts difference was significant (p=<0.05 to p=<0.01), when sporotrichoid lesions were compared with other acute lesions (single and multiple). CONCLUSION: The sporotrichoid variant of cutaneous leishmaniasis may be due to a different parasite species, which provokes a different cellular immune response.

Acute Disease↗

Behavioral and neural influences on cellular immune responses: effects of stress and interleukin-1.

A series of experiments examined effects of stressful conditions on several cellular immune responses and attempted to elucidate the physiological mechanisms underlying these effects. Initial studies showed that stressful conditions can profoundly suppress immune responses of blood and splenic lymphocytes, including T-cell mitogenesis, natural killer cell activity, production of interleukin-2 (IL-2) and interferon and IL-2 receptor expression. Subsequent studies found that (1) multiple physiological pathways mediate stress-induced suppression of these responses; (2) stress-induced suppression of these responses is produced, at least in part, by a peptide with molecular weight greater than 10 kilodaltons, which stressed animals release into circulation; (3) whereas most stressful conditions suppress immune responses, stressful conditions of moderate intensity can enhance cellular immune responses; and (4) extremely small quantities of interleukin-1 (IL-1) acting in the brain (e.g., 3.1-12.4 X 10(-15) moles) bring about suppression of cellular immune responses very rapidly and for a prolonged period of time. The relationship between the newly-discovered immunosuppressive influence of IL-1 in the brain and immunosuppression produced by stressful conditions remains to be determined.

Animals↗

Opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity.

We evaluated the cellular immunity of 408 clinically stratified subjects at risk for acquired immune deficiency syndrome (AIDS), to define the role of interferon-alpha production deficits in the pathogenesis of opportunistic infections (OI). We followed 115 prospectively for up to 45 mo. Onset of OI was associated with, and predicted by, deficiency both of interferon-alpha generation in vitro, and of circulating Leu-3a+ cells. Interferon-alpha production is an index of the function of certain non-T, non-B, large granular lymphocytes (LGL) that are independent of T cell help. Leu-3a+ cell counts are a marker of T cell function. OI did not usually develop until both of these mutually independent immune functions were simultaneously critically depressed, leading to a synergistic interaction. These data suggest that the AIDS virus affects a subset of LGL, and that cytokine production by these cells is an important component of the host defense against intracellular pathogens that becomes crucial in the presence of severe T cell immunodeficiency.

Acquired Immunodeficiency Syndrome↗

Cellular immune responses to acute stress in female caregivers of dementia patients and matched controls.

This study investigated whether the stress of caregiving alters cellular immune responses to acute psychological stressors. Twenty-seven women caring for a spouse with a progressive dementia (high chronic stress) and 37 controls matched for age and family income performed a 12-min laboratory stressor. Cellular immune function was assessed by both functional and quantitative measures taken before (low acute stress), immediately after (high acute stress), and 30 min after (recovery from stress) exposure to the laboratory stressors. The laboratory challenges were associated with diminished proliferative responses but elevated natural killer (NK) cell cytotoxicity; however, subsequent analyses suggested that this elevated cytotoxicity was largely attributable to an increase in the number of NK cells in peripheral blood. The results suggest that although the stress of caregiving diminishes cellular immune function, caregiving appears to have little effect on cellular immune responses to or recovery from brief psychological challenges.

Aged↗

In vitro studies on the mechanism of acquired resistance to tuberculous infection. I. The relationship between lymphocytes and macrophages in cellular immunity to tuberculous infection.

The relationship between lymphocytes and macrophages in cellular immunity against tuberculous infection was studied by means of an in vitro cell culture system without addition of streptomycin. The peritoneal macrophages were obtained from normal mice or mice immunized with heat-killed tubercle bacilli in paraffin oil, boosted with live BCG and infected with H37Rv cells in vitro. The infected monolayers of macrophages were cultivated for 48 hr with immune lymphoid cells obtained from immunized mice. The intracellular growth of H37Rv cells 3,5 and 7 days after infection was examined by counting tubercle bacilli within infected macrophages under a microscope. 1) The increase of bacilli within macrophages derived from immunized mice was slightly smaller than that in normal macrophages. 2) The addition of immune lymph node cells to the macrophage monolayers resulted in a marked decrease in the number of bacilli within both normal and "immune" macrophages. Conversely, normal lymph node cells exhibited an enhancing effect on the intracellular bacillary growth. 3) Immune lymph node cells showed a higher capacity to cause macrophages to suppress intracellular growth of bacilli than that of splenic lymphoid cells or thyrmocytes after addition to macrophage monolayers. 4) The treatment of lymphoid cells with inhibitors of protein synthesis, cycloheximide or streptovitacin A, resulted in a remarkable reduction of the ability of sensitized lymphocytes to cause macrophages to suppress multiplication of intracellular bacilli.

Animals↗

Acute retinal necrosis: a result of immune dysfunction? Report of a case with subacute evolution and relapses in a patient with impaired cellular immunity.

We report an atypical case of acute retinal necrosis (ARN) with a subacute course and relapses lasting for more than 4 years in an apparently immunocompetent 71-year-old female who had been followed for 4.5 years for recurrent retinochoroidal lesions with transient exudative retinal detachments and areas of consecutive chorioretinal atrophy. The diagnosis of varicella-zoster virus (VZV)-induced ARN was finally made on the basis of anterior granulomatous uveitis, typical retinal necrosis and the detection of anti-VZV antibodies in the aqueous humor. A widespread lumbar zoster dermatitis, cutaneous anergy and depressed in vitro lymphocyte activation indicated depressed cellular immunity. Absolute and relative numbers of B lymphocytes were increased. It is suspected that depressed cellular immunity and maintained B cell function might possibly be at the origin of ARN. The protracted course of ARN in this patient also suggests that the dysregulation of the immune system has probably existed for a long time.

Aged↗

Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine.

Humoral immunity in response to an octavalent O-polysaccharide-toxin A conjugate Pseudomonas aeruginosa vaccine is well studied, and a Phase III clinical study in cystic fibrosis (CF) patients is currently ongoing. In contrast, little is known about cellular immunity induced by this vaccine. Fifteen healthy volunteers were immunized on days 1 and 60. Parameters of cellular immunity were studied before vaccination on day 1, and on day 74. Analyses included flow cytometry of whole blood, and antigen-induced proliferation of and cytokine production by lymphocyte cultures. The effects of immunization on the composition of peripheral blood lymphocytes as determined by flow cytometry were minor. In contrast, after immunization a highly significant increase of proliferation in response to stimulation with detoxified toxin A was noted: the stimulation index rose from 1.4 on day 1 to 42.2 on day 74 (restimulation with 0.4 microg/ml; P = 0.003). Immunization led to significant production of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha by antigen-stimulated lymphocytes. In contrast, no significant induction of interleukin (IL)-4 or IL-10 was observed. In conclusion, immunization of healthy volunteers led to activation of cellular immunity including strong antigen-specific proliferation and cytokine production. In CF patients priming of the cellular immune system towards a Th1-like pattern would be of potential advantage. Therefore, confirmatory analyses in immunized CF patients with and without chronic infection with P. aeruginosa are foreseen.

Antibodies, Bacterial↗

Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine.

Humoral immunity in response to an octavalent O-polysaccharide-toxin A conjugate Pseudomonas aeruginosa vaccine is well studied, and a phase III clinical study in cystic fibrosis (CF) patients is currently ongoing. In contrast, little is known about cellular immunity induced by this vaccine. Fifteen healthy volunteers were immunized on days 1 and 60. Parameters of cellular immunity were studied before vaccination on day 1, and on day 74. Analyses included flow cytometry of whole blood and antigen-induced proliferation of and cytokine production by lymphocyte cultures. The effects of immunization on the composition of peripheral blood lymphocytes as determined by flow cytometry were minor. In contrast, after immunization a highly significant increase of proliferation in response to stimulation with detoxified toxin A was noted: the stimulation index rose from 1.4 on day 1 to 42.2 on day 74 (restimulation with 0.4 microg/ml; P = 0.003). Immunization led to significant production of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha by antigen-stimulated lymphocytes. In contrast, no significant induction of interleukin (IL)-4 or IL-10 was observed. In conclusion, immunization of healthy volunteers led to activation of cellular immunity including strong antigen-specific proliferation and cytokine production. In CF patients priming of the cellular immune system towards a Th1-like pattern would be of potential advantage. Therefore, confirmatory analyses in immunized CF patients with and without chronic infection with P. aeruginosa are foreseen.

Adult↗