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Coccidioidomycosis in acquired immune deficiency syndrome. Depressed humoral as well as cellular immunity.

Progressive pulmonary coccidioidomycosis has not been previously reported in the setting of acquired immune deficiency syndrome (AIDS). A patient with AIDS, progressive pulmonary coccidioidomycosis, Pneumocystis carinii pneumonia, and disseminated cytomegalovirus is described. Diagnosis of these opportunistic pathogens was made by bronchoalveolar lavage and transbronchial lung biopsy. Results of traditional complement fixation serologic testing for cytomegalovirus were negative; however, the more sensitive enzyme-linked immunosorbent assay did indicate infection. Coccidioidal complement fixation tests, precipitin tests, counter-immunoelectrophoresis, and immunodiffusion tests demonstrated negative findings. These results provide additional evidence that some patients with AIDS have defects in humoral as well as cellular immunity.

Acquired Immunodeficiency Syndrome↗

Discussion paper: specific paralysis of the antitumor cellular immune response produced by growing tumors studied with a radioisotope footpad assay.

The kinetics of the antitumor cellular immune response of mice with progressively growing syngeneic tumors were determined in vivo using a quantitative radioisotopic footpad assay. A close correlation was found between the size of the tumor and the degree of the cellular immune response. An initial phase of cellular immune stimulation was followed by specific suppression and subsequent immunologic paralysis as the tumor grew larger. This immune paralysis was attributed to increased tumor load since a homogenate of an SV40 transformed fibrosarcoma injected intraperitoneally into tumor-immune mice specifically depressed their cellular immune response. The fraction of the tumor homogenate that brought about this depression was present in the high speed supernatant and pellet of a 3M KCl extract of the tumor. The specificity of the depression was determined in vivo by the radioisotopic footpad assay and in vitro by a 51Cr cytolysis assay. Unwashed spleen cells harvested from mice bearing large tumors were unreactive in a local adoptive footpad assay. However, reactivity could be restored by repeatedly washing the spleen cells.

Animals↗

Replicating Ad-recombinants encoding non-myristoylated rather than wild-type HIV Nef elicit enhanced cellular immunity.

OBJECTIVE: To determine if immunization with non-myristoylated nef would elicit enhanced cellular immune responses resulting from improved presentation of Nef peptides by MHC-I on the cell surface, and enhanced T-cell help. DESIGN: The myristoylation site of HIV and SIV Nef is required for several Nef functions that modulate the immune response in an infected host, including downregulation of MHC-I, MHC-II, and CD4, and increased expression of the invariant chain on the cell surface. We constructed replication-competent Ad5- and Ad7-HIV recombinants encoding wild-type nef (nefWT) or a nef mutant (nefNM) lacking 19 amino-terminal amino acids, including the myristoylation site, and sequentially immunized chimpanzees mucosally, first with Ad5-HIVnef recombinants and subsequently with Ad7-HIVnef recombinants. METHODS: Peripheral blood lymphocytes were evaluated over the immunization course for Nef-specific cellular immune responses by interferon (IFN)-gamma ELISPOT and T-cell proliferation assays. Nef-specific CD4 and CD8 memory T cells that produced intracellular IFN-gamma, interleukin-2, and tumor necrosis factor (TNF)-alpha were assessed by flow cytometry. RESULTS: In comparison to immunization with Ad-HIVnefWT, Ad-HIVnefNM elicited statistically significant increases in numbers of IFN-gamma-secreting cells after the Ad7-HIVnefNM immunization and increased T-cell proliferative responses following both Ad5- and Ad7-HIVnefNM immunizations. Nef-specific CD4 and CD8 memory T-cell populations secreting TNF-alpha were also significantly increased in the Ad-HIVnefNM immunization group. CONCLUSIONS: The results support the hypothesis that immunization with Ad-recombinants encoding HIVnefNM rather than HIVnefWT elicits enhanced cellular immunity resulting from improved antigen presentation and greater T-cell help.

AIDS Vaccines↗

Cellular immune response to cytomegalovirus infection after renal transplantation.

A prospective study of 15 patients who received renal transplants defined the effect of renal transplantation on the cellular immune response to cytomegalovirus infection. Of 15 patients, 14 developed cytomegalovirus infection, usually in the first 2 months after transplantation, and all infections were accompanied by a normal humoral immune response. After the initiation of immunosuppressive therapy and transplantation, there was a general depression of lymphocyte transformation, as reflected in the response to phytohemagglutinin, accompanied by a specific defect in cellular immunity, as indicated by lymphocyte transformation to cytomegalovirus antigen. Eleven patients had cellular immunity to cytomegalovirus before transplantation, and all of these became negative in the first month after transplantation. In subsequent months, only 6 of the 14 study patients with cytomegalovirus infection developed specific cellular immune responses to cytomegalovirus. This occurred most often in patients who had severe febrile illnesses in association with infection. The specific cellular immune response which developed in the posttransplant period did not persist in three of the patients. This study demonstrates the dissociation of the humoral and cellular immune response to cytomegalovirus infection in renal transplant patients and indicates the importance of the loss of cellular immunity in the appearance of infection. Previously infected patients lost their cell-mediated immunity and had reactivation infections despite the presence of serum antibody.

Adult↗

[Cellular immunity in melanomalignome (author's transl)].

Cellular immunological reactivity was examined in 20 patients having melanomalignoma at different clinical stages, using Leukocyte-Migration-Inhibition-Test. As antigens three homologous melanoma-extracts were used, produced by our own method. Independent from the clinical stages cell-migration inhibition could be established in 15 out of the 20 patients. In this way, these tumor extracts have been shown to contain melanoma-associated antigens. Regardless of the clinical stage of the disease, the melanomalignomas patient produces cellular immunity against those tumor-antigens. It is note-worthy that the actual course of the disease seems not to be influenced by immun-mechanisms.

Adult↗

Cellular immune responses in mice immunized with Anisakis simplex larval antigens.

Cellular immune responses to Anisakis simplex L3 antigens were investigated in BALB/c mice injected subcutaneously with a homologous crude extract (CE). Popliteal lymph nodes (PLN) were found to be increased in size and weight after A. simplex CE footpad injection. The effects of A. simplex CE in vitro proliferation were assayed with non-fractionated PLN cells or nylon-wool purified T cells derived from pooled lymph node cells of mice subcutaneously injected with CE. Spleen cells from immunized animals (antigen alone, or larva alone, or antigen plus larva) were studied by flow cytometry. The immunization induced a high proportion of CD4 + and TCRalphabeta + T cells. The number of B cells (CD45 + and TCRalphabeta-) in pre-immunized and infected mice was lower than that observed in animals subjected to infection only. The number of CD4+ T cells increased in the infected and in the pre-immunized and infected mice. In the latter, a decrease of CD8a + T cells was noted. The greatest increase in CD8a+ and TCRalphabeta- T cells was found in mice that had been subjected to infection only. Histological analysis showed that the most prominent lesions were gastric and intestinal in animals infected orally with one larva.

Animals↗

Potential significance of the cellular immune response against the macaque strain of simian immunodeficiency virus (SIVMAC) in immunized and infected rhesus macaques.

The cellular immune response of seven rhesus macaques immunized with Tween-ether-treated macaque strain of simian immunodeficiency virus (SIVMAC) and three non-vaccinated control animals was investigated. Immunization elicited antigen-specific proliferating CD4+ cells in five of seven monkeys. Proliferating T cells were found in all animals protected from a first virus challenge. Cytotoxic T lymphocytes (CTLs) were not induced by the immunization. After the second challenge, the four formerly protected animals became infected, despite a strong proliferative CD4+ cell activity in three of them. All animals lost their proliferative activity 2 weeks after infection. After the first challenge four of the six infected animals exhibited a CTL response and after the second challenge, one of four newly infected macaques acquired a CTL response. The five animals with a CTL activity against SIVMAC proteins were protected from severe thrombocytopenia, which appeared in the five CTL-negative animals after infection. Our data show the induction of proliferative T cells by immunization with soluble SIVMAC antigen. This T cell reactivity was found in all animals protected from the first virus challenge, but did not confer protection from the second challenge. Interestingly, the proliferative T cell reactivity disappeared 2 weeks after virus infection. Furthermore a CTL response against viral proteins seems to protect infected animals from severe thrombocytopenia which is an early sign of AIDS in monkeys.

Animals↗

Cellular immunity in pediatric uveitis.

To evaluate cellular immunity in children with uveitis, we used the flow cytometry method to study the T lymphocyte subpopulation in peripheral blood. Cytometric analysis of peripheral blood lymphocytes using fluorochrome-marked monoclonal antibodies was carried out in 29 children aged 6-18 years with parasitic uveitis (group A) and with uveitis of another etiology (group B). The control group consisted of 28 healthy children aged 6-15 years. A substantially higher percentage of B lymphocytes (19.0 +/- 6.03) was observed in the children with parasitic uveitis than was observed in the healthy children. Moreover, the absolute values were higher in groups A (1.60 +/- 0.53) and B (1.81 +/- 0.40) than in controls (1.50 +/- 0.38). The lowest percentage of CD4+ lymphocytes (34.25 +/- 6.06) and the highest percentage of CD8+ lymphocytes (31.14 +/- 6.50) was found in children with parasitic uveitis. The lowest index CD4+/CD8+ (1.29 +/- 0.53) in the group of children with parasitic uveitis reflected severe disorders in response regulation. However, the percentage values of natural killer cells was lower in the two groups of patients than in controls. These results suggest that quantitative changes in the subpopulation of peripheral blood lymphocytes are more pronounced in parasitic uveitis.

Adolescent↗

[Preliminary study on the cellular immune abnormality in rheumatoid arthritis].

The cellular immunological abnormalities in 21 patients with rheumatoid arthritis (RA) were studied with flow cytometer. In the peripheral blood monocytes (PBM) from patients with active RA the number of HLA-DR positive cells were remarkably increased. The activity of NK cells and Leull C+ cells reduced to 1/2-1/3 of the normal limits. The AMLR and mitogen-inducing reaction decreased significantly. These data suggest that the changes of cellular immune reaction and immunoregulation may be related to the pathogensis of RA.

Adolescent↗

Time-dependence of urinary neopterin, a marker of cellular immune activity.

Neopterin, a marker of cellular immune system activation, is produced by human macrophages after induction by interferon gamma (secreted by T-lymphocytes) and is eliminated mostly in urine. We have documented the circadian rhythm of urinary neopterin in five healthy young men (about 25 years old), using voidings collected during 48 h at fixed 4-h intervals. We repeated the experiment three times, one week apart. Neopterin was measured by high-performance liquid chromatography (HPLC). We clearly show a peak of the excretion of neopterin in the early morning (around 0630 hours +/- 2 h), with total variability (peak-trough difference) reaching 51%. Neopterin is commonly assayed in urinary fractions, so it is imperative to use urine specimens collected at the same time of day--e.g., the first morning urines--to avoid misinterpretation in follow-up of patients.

Adult↗

Analysis of the persistence of humoral and cellular immunity in children and adults immunized with varicella vaccine.

The persistence of humoral and cellular immunity to varicella-zoster virus (VZV) was evaluated in 60 children and 18 adults immunized with live attenuated VZV vaccine. At a mean of 5 years after vaccination, 93% of children and 94% of adults had IgG antibodies to VZV as determined by ELISA. VZV antibody concentrations were significantly higher at 5 years than at 1 year after immunization in children and adults. Cell-mediated immunity to VZV was detected in 87% of children and 94% of adults at 5 years. The mean stimulation index was significantly higher at 5 years than at 1 year among children and adults. Cytokine responses to VZV, including interleukin-2, interferon-gamma, and interleukin-10 were equivalent between children and adults at 5 years. In summary, varicella immunization induced long-term humoral and cellular immunity, and initial differences between cell-mediated responses in children and adults diminished over time.

Adolescent↗

Regulation of the insect immune response: the effect of hemolin on cellular immune mechanisms.

Hemolin is a bacteria-inducible protein of the immunoglobulin superfamily identified in the silk moth Hyalophora cecropia. The role of this protein, in hemocyte aggregation and phagocytosis, was studied in vitro. Hemocyte aggregation, stimulated by phorbol myristate acetate or lipopolysaccharide (LPS), was prevented by hemolin in a dose-dependent fashion, but hemolin did not disrupt aggregates once they had been formed. Furthermore, hemolin was able to stimulate phagocytic activity in both hemocytes and hemocytic mbn-2 cells and this activity was enhanced by LPS. The enhanced phagocytosis produced by a combination of hemolin and LPS was prevented by the protein kinase C (PKC) inhibitors staurosporine and H-7, and PKC activity in hemocyte crude extracts was enhanced by hemolin and LPS, with the highest activity observed in the presence of both. Hemolin affected tyrosine phosphorylation of hemocyte proteins, enhancing the phosphorylation of two proteins of 20 and 30 kDa and preventing tyrosine phosphorylation of two proteins of 35 and 40 kDa. These results suggest that hemolin is involved in the regulation of the cellular immune responses via a pathway that includes PKC activation and protein tyrosine phosphorylation.

Animals↗

Cellular immune function in rheumatic disease.

Investigation of the cellular immune function in patients with rheumatic diseases is important in elucidating the pathogenesis of the disease processes and in determining the associated abnormalities of recognition and regulation exerted by the immune system. However, because of the lack of specificity and the variations noted from laboratory to laboratory, tests of cellular immune function are, at present, of little value in the laboratory diagnosis of these diseases. The abnormalities found in the rheumatic diseases occur with many autoimmune diseases and other inflammatory states. The common pathway of immune abnormalities appears to be influenced by several factors. They include several genetic loci, possible environmental factors, and immunologic mechanisms, which appear to interact in an intimate way to induce various autoimmune diseases.

Arthritis, Rheumatoid↗

Nature of "memory" in T-cell mediated antibacterial immunity: cellular parameters that distinguish between the active immune response and a state of "memory".

Immunizing infection in mice with Listeria monocytogenes resulted in the generation of two distinct states of immunological reactivity. There was generated (i) a short-lived state of active immunity that functioned to urgently eliminate the infection organism from the tissues and (ii) a long-lives state of increased immunological potential that enabled the host to respond to seconday infection in an accelerated manner. Short-lived active immunity was mediated by replicating T cells and expressed by activated macrophages, and it ended when these cell types disappeared from the tissue soon after complete elimination of the parasite. Long-lived immunological protential was associated with a persistent level of delayed sensitivity and with the presence of a small number of nonreplicating protective T cells. It is suggested that the state of delayed sensitivity represents a state of immunological T-cell memory of the cell-mediated type.

Animals↗

Enhancing effect of passive immunization with mycobacterial antibodies on humoral and cellular immunity in BCG-infected mice.

The present paper is an attempt to get insight about the mechanisms involved in the enhancing phenomenon that occurs in bacterial infections. Mice infected with small doses of the BCG strain of M. bovis and treated with a M. tuberculosis H37Rv antiserum investigated at various intervals for their capacity to synthesize haemagglutinating antimyco-bacterial antibodies and to develop delayed hypersensitivity to PPD. As controls, BCG-infected mice were treated with the antiserum freed from its mycobacterial antibodies. It was found that the passive immunization of BCG-infected mice promotes the growth of bacilli in their spleen and induces a late formation of antimycobacterial antibodies which do not seem to be related to the development of delayed hypersensitivity.

Animals↗

Prime-boost immunization schedules based on influenza virus and vaccinia virus vectors potentiate cellular immune responses against human immunodeficiency virus Env protein systemically and in the genitorectal draining lymph nodes.

Vaccines that elicit systemic and mucosal immune responses should be the choice to control human immunodeficiency virus (HIV) infections. We have previously shown that prime-boost immunizations with influenza virus Env and vaccinia virus (VV) WR Env recombinants induced an enhanced systemic CD8(+) T-cell response against HIV-1 Env antigen. In this report, we analyzed in BALB/c mice after priming with influenza virus Env the ability of two VV recombinants expressing HIV-1 Env B (VV WR Env and the highly attenuated modified VV Ankara [MVA] Env) to boost cellular immune responses in the spleen and in the lymph nodes draining the genital and rectal tracts. Groups of mice were primed by the intranasal route with 10(4) PFU of influenza virus Env and boosted 14 days later by the intraperitoneal or intranasal route with 10(7) PFU of MVA Env or VV WR Env, while the control group received two immunizations with influenza virus Env. We found that the combined immunization (Flu/VV) increased more than 60 times the number of gamma interferon-specific CD8(+) T cells compared to the Flu/Flu scheme. Significantly, boosting with MVA Env by the intraperitoneal route induced a response 1.25 or 2.5 times (spleen or genital lymph nodes) higher with respect to that found after the boost with VV WR Env. Mice with an enhanced CD8(+) T-cell response also had an increased Th1/Th2 ratio, evaluated by the cytokine pattern secreted following in vitro restimulation with gp160 protein and by the specific immunoglobulin G2a (IgG2a)/IgG1 ratio in serum. By the intranasal route recombinant WR Env booster gave a more efficient immune response (10 and 1.3 times in spleen and genital lymph nodes, respectively) than recombinant MVA Env. However, the scheme influenza virus Env/MVA Env increased four times the response in the spleen, giving a low but significant response in the genital lymph nodes compared with a single intranasal immunization with MVA Env. These results demonstrate that the combination Flu/MVA in prime-booster immunization regimens is an effective vaccination approach to generate cellular immune responses to HIV antigens at sites critical for protective responses.

3T3 Cells↗

Cytomegalovirus-specific humoral and cellular immune responses in human pregnancy.

Cytomegalovirus (CMV)-specific humoral and cellular immunity was evaluated prospectively during and after 19 normal human pregnancies. Seropositive pregnant subjects had lymphocyte proliferative responses to purified CMV antigen that were markedly depressed by the end of the third trimester of pregnancy despite persistent levels of complement-fixing and immunofluorescent antibodies to CMV. These reduced lymphocyte proliferative responses returned to levels detected early in pregnancy by one year after delivery. None of the subjects excreted CMV during the study period. General parameters of cellular immunity, including thymus derived-cell counts as determined by formation of erythrocyte rosettes and mitogen-induced lymphocyte proliferation, were unaffected. Reactivation of latent CMV during pregnancy might be related to transient depression of CMV-specific cellular immunity.

Antibodies, Viral↗

The cellular immune response to immunization with zona pellucida antigens.

The cellular immune response of mice to porcine and rat zona pellucida and cynomolgus macaques to porcine zona pellucida antigens was evaluated. Mice mounted a vigorous cellular response to both antigens, as determined by the T cell proliferation response in vitro. There was poor cross-reactivity to murine zonae by T cells or serum antibodies from mice immunized with rat zona pellucida. Nevertheless, ovaries from the mice immunized with rat zona had significantly fewer antral follicles than adjuvant-treated controls, suggesting that the immune response to the zona antigen disrupted follicular development. T cells from two macaques that had been immunized with porcine zona pelludica proteins proliferated in vitro in response to this antigen. Both macaques also had strong antibody responses. The patterns of urinary steroid metabolites in these animals provided clear evidence of ovarian malfunction following immunization. The data indicate that a significant cellular immune response is generated upon immunization of animals with zona pellucida antigens regardless of whether the antigens are cross reactive with the host zona antigens. Whether impaired ovarian function and follicular development are related to the cellular response must be determined in future studies.

Animals↗