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Cellular immune responses to HIV.

The cellular immune response to the human immunodeficiency virus, mediated by T lymphocytes, seems strong but fails to control the infection completely. In most virus infections, T cells either eliminate the virus or suppress it indefinitely as a harmless, persisting infection. But the human immunodeficiency virus undermines this control by infecting key immune cells, thereby impairing the response of both the infected CD4+ T cells and the uninfected CD8+ T cells. The failure of the latter to function efficiently facilitates the escape of virus from immune control and the collapse of the whole immune system.

AIDS Vaccines↗

Liposome encapsulated tumor-associated antigens elicited humoral and cellular immune responses in mice bearing tumor.

Chemically induced tumors in mice provide a system to investigate tumor-associated antigens (TAA). The cell surface glycoprotein antigens on such tumor cells have been identified as suitable targets for immune attack. The induction of immune responses against (TAA) in N-nitrosodiethylamine (DEN) exposed mice has been examined. In order to present antigens to the immune system, the liposome was used as vehicle to deliver the TAA. Liposomal-TAA formulation, elicited both humoral and the cellular immune responses, when administered intramuscularly in DEN-exposed mice. Presence of circulatory antibodies against TAA and the induction of cellular responses in immunized mice were monitored using ELISA and in vitro cell proliferation assay of lymphocytes respectively. Specificity of antibody against TAA in immune sera was analysed using immunoblotting technique. Based on these results, it is proposed that the liposome encapsulated TAA may successfully be used to induce humoral and cellular immune responses against tumor.

Animals↗

Preclinical evaluation of cellular immune responses elicited by a polyvalent DNA prime/protein boost HIV-1 vaccine.

While DNA vaccines have been shown to prime cellular immune responses, levels are often low in nonhuman primates or humans. Hence, efforts have been directed toward boosting responses by combining DNA with different vaccination modalities. To this end, a polyvalent DNA prime/protein boost vaccine, consisting of codon optimized HIV-1 env (A, B, C, E) and gag (C) and homologous gp120 proteins in QS-21, was evaluated in rhesus macaques and BALB/c mice. Humoral and cellular responses, detected following DNA immunization, were increased following protein boost in macaques and mice. In dissecting cellular immune responses in mice, protein-enhanced responses were found to be mediated by CD4+ and CD8+ T cells with a Th1 cytokine bias. Our study reveals that, in addition to augmenting humoral responses, protein boosting of DNA-primed animals augments cellular immune responses mediated by CD8+ CTL, CD4+ T-helper cells and Th1 cytokines; thus, offering much promise in controlling HIV-1 in vaccinees.

AIDS Vaccines↗

Decreased cellular immune response of germ-free mice.

Cellular immune response to intracerebral lymphocytic choriomeningitis infection was studied in mice belonging to an identical strain but different in breeding conditions. In consequence of the cellular immune reaction on the leptomeninx, lymphocytic choriomeningitis developed and caused death in 100% of conventionally bred mice, whereas 80% of germ-free and 15% of mouse-pathogen-free mice failed to display lymphocytic infiltration of the leptomeninx and survived the infection as chronic virus carriers. This finding pointed to a deficient cellular immune response of germ-free and mouse-pathogen-free mice. The under-development of the lymphoid system due to the antigen-poor breeding conditions might be responsible for the deficiency.

Animals↗

An archived lot of coccidioidin induces specific coccidioidal delayed-type hypersensitivity and correlates with in vitro assays of coccidioidal cellular immune response.

No test for assessing cellular immune response in coccidioidomycosis is currently available in the United States. In the present study, we tested 49 healthy subjects living in the coccidioidal endemic region with a 1:55.8 dilution of a single lot of coccidioidin archived since the 1970s. In this group, 23 evaluable subjects demonstrated >/=5 mm of induration at 24, 48 or 72 h, with a mean+/-SEM maximum induration of 18.4+/-4.0 mm. The induration results among 14 subjects reactive at 24 h were compared to those from 179 individuals in an historical cohort studied in the 1980s using a reference lot of coccidioidin. Results were within 5% and not significantly different (P=0.924). The maximum induration response of all evaluable subjects correlated significantly with the results of in vitro tests of coccidioidal cellular immunity using supernatant interferon-gamma concentration and CD69 expression on T cells (Spearman rank correlation coefficients 0.69 and 0.68, respectively; P<0.01 for both). These data suggest that archived coccidioidin retains its potency and specificity and that in vitro test of coccidioidal immunity may have utility in the measurement of coccidioidal cellular immunity.

Adolescent↗

T cell receptor-transgenic mouse models for studying cellular immune responses to Salmonella in vivo.

Cellular immune responses are crucial both for protective immunity against salmonellosis, and for the immunogenicity of oral vaccines based on avirulent live Salmonella as antigen carriers. The crucial early steps of T cell induction are difficult to investigate in conventional animals, but recently developed T cell receptor (TCR)-transgenic models allow visualization of antigen-specific T cells in vivo while they become induced. In this review, the results obtained with four different TCR-transgenic Salmonella infection models are described, and advantages and potential limits of each of the different models are compared.

Animals↗

Transfer factor and cellular immune response in urinary tract infections in children.

Cellular immune responses in vivo and in vitro were studied in 20 children with chronic or relapsing urinary tract infections. Skin tests revealed decreased immune responses to PPD in cases with chronic or recurrent pyelonephritis and to OM, in these cases and in cases of lower urinary tract infections. Blast transformation responses to PPD, OM and PHA were at least as high as in controls. Administration of chromatographically purified fraction from human leucocyte transfer factor resulted in a positive skin reaction with antigen concentration, which before TF administration had caused a negative reaction. The results suggest that the action of the transfer factor component used in this study is based on an immunologically nonspecific stimulation of the cellular immune response.

Adolescent↗

SIV DNA vaccine co-administered with IL-12 expression plasmid enhances CD8 SIV cellular immune responses in cynomolgus macaques.

Current evidence suggests that a strong induced CD8 human immunodeficiency virus type 1 (HIV-1)-specific cell mediated immune response may be an important aspect of an HIV vaccine. The response rates and the magnitude of the CTL responses induced by current DNA vaccines in humans need to be improved and cellular immune responses to DNA vaccines can be enhanced in mice by co-delivering DNA plasmids expressing immune modulators. Two reported to work well in the mouse systems are interleukin (IL)-12 and CD40L. We sought to compare these molecular adjuvants in a primate model system. The cDNA for macaque IL-12 and CD40L were cloned into DNA vectors. Groups of cynomolgus macaques were immunized with 2 mg of plasmid expressing SIVgag alone or in combination with either IL-12 or CD40L. CD40L did not appear to enhance the cellular immune response to SIVgag antigen. However, more robust results were observed in animals co-injected with the IL-12 molecular adjuvant. The IL-12 expanded antigen-specific IFN-gamma positive effector cells as well as granzyme B production. The vaccine immune responses contained both a CD8 component as well a CD4 component. The adjuvanted DNA vaccines illustrate that IL-12 enhances a CD8 vaccine immune response, however, different cellular profiles.

Animals↗

The host response in gingival crevicular fluid: potential applications in periodontitis clinical trials.

Traditional clinical variables of periodontal pathology have only limited value as indicators for future disease progression in patients with adult periodontitis. Consequently, other aspects of the periodontal lesion are being examined for their diagnostic utility. Analysis of the host response in gingival crevicular fluid (GCF) is among the most intensely studied of these new diagnostic approaches. Specific indicators of the humoral immune response, cellular immune response, and acute inflammatory response have been identified in GCF. The relationship of indicators of the humoral immune response to active periodontal disease is equivocal. Specific indicators of the cellular immune response in GCF may ultimately prove to be important diagnostically, but the relationship of any specific marker to active periodontal disease has not been reported. In contrast, the acute inflammatory response in GCF has been extensively studied and a number of factors appear to be associated with an increased risk for future disease progression. Indicators of enhanced polymorphonuclear leukocyte activity, (lysosomal beta-glucuronidase, lysosomal collagenase), prostaglandin E2, and an indicator of acute tissue destruction (the cytoplasmic enzymes aspartate aminotransferase) have been associated with the occurrence of clinical attachment loss. An example of the application of a GCF marker in a periodontitis clinical trial is provided by describing the relationship of lysosomal beta-glucuronidase in GCF at baseline and 2 weeks following root planing and scaling to the occurrence of disease activity during the following 6 months. Persistently elevated levels of this enzyme were related to clinical attachment loss. The positive, negative, and total predictive values for beta-glucuronidase as an identifier of clinical attachment loss were 86%, 71%, and 76%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggressive Periodontitis↗

[Humoral and cellular immune responses to retinal S-antigen in uveitis patients].

Humoral and cellular immune responses to purified S-Ag were determined in 73 patients with anterior-, intermediate- and pan-uveitis and in 55 healthy subjects by ELISA and leucocyte migration inhibition test. The positive rates of humoral immune response to S-Ag in patients and controls were comparable; however, the positive rate of cellular immune response to S-Ag in the patients (54.6%) was significantly higher than that in the controls (3.3%), and that in pan-uveitis patients (69.4%) was significantly higher than in patients with anterior uveitis (15.4%), highly suggesting that the cellular immune response to S-Ag was involved in the onset of uveitis, especially when the choroid and retina were affected. The breakdown of anterior chamber associated immune deviation and abnormal expression of intraocular MHC-II antigens may contribute to the development of cellular immune response. More studies are needed.

Adolescent↗

Experimental Mycoplasma pulmonis infection of rats suppresses humoral but not cellular immune response.

Humoral antibody response to sheep red blood cells and cellular immune response to bovine serum albumin were studied in Mycoplasma pulmonis infected, adult, male Sprague-Dawley rats. The hemagglutinating antibody response to sheep red blood cells was evaluated at 0, 3, 5, 7, 14, 21 and 28 days postinfection. Antibody titers during all days postinfection were depressed significantly (p less than 0.05) in infected rats as compared to noninfected controls. Cellular immune responses were evaluated by a delayed hypersensitivity response. Rats were sensitized at 0, 3, 5, 7, 14, 21 or 28 days postinfection with bovine serum albumin and challenged with heat aggregated bovine serum albumin 7 days later. Cell-mediated immune responses in infected rats were not significantly different at any point from controls. These results indicate that M. pulmonis infection in rats suppresses the humoral antibody response to sheep red blood cells, but not the cellular immune response to bovine serum albumin.

Animals↗

Time-response studies of the cellular immune response to cell membrane antigens.

It was the objective of these experiments to study the time-related changes in the responsiveness of the cellular elements of the immune system following contact with single non-H-2 or multiple H-2 histocompatibility antigens. The reactivity of spleen cells from mice that received injections of spleen cells bearing H-1c, H-3c, H-13a, or H-2b cell membrane alloantigens was characterized at intervals following antigen contact. Spleen cells taken from mice not receiving injections showed no in vitro proliferative or cytolytic responsiveness to cells bearing individual non-H-2 antigens; after in vivo antigen contact with single non-H-2 antigens there was an interval of specific cellular unresponsiveness followed by alternating periods of responsiveness and unresponsiveness. The duration of the unresponsiveness immediately following injection correlated with the strength of the injected antigen--specifically, the stronger the antigen, the shorter the period of unresponsiveness. The data indicate fluctuation in the level of helper T lymphocyte activity, as well as cytotoxic T lymphocyte activity. In contrast, in vitro responsiveness elicited by H-2b antigens with and without prior in vivo antigen contact was of a similar magnitude, and both persisted at a relatively constant level. Suppressor mechanisms were not studied. Of particular interest was the observation that in vivo contact with non-H-2 antigens resulted in suppression of spleen cell production of IL-2 in response to lectin stimulation and fluctuation in the magnitude of the primary response of cytotoxic T lymphocytes to H-2 antigens.

Animals↗

Immunization with cytoplasmic repetitive antigen and flagellar repetitive antigen of Trypanosoma cruzi stimulates a cellular immune response in mice.

In previous studies, we demonstrated that CRA and FRA recombinant proteins, used for diagnosis of Chagas' disease, elicited a humoral immune response in susceptible and resistant mice. To understand better the immune response to these proteins, we have evaluated, the cellular immune response in CRA- and in FRA-immunized BALB/c and C57BL/6 mice. A specific cellular lymphoproliferative response was observed in both strains of mice. Spleen cell cultures mainly from CRA-immunized C57BL/6 and FRA-immunized BALB/c mice produced high levels of IFN-y, indicating the induction of a Type 1 immune response. Regarding the T cell subsets, CD4+ T cells were the major source of IFN-y in CRA- and FRA-immunized mice. These results suggest that CRA and FRA are important immunogens in inducing a Type 1 immune response and that they may be considered as potential vaccine antigens.

Animals↗

T cells are responsible for the enhanced synovial cellular immune response to triggering antigen in reactive arthritis.

In reactive arthritis (ReA) there is specific proliferation of synovial fluid (SF) mononuclear cells (MNC) to the triggering bacterial antigen; comparatively little or no response is seen in peripheral blood (PB). To investigate the mechanism of this elevated local immune response, we examined patients with typical ReA who showed an enhanced antigen-specific synovial immune response in bulk culture. Using separated fractions of T cells and antigen-presenting cells (APC) from PB and SF we showed that the synovial T cells rather than SF APC are responsible for the specific proliferation. By limiting dilution analysis, the frequency of T cells responding to the specific antigen was found to be significantly increased compared with the frequency of irrelevant antigen-specific T cells. Furthermore, the frequency of T cells responding to the specific antigen was higher in SF (between 1/619 and 1/4846, mean 1/2389) than in PB (between 1/1286 and 1/16,279, mean 1/7350). We conclude that the specific synovial cellular immune response in ReA is mainly due to an expansion of antigen-specific T cells within the joint. However, the non-specific hyper-reactivity of SF T cells and differences between SF and PB APC may make a more minor contribution.

Adult↗

Abnormal cellular immune responses during acquired zinc deficiency.

The cellular immune response of a 17-year-old decerebrate male with acquired zinc deficiency was studied. He had been fed a commercial formula which contained 7.6 mg zinc per kilogram. His caloric intake had been inadequate as judged by his cachexia. A detailed pretreatment nutritional assessment (five separate observations) which included total serum protein and globulins, albumin, folate, vitamins A, B2, C, ceruloplasmin, and plasma zinc, copper, iron, and total iron binding capacity revealed that the patient was deficient only in zinc and calories. His plasma zinc was 41 +/- 5 microgram/d1 compared with our laboratory norm of 89 +/- 9 microgram/d1 for young adult males. Cellular immunity was assessed by delayed skin reactivity to dinitrochlorobenzene and by in vitro lymphocyte transformation studies. Before zinc therapy the patient rendered a negative skin reaction to dinitrochlorobenzene, and the ability of his lymphocytes to undergo blast transformation in response to mitogen stimulation was significantly depressed with a stimulation index of 4.7 +/- 0.8 as compared with 139.1 +/- 77.3 for controls. Within 3 weeks after zinc therapy (22.7 mg zinc per day) he demonstrated a positive delayed skin reaction to dinitrochlorobenzene and a normal lymphocyte response stimulation index = 205.5 +/- 42.6 versus 199.3 +/- 58.2 for control). In addition, a pretreatment facial seborrhea and a decubitus ulcer rapidly healed.

Adolescent↗

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↗

Humoral and cellular immune responses in mice immunized with recombinant Mycobacterium bovis Bacillus Calmette-Guérin producing a pertussis toxin-tetanus toxin hybrid protein.

The development of combined vaccines constitutes one of the priorities in modern vaccine research. One of the most successful combined vaccines in use is the diphtheria-pertussis-tetanus vaccine. However, concerns about the safety of the pertussis arm have led to decreased acceptance of the vaccine but also to the development of new, safer, and effective acellular vaccines against pertussis. Unfortunately, the production cost of these new vaccines is significantly higher than that of previous vaccines. Here, we explore the potential of live recombinant Mycobacterium bovis BCG producing the hybrid protein S1-TTC, which contains the S1 subunit of pertussis toxin fused to fragment C of tetanus toxin, as an alternative to the acellular vaccines. S1-TTC was produced in two different expression systems. In the first system its production was under the control of the 85A antigen promoter and signal peptide, and in the second system it was under the control of the hsp60 promoter. Although expression of the hybrid antigen was obtained in both cases, only the second expression system yielded a recombinant BCG strain able to induce both a specific humoral immune response and a specific cellular immune response. The antibodies generated were directed against the TTC part and neutralized toxin activity in an in vivo challenge model, whereas interleukin-2 production was specific for both parts of the molecule. Since protection against tetanus is antibody mediated and protection against pertussis may be cell mediated, this constitutes a first promising step towards the development of a cost-effective, protective, and safe combined vaccine against pertussis, tetanus, and tuberculosis.

Animals↗

A recombinant Leishmania chagasi antigen that stimulates cellular immune responses in infected mice.

Cellular immune mechanisms resulting in gamma interferon production are critical for protection against visceral leishmaniasis. Antigens stimulating T-cell responses are likely present in the intracellular amastigote form of the parasite, since this is the form found in a mammalian host. To identify T-cell antigens of Leishmania chagasi, the parasite causing South American visceral leishmaniasis, we used a double antibody-T-cell technique to screen an amastigote cDNA library. One cDNA selected (Lcr1) encodes an antigen that stimulated proliferation of splenic T lymphocytes from infected mice that were either resistant (C3H.HeJ) or susceptible (BALB/c) to L. chagasi infection. The Lcr1 cDNA contains four highly divergent 201-bp repeats homologous to the 204-bp repeat of a Trypanosoma cruzi flagellar antigen gene. Results are consistent with a single copy of the Lcr1 gene producing an mRNA of > 10 kb and a protein of > 200 kDa. Recombinant Lcr1, cloned adjacent to polyhistidine and purified on a nickel affinity column, stimulated gamma interferon but not interleukin-4 (IL-4), IL-5, or IL-10 secretion by T-cell-enriched splenocytes from either susceptible or resistant mice during L. chagasi infection. Immunization with Lcr1 partially protected BALB/c mice against challenge with L. chagasi, indicating the utility of the double screening approach in selecting relevant T-cell antigens.

Amino Acid Sequence↗