Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphotactin (Ltn) is the sole member of C chemokines which attracts T cells and NK cells specially. Ltn gene was transferred in vivo to improve the antitumor efficacy of cytosine deaminase (CD) gene therapy. Upregulation of CD80 and CD54 on murine CT26 colon carcinoma cells was observed after combined transfection with adenovirus encoding CD (AdCD) and adenovirus encoding murine Ltn (AdLtn) followed by administration of 5-fluorocytosine (5FC) in vitro. AdCD/5FC treatment also increased the expression of CD95 and induced obvious apoptosis of CT26 cells. After combined treatment with AdLtn and AdCD/5FC, the pre-established murine model with subcutaneous CT26 colon carcinoma exhibited most significant tumor growth inhibition, and four of eight tumor-bearing mice were tumor free, while tumors in other mice grew more progressively. Examination of lymphocyte infiltration and cytokine gene expression in tumor tissue revealed that tumors from AdLtn/AdCD/5FC-or AdLtn-treated mice were heavily infiltrated with CD4+, CD8+ T cells and NK cells, and IL-2 and IFN-gamma mRNA expression were present in parallel with T cell and NK cell infiltration. Splenic NK and CTL activities increased significantly after the combination therapy. In vivo depletion analysis showed that NK cells, CD4+ T cells and CD8+T cells participated in the antitumor effect of the host with CD8+T cells being the main T cell subset responsible for the enhanced antitumor immune response. These findings suggested that increased immunogenicity and induction of apoptosis of the tumor cells, and efficient induction of local and systemic antitumor immunity of the host might contribute to the enhanced antitumor effects of the combined Ltn and CD suicide therapy. Gene Therapy (2000) 7, 329-338.
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PMID:Adenovirus-mediated lymphotactin gene transfer improves therapeutic efficacy of cytosine deaminase suicide gene therapy in established murine colon carcinoma. 1069 14

Activation of cytotoxic T cells without MHC restriction was attempted by expressing single-chain antibodies (scFv) against CD3 on the surface of tumor cells. A chimeric protein consisting of a scFv of mAb 145.2C11, the hinge-CH2-CH3 region of human IgG1, and the transmembrane and cytosolic domains of murine CD80 formed disulfide-linked dimers on the plasma membrane of cells and specifically bound lymphocytes. Anti-CD3 scFv dimers expressed on the cell surface induced CD25 (IL-2 receptor alpha-chain) expression and proliferation of splenocytes. CT26 tumor cells engineered to express surface scFv dimers (CT26/2C11) also induced potent lymphocyte cytotoxicity with or without addition of exogenous IL-2. Splenocytes activated by CT26/2C11 cells also killed wild-type CT26 cells, indicating that activated splenocytes could kill bystander tumor cells. Immunization of BALB/c mice with irradiated CT26/2C11 cells did not protect against a lethal challenge of CT26 cells, suggesting that systemic immunity was not induced. However, the growth of CT26 tumors containing 50% CT26/2C11 cells was significantly retarded compared with CT26 tumors, whereas CT26/2C11 tumors did not grow in syngeneic mice. These results suggest that expression of anti-CD3 scFv dimers on tumors may form the basis for a novel therapeutic strategy for tumors that exhibit defects in antigen processing or presentation. Gene Therapy (2000) 7, 339-347.
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PMID:Activation of lymphocytes by anti-CD3 single-chain antibody dimers expressed on the plasma membrane of tumor cells. 1069 15

We evaluated the effect of potential therapeutic genes, GM-CSF and IL-2 respectively, or in combination of both cytokines, on the activation of systemic antitumor responses. CT26 tumor cells were modified to secrete GM-CSF and/or IL-2. The growth rate of the modified tumor cells versus the parental CT26 cells did not show any difference. When we implanted the CT26 tumor cells which secrete either GM-CSF or IL-2, delayed and suppressed tumorigenicity was observed. However, another CT26 cell line which expresses both GM-CSF and IL-2 (CT26/GMCSF/IL-2) did not form any tumor mass in the immunocompetent syngeneic Balb/c mice, showing the potential immune responses. Immunohistochemical examination of the modified tumor masses implanted with the cells expressing GM-CSF or IL-2 showed increased necrosis and infiltration of NK (CD56+) lineage cells and macrophage/monocytes. In the vaccination model, the growth of rechallenged wild-type CT26 was more suppressed int he mice which were injected with GM-CSF or IL-2, however, the wild-type CT26 tumor formed normal tumor mass in the mice vaccinated with CT26/GM-CSF/IL-2 showing acute non-T-cell mediated immune response. As a treatment, we injected those modified tumor cells into the established tumor. There we could find tumor growth suppression by the injection of cytokine-modified CT26 cells, especially by the CT26/GM-CSF/IL-2. In the present study we could induce the eradication of tumorigenicity by the transfection of both GM-CSF and IL-2 genes and a potent role in the growth suppression of an established tumor.
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PMID:Effect of GM-CSF and IL-2 co-expression on the anti-tumor immune response. 1095 43

There exists cancer-associated immunosuppression, and the generation of lymphokine-activated killer (LAK) cells is impaired in patients with advanced cancer. Telomerase has been reported to be upregulated in the activation of lymphocytes to proliferate against immune stimulation as well as in the malignant transformation of immortal cancer cells. We attempted to clarify the involvement of telomerase in the impairment of LAK cell generation in patients with advanced cancer. LAK cells were generated by stimulation with interleukin (IL)-2 and immobilized anti-CD3 antibody (IL-2/CD3 system) from peripheral blood mononuclear cells of healthy volunteers (he-LAK) or patients with advanced cancer (ca-LAK), and proliferative potential of LAK cells was evaluated on the basis of population doubling level (PDL). Telomere length and telomerase activity of LAK cells were measured by the hybridization with oligonucleotide (TTAGGG)4 and by the telomeric repeat amplification protocol (TRAP) assay, respectively. Effects on telomerase activity in LAK cells of serum from cancer patients, transforming growth factor (TGF)-beta, and IL-10 were also examined. The lifespan of ca-LAK (15.2 +/- 5.1 PDLs) was significantly shorter than that of he-LAK (22.6 +/- 8.3 PDLs) (p = 0.0358). There were no significant differences between he- and ca-LAK in telomere length before IL-2/CD3 stimulation and maximal telomerase activity induced. The telomerase activity induced in ca-LAK failed to elongate sufficiently the telomeric ends (-35.2 +/- 46.2 bp) compared with that in he-LAK (16.8 +/- 41.5 bp) (p = 0.0448). The telomerase activity was initially detectable on day 2 in all he-LAK, whereas 8 (61.5%) of 13 ca-LAK expressed telomerase activity on day 3 or later following the stimulation, showing a significant retardation of telomerase expression (p = 0.0116). The addition to the LAK cell generation system of serum from cancer patients, as well as IL-10, but not transforming growth factor (TGF)-beta, suppressed the telomerase activity. This serum-induced suppression of telomerase activity in LAK cells was abrogated with the addition of anti-IL-10 antibody but not with anti-TGF-beta antibody. It is suggested that the dysregulation of telomerase activity and expression exists in LAK cells of cancer patients, resulting in the impairment of LAK cell generation in patients with advanced cancer. Serum IL-10 may be involved in the impairment of LAK cell generation by the suppression of telomerase activity of lymphocytes in vivo. Thus, the dysregulation mechanism of telomerase activity and expression in lymphocytes of cancer patients may be attributable, in part, to cancer-associated immunosuppression.
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PMID:Dysregulation of telomerase activity and expression in lymphokine-activated killer cells from advanced cancer patients: possible involvement in cancer-associated immunosuppression mechanism. 1129 96

Interleukin (IL)-2 is a cytokine that influences exploratory behavior and central dopamine activity in rodents, and induces schizophrenic-like behavior and cognitive deficits in humans. We presently report that a single i.p. injection of murine IL-2 (0.05-0.80 microg/mouse) induced significant increases in novelty-induced locomotion and exploration in BALB/c mice. These measures were not significantly altered in mice that were pre-exposed to the test cage prior to cytokine injection. The IL-2-induced behavioral changes were not further augmented by repeated intermittent injections (five daily i.p. injections; 0.4 microg/mouse), however. Nonetheless, during the treatment period, activity scores of IL-2-treated mice significantly exceeded those of mice receiving saline; hence, repeated injections of IL-2 induced a persistent behavioral activation. IL-2 treatment also increased sensitivity to the behavior-stimulating effects of GBR 12909, a highly selective dopamine uptake inhibitor. This effect was a very long-lasting one since the dopamine agonist was administered 6 weeks after cessation of IL-2 treatment. The latter finding indicates that IL-2 interacts with the mesolimbic dopamine system, changing its sensitivity to seemingly different substances. Based on these data, and those of Zalcman and colleagues (S. Zalcman, I. Savina, R.A. Wise, Interleukin-6 increases sensitivity to the locomotor-stimulating effects of amphetamine in rats, Brain Res. 847 (1999) 276-283), it is suggested that cytokines can influence the development of behavioral abnormalities that are characteristic of aberrant mesolimbic dopamine activity via sensitization-like processes.
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PMID:Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity. 1131 62

Social isolation and lack of social support have deleterious effects on health, thus being regarded as one of the most relevant causes of diseases in human and other mammalian species. However, only few are the studies aimed at evaluating the psychoneuroimmunological functions of individually housed subjects. The present study was designed to understand how the behavior and the physiology of male house mice might be affected by individual housing. We first analyzed whether individual housing of different duration (1-42 days) would result in immuno-endocrine dysfunction (experiment 1). Then we investigated whether housing conditions would affect the reaction to an acute mild psychological stress (experiments 2 and 3). There were three main findings: first, individually housing mice for increasing time periods did not induce any major immuno-endocrine effects compared to a stable sibling group housing. Therefore, prolonged isolation does not seem to dramatically impair mice immuno-endocrine functions. Second, when exposed to a mild acute stress, i.e. forced exposure to a novel environment, isolated mice showed higher basal corticosterone and lower type 1 (IL-2) and type 2 (IL-4) cytokines as well as splenocytes proliferation compared to group housed male mice. Finally, when faced with a free choice between a novel environment and their home cage, individually housed mice showed reduced neophobic responses resulting in increased exploration of the novel environment, thus suggesting a low anxiety profile. Altogether, our findings suggest that individual housing in itself does not change immunocompetence and corticosterone level, but does affect reactivity to a stressor. In fact, individually housed mice showed high behavioral arousal, as well as altered immuno-endocrine parameters, when challenged with mild psychological novelty-stress.
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PMID:Individual housing induces altered immuno-endocrine responses to psychological stress in male mice. 1268 11

DNA vaccines, comprised of plasmid DNA encoding proteins from pathogens, allergens, and tumors, are being evaluated as prophylactic vaccines and therapeutic treatments for infectious diseases, allergies, and cancer; plasmids encoding normal human proteins are likewise being tested as vaccines and treatments for autoimmune diseases. Examples of in vivo prophylaxis and immunotherapy, based on different types of immune responses (humoral and cellular), in a variety of disease models and under evaluation in early phase human clinical trials are presented. Viral vectors continue to show better levels of expression than those achieved by DNA plasmid vectors. We have focused our clinical efforts, at this time, on the use of recombinant viral vectors for both vaccine as well as cytokine gene transfer studies. We currently have four clinical programs in cancer immunotherapy. Two nonspecific immunotherapy programs are underway that apply adenoviral vectors for the transfer of cytokine genes into tumors in situ. An adenovirus-IFN gamma construct (TG1042) is currently being tested in phase II clinical trials in cutaneous lymphoma. A similar construct, adenovirus-IL2 (TG1024), also injected directly into solid tumors, is currently being tested in patients with solid tumors (about one-half of which are melanoma). Encouraging results are seen in both programs. Two cancer vaccine immunotherapy programs focus on two cancer-associated antigens: human papilloma virus E6 and E7 proteins and the epithelial cancer-associated antigen MUC1. Both are encoded by a highly attenuated vaccinia virus vector [modified vaccinia Ankara (MVA)] and both are coexpressed with IL-2. Encouraging results seen in both of these programs are described.
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PMID:Gene-based vaccines and immunotherapeutics. 1533 50

Environmental enrichment is intended to improve the welfare of laboratory animals. However, regarding male mice, numerous studies indicate an increase in aggressive behavior due to cage structuring. On the one hand, this might be a problem concerning animal welfare. On the other hand, enrichment is though to hamper environmental standardization and to increase variability of data. Furthermore, increasing fights, arousal, and/or injury in enriched housed animals might superimpose other (positive) environmental effects on behavior and physiology. Therefore, the present study investigated effects of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice of the docile inbred strain ABG. From weaning until day 77+/-3 of life, animals were kept in stable sibling groups of four under three different housing conditions: (A) nonstructured Makrolon type III laboratory cages ("standard housing"=S); (B) equivalent laboratory cages that were enriched with a box and scaffolding ("enriched housing"=E); and (C) spacious terrariums that were structured richly ("super-enriched housing"=SE). No differences in agonistic behavior, levels of plasma corticosterone (CORT), and activities of adrenal tyrosine hydroxylase (TH) existed among S-, E-, and SE-housed ABG males. Play behavior and general activity increased significantly with increasing enrichment. Concerning immunological parameters, males of both forms of enriched housing showed significantly lower percentages of CD4 and CD8 cells compared to S-housed mice. However, regarding the ratio of CD4/CD8 cells, IL-2, IL-4, IL-10, IFN-gamma, IgG1, and IgG2a, no significant housing-dependent differences were found. Enrichment did neither hamper standardization nor negatively influence the variability of physiological parameters. In summary, using a docile strain of mice revealed the positive effects of environmental enrichment also on male mice. The lack of adverse effects on behavior, physiology, standardization, and variability of data defuses these arguments against providing docile male mice with enrichment.
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PMID:Effects of environmental enrichment on males of a docile inbred strain of mice. 1545 40

T-regulatory (Treg) cells play a major role in cancer by suppressing protective antitumor immune responses. A series of observations (from a single laboratory) suggest that Treg cells are protective in cancer by virtue of their ability to control cancer-associated inflammation in an interleukin (IL)-10-dependent manner. Here, we report that the ability of Treg cells to produce IL-10 and control inflammation is lost in the course of progressive disease in a mouse model of hereditary colon cancer. Treg cells that expand in adenomatous polyps no longer produce IL-10 and instead switch to production of IL-17. Aberrant Treg cells from polyp-ridden mice promote rather than suppress focal mastocytosis, a critical tumor-promoting inflammatory response. The cells, however, maintain other Treg characteristics, including their inability to produce IL-2 and ability to suppress proliferation of stimulated CD4 T cells. By promoting inflammation and suppressing T-helper functions, these cells act as a double-edged knife propagating tumor growth.
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PMID:T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. 1956 69

Immune stimulating complexes (ISCOMs) incorporating recombinant hepatitis B surface antigen (rHBsAg) were prepared for induction of humoral and cellular immunity by subcutaneous administration. Prepared ISCOMs were characterized for their size, shape, incorporation efficiency, zeta potential, antigen integrity, antigen conformation and immunogenicity by biophysical and immunological techniques including transmission electron microscopy (TEM), Dynamic light scattering (DLS), SDS-PAGE, fluorescence spectroscopy, in vitro potency test and in vivo humoral and cellular immune stimulatory efficacy in Balb/c mice. Prepared ISCOM particles show characteristic cage like morphology with average size of 44 approximately nm, polydispersity index 0.1, negative zeta potential (-21.7 mV) and antigen association efficiency approximately 39%. Tryptophan emission fluorescence and in vitro potency assay data suggest that association of rHBsAg with ISCOMs results in local electrostatic interactions, motional restriction of tryptophan residues of the protein resulting in reduction of anti-rHBsAg monoclonal antibodies binding affinity. Immunization with rHBsAg ISCOMs resulted in upregulation of specific cellular (IFN-gamma and IL-2) as well as IgG response (IgG2a isotype biased) humoral response in Balb/c mice. Immune responses were significantly higher than those produced by of alum-adsorbed antigen (alum-rHBsAg) after (one booster) (p < 0.001). These data demonstrate that although the conformation of rHBsAg after incorporation into ISCOMs was moderately altered but due to strong adjuvant ability, rHBsAg ISCOMs were highly immunogenic as compared to marketed rHBsAg formulations by subcutaneous route of administration.
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PMID:Evaluation of ISCOMs for immunization against hepatitis B. 1975 Nov 76


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