Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.79 (granzyme B)
 3,301 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Staphylococcal enterotoxin superantigens (SAg) bind class II major histocompatibility complex (MHC) molecules on antigen-presenting cells (APC) and upon cell-to-cell contact stimulate proliferation of T cells expressing appropriate V beta gene products. In addition, SAg can also deliver negative signals to Ag-specific T cells resulting in a state of unresponsiveness or a loss of viability. The present study examines the functional consequences of a direct interaction of SAg with alloAg-specific class II MHC+ CD4+ T cell lines (TCL). Our results demonstrate that SAg induce programmed death (apoptosis) in a majority of Ag-specific CD4+ T cells accompanied by genomic DNA fragmentation. SAg binding to Ag-specific TCL resulted in a rapid mobilization of intracellular free calcium ([Ca2+]i) and transcription of a number of cytokine genes including interleukin-2(IL-2), IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granzyme B indicating the activation of primed T cells. Both SAg-induced cytokine gene expression as well as subsequent death were significantly inhibited by a tyrosine kinase inhibitor herbimycin A and also by cyclosporin A. SAg-induced death of primed T cells was also inhibited by monoclonal antibodies (mAb) directed at the CD11a/CD18 molecule but not those reactive with other T cell surface molecules such as CD2, CD7, CD28, CD29 or CD49d. None of these mAb, including anti-CD11a/CD18, had any effect on SAg-induced expression of IL-2 and IL-4 genes or SAg-induced [Ca2+]i response. Addition of cytokines such as IL-1 alpha, IL-2, IL-4, IL-6, GM-CSF, IFN-gamma, tumor necrosis factor (TNF-alpha, or TNF-beta), or neutralizing Ab to these cytokines had no effect on SAg-induced death of Ag-specific TCL. The T cells which survived the death-inducing effects of SAg showed down-regulation of the CD3/T cell receptor and up-regulation of CD2 and HLA-DR expression, and upon re-exposure to the same SAg upregulated expression of mRNA for IL-2 and IFN-gamma. Presentation of SAg by B7+ ICAM-1+ LFA-3+ DR+ professional APC was also able to induce the death of Ag-specific TCL. Together these results suggest that the activation with SAg causes programmed death of Ag-specific TCL cells via a mechanism that requires late participation of the CD11a/CD18 molecule.
 ...
PMID:Activation with superantigens induces programmed death in antigen-primed CD4+ class II+ major histocompatibility complex T lymphocytes via a CD11a/CD18-dependent mechanism. 810 Jul 73

Despite good initial success in vivo, gene transfer using first-generation replication-defective adenovirus has been reported to lead to transient reporter gene expression and to trigger inflammatory reactions in various organs and animal models. To gain more knowledge on this phenomenon, immune reactions were investigated following in vivo transfection of adult immunocompetent mouse muscle using a delta E1/E3a adenoviral vector encoding a beta-galactosidase (beta-Gal) expression cassette. Cellular and humoral immune reactions, and rejection of beta-Gal-positive muscle fibers, occurred within 3 weeks. The muscles showed massive infiltration by macrophages, natural killer cells, and CD8+ leukocytes. The mRNA levels of granzyme B and interferon-gamma were increased 6 days after vector injection, indicating that the infiltrating lymphocytes were activated. Antibodies were formed against the adenovirus group antigen and the beta-Gal gene product 2 weeks after construct injection. The immunosuppressant FK506, however, blocked the cellular infiltration and the humoral response and allowed strong, stable transgene expression over 1 month. These data emphasize the immune problems related to the use of delta E1/E3a adenoviruses as vectors for gene therapy, and they underline the potential of FK506 as an immunosuppressant adjunct treatment for adenovirus-mediated gene transfer.
 ...
PMID:FK506 immunosuppression to control the immune reactions triggered by first-generation adenovirus-mediated gene transfer. 857 12

We have investigated the effect of interferon-gamma (IFN-gamma) and interleukin (IL)-10 on granzyme B expression and the induction of major histocompatibility complex (MHC)-unrestricted cytotoxic activity in mouse T cell cultures following activation with anti-CD3 monoclonal antibody (mAb). First, metabolic inhibitors of granule-dependent and granule-independent cytolytic pathways were used to show that anti-CD3-activated killer T (AK-T) cells kill allogeneic P815 mastocytoma target cells primarily by the granule-dependent granzyme/perforin pathway. In comparison to control AK-T cells, lower levels of cytolytic activity were evident when AK-T cells were generated in the presence of anti-IFN-gamma neutralizing mAb or exogenous IL-10, whereas enhanced cytotoxicity was observed when AK-T cell cultures contained anti-IL-10 neutralizing mAb or exogenous IFN-gamma. In addition, granzyme B mRNA expression by AK-T cells was diminished when IFN-gamma bioactivity was neutralized or exogenous IL-10 was present in AK-T cell-cultures, whereas neutralization of IL-10 bioactivity or the addition of exogenous IFN-gamma resulted in increased expression of granzyme B mRNA. Similar results were obtained when granzyme B enzymatic activity in AK-T cell lysates was quantified using a colorimetric granzyme B assay. Altered cytotoxic potential, granzyme B mRNA expression, and granzyme B enzymatic activity following T cell activation in the presence of anti-IFN-gamma or anti-IL-10 neutralizing mAb or exogenous IFN-gamma or IL-10 could not be attributed to gross changes in T cell activation status or to altered percentages of CD4+ and CD8+ T cells in AK-T cell cultures. We conclude that IFN-gamma and IL-10 cross-regulate the induction of the granule-dependent cytolytic machinery of AK-T cells.
 ...
PMID:Anti-CD3-activated killer T cells: interferon-gamma and interleukin-10 cross-regulate granzyme B expression and the induction of major histocompatibility complex-unrestricted cytotoxicity. 883 20

Apoptosis induced in myeloid leukemic cells by wild-type p53 was suppressed by different cleavage-site directed protease inhibitors, which inhibit interleukin-1 beta-converting enzyme-like, granzyme B and cathepsins B and L proteases. Apoptosis was also suppressed by the serine and cysteine protease inhibitor N-tosyl-L-phenylalanine chloromethylketone (TPCK) [corrected], but not by other serine or cysteine protease inhibitors including N alpha-p-tosyl-L-lysine chloromethylketone (TLCK), E64, pepstatin A, or chymostatin. Protease inhibitors suppressed induction of apoptosis by gamma-irradiation and cycloheximide but not by doxorubicin, vincristine, or withdrawal of interleukin 3 from interleukin 3-dependent 32D non-malignant myeloid cells. Induction of apoptosis in normal thymocytes by gamma-irradiation or dexamethasone was also suppressed by the cleavage-site directed protease inhibitors, but in contrast to the myeloid leukemic cells apoptosis in thymocytes was suppressed by TLCK but not by TPCK. The results indicate that (i) inhibitors of interleukin-1 beta-converting enzyme-like proteases and some other protease inhibitors suppressed induction of apoptosis by wild-type p53 and certain p53-independent pathways of apoptosis; (ii) the protease inhibitors together with the cytokines interleukin 6 and interferon-gamma or the antioxidant butylated hydroxyanisole gave a cooperative protection against apoptosis; (iii) these protease inhibitors did not suppress induction of apoptosis by some cytotoxic agents or by viability-factor withdrawal from 32D cells, whereas these pathways of apoptosis were suppressed by cytokines; (iv) there are cell type differences in the proteases involved in apoptosis; and (v) there are multiple pathways leading to apoptosis that can be selectively induced and suppressed by different agents.
 ...
PMID:Differential suppression by protease inhibitors and cytokines of apoptosis induced by wild-type p53 and cytotoxic agents. 890 12

The regulation of human natural killer (NK) cell activation is under the control of a network of regulatory signals provided by cytokines. In the present study, we investigated the functional interaction between interleukin (IL)-4 and two monocyte/macrophage-derived cytokines, IL-12 and IL-15, during the process of NK stimulation. Using freshly isolated human NK cells, we have demonstrated that IL-4 negatively regulates lymphokine-activated killer (LAK) activity induced by IL-15 against the NK-resistant Daudi target cells. In contrast, IL-4 had no effect on IL-12-stimulated LAK generation. The differential effect of IL-4 on NK cell activation by IL-12 and IL-15 correlates with its ability to increase or to down-regulate the level of tumor necrosis factor-alpha and interferon-gamma release by NK cells, respectively. In contrast, endogenous transforming growth factor-beta 1 does not appear to be involved in the IL-4 regulatory pathway. Furthermore, while IL-4 was found to decrease the basal expression of the IL-2 receptor beta subunit utilized by IL-15, it had no effect on the expression of the beta 1 chain of the IL-12 receptor compared to untreated cells. Northern blot analysis indicated that the IL-4 regulatory effect on NK lytic function was associated with its capacity to down-regulate granzyme B and perforin gene transcription in response to IL-15 and its failure to affect the expression of both gene's in response to IL-12. Together, these data suggest the existence of a distinct cross-talk between IL-4 and IL-15 or IL-12 signaling pathways during the regulation of human non-major histocompatibility complex-restricted cytotoxicity.
 ...
PMID:Differential regulation of interleukin-12- and interleukin-15-induced natural killer cell activation by interleukin-4. 892 63

Pentoxifylline (PTX), a methylxanthine derivative, is known to inhibit the production of the TH1 cytokines interleukin-2, tumour necrosis factor-alpha and interferon-gamma. Because these cytokines play an important role in promoting the development of cell-mediated immunity, we hypothesized that PTX would also interfere with the generation of cytotoxic effector cells in response to an immunological stimulus. In this study we used a mouse model system to investigate the effect of PTX on the induction of non-specific killer lymphocytes by anti-CD3 monoclonal antibody. Anti-CD3-induced T-cell proliferation, and the generation of anti-CD3-activated killer (AK) cells was inhibited in a dose-dependent fashion by PTX (25-100 micrograms/ml). The inhibitory effect of PTX could not be attributed to a defect in the recognition/adhesion phase of cytolysis because AK cells generated in the presence of PTX conjugated normally with P815 tumour target cells. However, AK cell expression of the cytoplasmic granule-associated cytolytic effector molecules granzyme B and perforin was markedly reduced when AK cells were induced in the presence of PTX. In eontrast, PTX had no effect on AK cell expression of Fas ligand, a cell-surface cytolytic effector molecule which is involved in granule-independent cytotoxicity. PTX thus has a profound inhibitory effect in vitro on the induction of granule-dependent cytolytic effector mechanisms in a mouse model system.
 ...
PMID:Pentoxifylline inhibits granzyme B and perforin expression following T-lymphocyte activation by anti-CD3 antibody. 908 6

Myoblasts obtained from donors histoincompatible for several non-major histocompatibility complex antigens (i.e., including minor histocompatibility antigens) and from syngeneic donors were transplanted without any immunosuppression into the muscles of male dystrophic C57BL/10J mdx/mdx mice. Myoblasts from syngeneic mice resulted in the formation of a high percentage of dystrophin-positive fibers 16 weeks after the transplantation. There was no evidence of a cellular immune reaction against the donor myoblasts, i.e., no infiltration by CD4 or CD8 lymphocytes and no increased expression of granzyme B and interferon-gamma mRNAs. Transplantation of myoblasts obtained from donors histoincompatible only for non- major histocompatibility complex antigens produced a transient increase of dystrophin-positive fibers at 4 weeks after transplantation for some donor strains but not for others. For donor strains that did produce an increase at 4 weeks, the number of dystrophin-positive fibers was reduced 16 weeks after the transplantation. There was evidence of a cellular immune reaction-infiltration by CD4 and by CD8 lymphocytes and increased expression of granzyme B and interferon-gamma mRNAs. Transplantation of myoblasts obtained from male C57BL/10J +/+ mice into female C57BL/10J mdx/mdx mice also led to the presence of only a few dystrophin-positive fibers with the same signs of cellular immune reaction. In this later case, the cellular immune response was attributed to the H-Y minor antigens. Finally, antibodies against fetal calf serum were detected after both syngeneic and nonsyngeneic transplantations, indicating that the culture medium may also be a source of antigens. In mice, the presence of these antibodies against culture medium did not reduce the success of a first syngeneic transplantation.
 ...
PMID:Role of non-major histocompatibility complex antigens in the rejection of transplanted myoblasts. 908 31

Human small intestine contains a very large population of intraepithelial T lymphocytes (IELs) that are oligoclonal, appear functionally to be cytolytic T cells, and may contribute to the normal and pathological turnover of intestinal epithelial cells. This report addresses the cytolytic function of IELs in normal small intestine by examining their expression of molecules that carry out cell-mediated cytolysis. Immunohistochemical analyses of granzyme B, perforin, Fas ligand, and tumor necrosis factor-alpha demonstrated these proteins were not expressed by small intestinal IELs in situ. These proteins also were not expressed by colonic IELs or by lamina propria lymphocytes in the small or large intestine. Granzyme A, however, was expressed by a large fraction of IELs. In contrast to these in situ results, isolated and in vitro activated IELs were shown to express effector proteins consistent with cytolytic T cells, including granzyme B, Fas ligand, tumor necrosis factor-alpha, and interferon-gamma. These results are most consistent with the vast majority of IELs in normal human small intestine being resting cytolytic T cells and suggest that these cells do not contribute to the apoptotic cell death of epithelial cells in normal intestine.
 ...
PMID:Intraepithelial lymphocytes in normal human intestine do not express proteins associated with cytolytic function. 925 Jan 56

Human natural killer (NK) cells are defined as being membrane CD3-, CD16+, and/or CD56+ lymphocytes; however, little is known about the ontogenic development and maturational pathways of human NK cells. The functional, phenotypic, and maturational characteristics of human umbilical cord blood (CB) NK cell subsets were studied to gain insight into the ontogenic and maturational pathways of human NK cells. We have previously shown that there is a novel subset of CD16+ CD56- NK cells present in CB. Here we further demonstrate differences in the expression of the NK-associated molecules CD2, CD7, CD8, and CD25 between CB and peripheral blood (PB) NK cells and between CB NK cell subsets. Although CB NK cell subsets were deficient in or had less lytic activity against K562 cells compared to PB NK cells, CB NK cells did possess the lytic molecules perforin and granzyme B and when artificially stimulated to secrete their granules during lytic assays, were capable of lytic activity equivalent to that of PB NK cells. Regardless of differences in phenotype and function of CB NK cell subsets, short-term and long-term incubation with cytokines induced functional (adult-like NK activity) and phenotypic (adult-like CD16+56+ or CD16-56+ surface antigen phenotype) maturation, respectively. Interleukin-2 (IL-2), IL-12, and IL-15, but not IL-7, interferon-gamma (IFN-gamma) nor tumor necrosis factor-alpha (TNF-alpha) induced functional and phenotypic maturation of CB NK cell subsets. Interestingly, culture of CB NK cell subsets with IL-2 or IL-15 led to acquisition of predominantly a CD16+56+ phenotype, while culture with IL-12 led to acquisition of both CD16+56+ and CD16-56+ phenotypes. Both functional and phenotypic maturation were not dependent upon proliferation. Studies using neutralizing anti-IFN-gamma and anti-TNF-alpha antibodies showed that survival and phenotypic maturation upon cytokine stimulation is influenced by endogenous production of TNF-alpha but not IFN-gamma. These results demonstrate that CB NK cell subsets are functionally and phenotypically immature but are capable of maturation. Additionally, CD16+56- NK cells are implicated as possible precursors of mature CD16+56+ and CD16-56+ NK cells.
 ...
PMID:Cord blood CD16+56- cells with low lytic activity are possible precursors of mature natural killer cells. 934 43

In a patient with metastatic melanoma transmitted by the renal allograft, HLA serves as an alloantigen per se and is associated with tumor antigens at the same time. The influence of this antigeneic pattern on the Vbeta T-cell repertoire in an allogeneic melanoma, allograft, and peripheral blood mononuclear cells (PBMC) was assessed by polymerase chain reaction. Vbeta13.1 and 19 were found in both the melanoma and the graft. Vbeta14 was detected only in the melanoma and Vbeta6 was detected only in the kidney. PBMC revealed an unrestricted Vbeta pattern. Markers for cytotoxic activity of T cells--granzyme B and perforin--were not expressed during immunosuppressive therapy as clinically reflected in a nonrejecting allograft and in a progressing melanoma. In vitro PBMC proliferated to recombinant interleukin-2, whereas recombinant interferon-gamma did not augment this response. Initiation of immune therapy, in addition to discontinuation of immunosuppression, might support the rejection of the allogeneic tumor by dominant Vbeta T cells.
 ...
PMID:Limited T-cell repertoire in renal allograft and allogeneic melanoma transmitted by the graft. 941 73


1 2 3 4 5 6 7 8 9 10 Next >>