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)

Curcumin (CCM; diferuoylmethane) is a dietary pigment in curry with known antineoplastic and anti-inflammatory effects. The immunosuppressive effects of CCM were studied in (1) rat heterotopic cardiac transplant models, using Brown-Norway (BN, RT1(n)) hearts to WKY (RT1(u)) hosts or Buffalo (BUF, RT1(b)) hearts to Wistar-Furth (WF, RT1(u)) hosts, (2) reverse transcriptase-polymerase chain reaction analysis of cytokines from transplanted specimens, and (3) mixed lymphocyte reactions (MLR). In the BN-to-WKY model, CCM alone significantly increased the mean survival time (MST) to 20.5 to 24.5 days, as compared to 9.1 days among nontreated controls. The combination of CCM and subtherapeutic doses of CsA produced further prolongation of the MST to 28.5 to 35.6 days, better than that of CCM or CsA alone (P <.05). In a BUF-to-WF model, CCM alone did not increased the MST, unless it was combined with subtherapeutic doses of CsA, wherein two thirds of the grafts survived for more than 60 days (P <.05 as compared to either treatment group). Cytokine analysis revealed significantly reduced expression of interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and granzyme B in the day 3 specimens of the CCM and CCM CsA-treated allografts compared with the nontreated allograft controls. MLRs using the two MHC-incompatible rat strains (BNxWKY) showed an effect of increasing concentrations of CCM and/or CsA, which by combination index (CI) analysis showed a synergistic effect (CI = 0.22 to 0.81). This study for the first time demonstrates the effectiveness of CCM as a novel adjuvant immunosuppressant with cyclosporine both in vivo and in vitro.
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PMID:Curcumin enhances the immunosuppressive activity of cyclosporine in rat cardiac allografts and in mixed lymphocyte reactions. 1282 32

Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8(+) or less frequently natural killer cells; in contrast, monoclonal expansions of CD4(+) T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4(+) T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4(+) T cells of a series of 34 consecutive cases. Like CD8(+) T-LGL leukemias, CD4(+) T-LGL leukemia patients have an indolent disease; however, in contrast to CD8(+) T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4(+) T-LGLshowed expression of TCRalphabeta, variable levels of CD8 (CD8(-/+dim)) and a homogeneous typical cytotoxic (granzyme B(+), CD56(+), CD57(+), CD11b(+/-)) and activated/memory T cell (CD2(+bright), CD7(-/+dim), CD11a(+bright), CD28(-), CD62L(-) HLA-DR(+)) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-gamma(++), tumor necrosis factor-alpha(++), interleukin (IL-2)(-/+), IL-4(-), IL-10(-), IL-13(-)]. Phenotypic analysis of the TCR-Vbeta repertoire revealed large monoclonal TCR-Vbeta expansions; only a restricted number of TCR-Vbeta families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRalphabeta(+)/CD4(+)/NKa(+)/CD8(-/+dim) T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8(+) T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder.
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PMID:TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder. 1287 95

T cells expressing CD57 (a natural killer cell marker) with interferon-gamma (IFN-gamma) producing capacity increase under various conditions. CD57+ T cells are also present in the bronchoalveolar lavage fluid (BALF) of sarcoidosis, and several phenotypical and functional analyses of these cells have been reported. In the present study, BALF T cells obtained from 52 patients with sarcoidosis were classified further into CD4+CD57+ T cells, CD4+CD57- T cells, CD8+CD57+ T cells and CD8+CD57- T cells and their phenotypes and functional characteristics were assessed. Substantial proportions of these T cell subsets expressed natural killer cell markers CD161 and CD122. The biased expansion of Vbeta2 T cells was observed in both CD4+CD57+ T cells and CD4+CD57- T cells in BALF from most patients, while the expansion of other Vbeta T cells was also observed in some patients. Unexpectedly, the biased expansion of certain Vbeta T cells was also seen in either CD8+CD57+ T cells or CD8+CD57- T cells, while the expanded Vbeta T cells in CD8+ T cells differed substantially among individuals. BALF T cells showed a remarkably lower T cell receptor (TCR) intensity than that of peripheral blood T cells. Both CD8+ T cell subsets in BALF of sarcoidosis expressed the intracellular perforin/granzyme B, while all four subsets expressed intracellular IFN-gamma after in vitro activation, and CD4+ T cells, especially CD4+CD57+ T cells, expressed tumour necrosis factor-alpha. These findings indicate that CD57+ T cells as well as CD57- T cells in the BALF are phenotypically and functionally different from peripheral blood T cells and may play an important role in the Th1 dominant state and inflammation in pulmonary sarcoidosis.
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PMID:Characterization of bronchoalveolar lavage T cell subsets in sarcoidosis on the basis of CD57, CD4 and CD8. 1293 Mar 72

Delayed xenograft rejection (DXR) of pig organs by baboons currently represents the major obstacle to successful xenotransplantation. Although antibodies (Abs) are believed to play a fundamental role in this form of rejection, so far little is known concerning the potential cellular component. Biopsies taken during DXR of human CD55 transgenic pig hearts by non-treated (n = 2), alpha-Gal immunoadsorbed (n = 2), or immunosuppressed (n = 9) baboons were studied. The cellular element was explored by determining not only its phenotype by classical immunohistochemical techniques but also its activity in terms of cytokines, cytolytic enzymes and other mediators using quantitative reverse transcription polymerase chain reaction. All porcine xenografts underwent DXR; within 5 days in non-treated and immunoadsorbed animals but significantly delayed (6 to 29 days) in immunosuppressed animals. Cellular infiltration in non-immunosuppressed grafts consisted predominantly of monocytes/macrophages, CD8 cells and a few CD4 T-cells. The predominant baboon transcripts detectable were the proinflammatory cytokines interleukin1-alpha and tumor necrosis factor-alpha, the lymphokine interferon-gamma and the cytotoxic enzyme granzyme B. However, these cellular components were lacking in the immunosuppressed animals. Despite these differences, strong immunoglobulin M (IgM) and C5b-9 complement deposition was observed in all animals at rejection. Together our findings suggest that although the humoral response plays a predominant role in DXR through IgM Abs and complement activation, there is a clear cellular infiltrate in DXR in this model that is likely to contribute to rejection through a strong pro-inflammatory and cytotoxic environment, necessitating substantial immunosuppression for a prolonged graft survival.
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PMID:Cellular participation in delayed xenograft rejection of hCD55 transgenic pig hearts by baboons. 1295 Sep 87

Fractalkine (now also called CX3CL1) is a unique chemokine that functions not only as a chemoattractant but also as an adhesion molecule and is expressed on endothelial cells activated by proinflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes, which contain high levels of intracellular perforin and granzyme B, and on macrophages. Soluble fractalkine causes migration of NK cells, cytotoxic T lymphocytes, and macrophages, whereas the membrane-bound form captures and enhances the subsequent migration of these cells in response to secondary stimulation with other chemokines. Furthermore, stimulation through membrane-bound fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of various clinical disease states or processes, such as atherosclerosis, glomerulonephritis, cardiac allograft rejection, and rheumatoid arthritis. In addition, polymorphisms in CX3CR1, which reduce its binding activity to fractalkine, have been reported to increase the risk of HIV disease and to reduce the risk of coronary artery disease. This review will examine new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in various clinical conditions, especially in atherosclerosis and vascular injury.
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PMID:Fractalkine in vascular biology: from basic research to clinical disease. 1296 92

Activated CD8+ T cells play a critical role in host defense against viruses, intracellular microbes, and tumors. It is not clear if a key regulatory transcription factor unites the effector functions of CD8+ T cells. We now show that Eomesodermin (Eomes), a paralogue of T-bet, is induced in effector CD8+ T cells in vitro and in vivo. Ectopic expression of Eomes was sufficient to invoke attributes of effector CD8+ T cells, including interferon-gamma (IFN-gamma), perforin, and granzyme B. Loss-of-function analysis suggests Eomes may also be necessary for full effector differentiation of CD8+ T cells. We suggest that Eomesodermin is likely to complement the actions of T-bet and act as a key regulatory gene in the development of cell-mediated immunity.
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PMID:Control of effector CD8+ T cell function by the transcription factor Eomesodermin. 1460 54

The time kinetics of five cytokines [interleukin-2 (IL-2), IL-5, interferon-gamma (IFN-gamma), granulocyte macrophage-colony stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha)] and one cytotoxic effector protein (granzyme B) was analysed by real-time quantitative polymerase chain reaction (PCR) following in vitro stimulation of human CD4 and CD8 T lymphocytes. Two stimuli were used, a mitogen [phytohemagglutinin (PHA)] and a recall antigen [purified protein derivative (PPD)]. The pattern of cytokine mRNA expression was found to be dependent on the T-cell subset and stimulus used. A wide interindividual variability in the cytokine gene expression pattern was demonstrated. Two expression patterns were observed. A bell-shaped expression profile was seen for most cytokines upon PHA activation in both subsets and PPD-activated CD4 T cells, whereas a biphasic/multiphasic expression pattern was noted in CD8 T cells upon PPD stimulation. For most cytokines, the time to induction was within 30 min of activation, and maximum accumulation seemed to be obtained after 4-8 h of activation. A sustained high level could, however, be noticed for up to 24 h. Granzyme B gene expression was also induced within 30 min of activation but showed a continuous gradual increase and late maximal accumulation (48-72 h). The findings of the present study are of importance when designing studies using the cytokine gene expression profile as a marker for antigen-specific T lymphocytes. It might be recommended that cytokine gene expression (IL-2, IL-5 and IFN-gamma) should be measured after 4-8 h of specific activation but also up to 24 h of stimulation is acceptable. Granzyme B should preferentially be measured after 48-72 h of activation.
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PMID:Kinetics of cytokine gene expression in human CD4+ and CD8+ T-lymphocyte subsets using quantitative real-time PCR. 1463 15

BACKGROUND: The interferon-gamma (IFN-gamma) ELISPOT assay is one of the most useful techniques for immunological monitoring of cancer vaccine trials and has gained increased application as a measure of specific T cell activation. However, it does not assess cell-mediated cytotoxicity directly as IFN-gamma secretion is not limited to only cytolytic cells. Granzyme B (GrB) is a key mediator of target cell death via the granule-mediated pathway. Therefore, the release of GrB by cytolytic lymphocytes upon effector-target interaction may be a more specific indicator of CTL and NK cytotoxic ability than IFN-gamma secretion. METHODS: We assessed whether the GrB ELISPOT assay is a viable alternative to the 51Cr-release and IFN-gamma ELISPOT assays for measuring antigen-specific CTL cytotoxicity. Direct comparisons between the three assays were made using human CTL cell lines (alphaEN-EBV and alphaJY) and an in vitro stimulated anti-Flu matrix peptide (FMP)-specific CTL. RESULTS: When the GrB ELISPOT was directly compared to the IFN-gamma ELISPOT and 51Cr-release assays, excellent cross-correlation between all three assays was shown. However, measurable IFN-gamma secretion in the ELISPOT assay was observed only after 1 hour of incubation and cytotoxicity assessed via the 51Cr-release assay after 4 hours, whereas GrB secretion was detectable within 10 min of effector-target contact with significant secretion observed after 1 h. Titration studies demonstrated a strong correlation between the number of effector cells and GrB spots per well. Irrelevant targets or antigens did not induce significant GrB secretion. Additionally, GrB secretion was abrogated when CTL cultures were depleted of CD8+ cells. CONCLUSION: Our findings demonstrate that the GrB ELISPOT assay is a superior alternative to the 51Cr-release assay since it is significantly more sensitive and provides an estimation of cytotoxic effector cell frequency. Additionally, unlike the IFN-gamma ELISPOT assay, the GrB ELISPOT directly measures the release of a cytotolytic protein. Detection of low frequency tumor-specific CTL and their specific effector functions can provide valuable insight with regards to immunological responses.
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PMID:The Granzyme B ELISPOT assay: an alternative to the 51Cr-release assay for monitoring cell-mediated cytotoxicity. 1469 97

We studied the induction of T cell responses against hepatitis C virus (HCV)-related cytotoxic T cell (CTL) epitopes in lymphocytes from human leukocyte antigen (HLA)-A2-positive, HCV-naive individuals. Peptide and lipopeptides corresponding to the epitope at amino acids (aa) 1073-1081 induced equivalent numbers of tetramer-positive CD8+ T cells and detectable interferon-gamma and granzyme B spot-forming cells (sfcs). Epitope aa 35-44 induction of CTLs was not achieved, despite detectable tetramer-positive CD8+ T cells. IFN-gamma sfcs could only be induced with lipopeptide aa 20-44 but not by conventional antigens, which indicates that lipopeptides may alter T cell functions, depending on the epitope.
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PMID:Hepatitis C virus-derived lipopeptides differentially induce epitope-specific immune responses in vitro. 1472 89

As part of a larger vaccine study, peripheral blood mononuclear cells (PBMC) were collected from volunteers for analysis of vaccine-induced T cell responses. The PBMC were re-stimulated in vitro with live dengue virus and assayed for T(H)1 or T(H)2 memory cell responses. Re-stimulated PBMC from the volunteers predominantly secreted interferon-gamma. Little interleukin-4 (IL-4) or IL-10 secretion was detected, indicating a T(H)1 type of T cell response. The interferon-gamma response was primarily serotype-specific with some serotype cross-reactivity. T cell depletion studies showed that the interferon-gamma was being secreted by CD4+ T lymphocytes and/or by cells other than CD8+ T lymphocytes that were being stimulated by the CD4+ T lymphocytes. CD3+ or CD8+ T cell depletion showed that granzyme B mRNA expression correlated with the presence of CD4+ T lymphocytes. However, depletion of CD4+ T cells after four days of stimulation indicated that the granzyme B mRNA was produced by cells in culture other than lymphocytes. In summary, an antigen-specific T(H)1 type T cell response was seen as a response to vaccination using live attenuated dengue virus.
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PMID:Serotype-specific T(H)1 responses in recipients of two doses of candidate live-attenuated dengue virus vaccines. 1474 Sep 54


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