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)

A previously undefined phenotype of CD8(+) cells that appears to represent in vivo activated CTL precursors (CTLP*) has been identified in the spleens of C57Bl/6 mice responding to a P815 tumor allograft. This population was first evident by the transient expression of very high levels of CD28 and CD44 on day 5 of the allograft response and reached maximal levels on days 7 and 8 before declining on day 9. A transient increase in CD69 expression was also observed on these cells on day 5. In contrast, CTL effectors (CTLE), identified by their CD8(+)CD44(hi)CD62LloCD45RBlo phenotype, were not appreciably detected in the spleen until day 8 and reached maximal levels on day 10. Further characterization of CTLP* on day 7 revealed that they represented blasting cells by increased light scatter and also expressed very high levels of CD54 but not CD122, CD152, or CD154. In addition, the cells had already up-regulated CD49d, asialo GM1, CD11a, and CD95L, and down-regulated their expression of CD62L. A small percentage of these cells also expressed CD25. Day 7 CTLP* sorted on the basis of their CD44(xhi) and CD54(xhi) phenotype did not exhibit cytolytic activity in a standard chromium release assay but became cytotoxic when they were cultured in the presence of exogenous murine IL-2 for 5 days. Granzyme B activity, however, was detected in CTLP* on day 7 at levels equivalent to CTLE on day 10. In order to establish a potential precursor relationship between CTLP* and CTLE, mice were treated with various doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical that has been shown to dose-dependently suppress the in vivo generation of CTLE to P815 tumor cells by altering an early stage of CTLP activation. Results indicated that CTLP* were suppressed by TCDD on day 7 to the same degree that CTLE were suppressed on day 10. Importantly, for controls and for all doses of TCDD, there were approximately 12.5 CTLE on day 10 for every CTLP* detected on day 7. These results suggested that TCDD acted identically across all doses to inhibit the early stages of activation of CTLP but did not affect the final stages of differentiation and expansion to CTLE. This interpretation supports the previous observation that TCDD exposure had to occur within the first 3 days of the allograft response in order to induce suppression of CTLE activity. Taken together, these results support the conclusion that in vivo activated CTLP can be identified by their unique expression of very high levels of CD44, CD28, and/or CD54 prior to their full maturation and clonal expansion to functional CTLE.
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PMID:Novel phenotype associated with in vivo activated CTL precursors. 1007 61

Hyperglycemia and increased insulin requirements are indicators of ongoing islet allograft rejection, but there are no methods to predict or confirm rejection. Elevation of cytotoxic lymphocyte (CL) gene expression in peripheral blood (PB) has been correlated with renal allograft rejection in humans, but no published study has assessed the utility of monitoring these markers as predictors of rejection before the onset of clinical symptoms. We have established quantitative real-time PCR methods to determine the levels of mRNA transcripts for the CL genes granzyme B (GB), perforin, and fas ligand in blood samples from rhesus and cynomolgus monkeys. Four rhesus monkeys with long-term islet allograft function were studied. Antirejection (anti-CD154) therapy was discontinued, and weekly PB samples were obtained to determine whether the levels of mRNA transcripts for CL genes correlated with and/or were predictive of islet allograft rejection, defined as a loss of C-peptide production. For all monkeys, elevation of CL gene expression preceded rejection by 83--197 days, with GB as the best predictor. Elevated mRNA levels were sustained for 2--2.5 months in three of four animals and 1 month in the other, thus suggesting that the testing of these parameters may have practical applications in clinical islet cell transplantation.
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PMID:Elevation of cytotoxic lymphocyte gene expression is predictive of islet allograft rejection in nonhuman primates. 1187 51

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.
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PMID:SIV DNA vaccine co-administered with IL-12 expression plasmid enhances CD8 SIV cellular immune responses in cynomolgus macaques. 1612 21

CD40L generates immune responses in leukemia-bearing mice, an effect that is potentiated by IL-2. We studied the feasibility, safety, and immunologic efficacy of an IL-2- and CD40L-expressing recipient-derived tumor vaccine consisting of leukemic blasts admixed with skin fibroblasts transduced with adenoviral vectors encoding human IL-2 (hIL-2) and hCD40L. Ten patients (including 7 children) with high-risk acute myeloid (n = 4) or lymphoblastic (n = 6) leukemia in cytologic remission (after allogeneic stem cell transplantation [n = 9] or chemotherapy alone [n = 1]) received up to 6 subcutaneous injections of the IL-2/CD40L vaccine. None of the patients were receiving immunosuppressive drugs. No severe adverse reactions were noted. Immunization produced a 10- to 890-fold increase in the frequencies of major histocompatibility complex (MHC)-restricted T cells reactive against recipient-derived blasts. These leukemia-reactive T cells included both T-cytotoxic/T-helper 1 (Th1) and Th2 subclasses, as determined from their production of granzyme B, interferon-gamma, and interleukin-5. Two patients produced systemic IgG antibodies that bound to their blasts. Eight patients remained disease free for 27 to 62 months after treatment (5-year overall survival, 90%). Thus, even in heavily treated patients, including recipients of allogeneic stem cell transplants, recipient-derived antileukemia vaccines can induce immune responses reactive against leukemic blasts. This approach may be worthy of further study, particularly in patients with a high risk of relapse.
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PMID:Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. 1624 92

Immunization of cattle with a Leptospira borgpetersenii serovar hardjo-bovis vaccine results in the development of a recall response by WC1(+) gammadelta T cells and CD4(+) alphabeta T cells characterized by proliferation and interferon-gamma production. It was hypothesized that these two T cell subpopulations had largely redundant effector functions, principally differing in their requirements for activation. To test this, gene expression in cells proliferating to antigen were compared utilizing RT-PCR and bovine microarrays. Both T cell populations had similar transcript profiles for effector molecules, including IFN-gamma, FasL and granzyme B. In contrast, transcripts for costimulatory receptors and ligands were notably different following activation, as WC1(+) T cells expressed no or lower levels of transcripts for CD28 and CD40L, while CD4(+) T cells expressed substantial levels of both. However, both cell types had high levels of CTLA-4 transcript suggesting the cells may be regulated similarly following activation but differ in their need for and ability to provide costimulation. Microarray analyses to extend the number of genes examined revealed that while both subpopulations upregulated anti-apoptotic genes as well as those involved in cell activation and protein biosynthesis, overall there were limited differences between the two antigen-activated cell populations. Those genes that did differ were involved in cell signaling, protein production and intracellular protein trafficking. These results strengthen the hypothesis that these particular activated WC1(+) and CD4(+) T cells have overlapping effector functions and therefore may differ principally with regard to how they are recruited into immune responses.
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PMID:Comparison of gene expression by co-cultured WC1+ gammadelta and CD4+ alphabeta T cells exhibiting a recall response to bacterial antigen. 1708 9

We have shown that alloreactive CD8 T cell activation may proceed via CD4-dependent and CD4-independent pathways, and that CD8 T cell activation in Ag-primed animals is independent of CD154 costimulation. In this report, we further analyzed the activation and function of alloreactive CD8 CTL effectors in CD4 knockout (KO) skin/cardiac allograft recipients. FACS analysis showed that alloreactive CD8 T cells were activated at a significantly reduced level in CD4 KO mice. Importantly, these helpless CD8 T cells failed to develop CD154 blockade resistance following reactivation by the same alloantigen, indicative of defective memory formation. Only transient CD4 help was required, as short-term CD4 blockade at the time of first skin graft challenge only delayed alloreactive CD8 activation, without affecting the CD8 T cell memory response to a second skin graft. Moreover, postoperative CD4 blockade had no effect on alloreactive CD8 activation. Alloreactive CD8 cells generated in the absence of CD4 help exhibited decreased effector responses. Interestingly, intragraft induction of T cell-targeted chemokines early after transplant was also dependent on CD4 help, as the induction kinetics of CXCL9 and CCL5 in CD4 KO recipients was significantly delayed, coupled with similarly delayed infiltration by CD3/CD8 cells. Remarkably, helpless CD8 cells ultimately entering the graft still displayed significantly diminished T cell effector molecules (IFN-gamma, granzyme B). Thus, CD4 help is critical for alloreactive CD8 activation, function, and memory formation.
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PMID:Defective alloreactive CD8 T cell function and memory response in allograft recipients in the absence of CD4 help. 1787 49

BK polyomavirus (BKV) reactivation is associated with a failure of T cell immunity in kidney transplant patients, and may lead to BKV-associated nephropathy (BKVN) and loss of the allograft. BKV reactivation in hematopoietic stem cell transplant recipients is associated with hemorrhagic cystitis. We have investigated T cell responses to overlapping peptide mixtures corresponding to the whole BKV major T antigen (TAg) and major capsid protein (VP1) in peripheral blood mononuclear cell samples from a cohort of healthy BKV-seropositive subjects. The majority of these individuals possessed populations of both CD8(+) and CD4(+) T cells specific for these BKV antigens. After expansion in culture, the majority of the BKV-specific CD4(+) T cells, in addition to expressing CD40L (CD154), secreted both interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha, contained both granzyme A and granzyme B, and degranulated/mobilized CD107 in response to antigen-specific stimulation. These T cells thus represent potentially functional BKV-specific cytotoxic CD4(+) T lymphocytes. Secretion of both TNF-alpha and IFN-gamma by CD154(+)CD4(+) T cells on BKV-specific stimulation was associated with higher levels of granzyme B and a higher proportion of degranulating cells compared with CD154(+)CD4(+) T cells producing only IFN-gamma or neither cytokine. These healthy subjects also harbored populations of functional CD8(+) T cells specific for one or more of three newly defined HLA-A 02-restricted cytotoxic T lymphocyte epitopes within the BKV TAg as well as two HLA-A 02-restricted epitopes within the BKV VP1 we have previously described. The BKV-specific CD4(+) T cells characterized in this study may play a part in maintaining persistent memory T cell responses to the virus and thus contribute to the immune control of BKV in healthy individuals.
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PMID:Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults. 1793 Nov 8

Neem leaf preparation (NLP) was found to activate natural killer (NK) cells (CD56(+)CD3(-)) to enhance their cytotoxic ability to tumor cells and stimulate the release of interleukin-12 (IL-12) from macrophages from healthy individuals and head-and-neck squamous cell carcinoma patients. NLP upregulated cytotoxic (CD16(+) and CD56(dim)) NK cells, and the cytotoxicity of NK-sensitive K562 cells by NLP-stimulated peripheral blood mononuclear cells decreased significantly after IL-12 neutralization. This NK-mediated cytotoxicity was manifest by upregulation of IL-12-dependent intracellular expression of the perforin-granzyme B system. Moreover, NK cytotoxic function was abolished after use of concanamycin A, a perforin inhibitor, but not by brefeldin A, a Fas inhibitor, confirming the participation of the perforin-granzyme B system. In addition NLP upregulated the expression of CD40 in CD14(+) monocytes and CD40L in CD56(+) lymphocytes. Neutralization of CD40 and CD40L in NLP-stimulated peripheral blood mononuclear cells culture resulted in significant downregulation of IL-12 release and cytotoxicity of NK cells, demonstrating the role of a CD40-CD40L interaction in the observed functions. Signals involved in the NLP-induced release of IL-12, and thereby induction of NK cell cytotoxicity, are mediated by activating p38MAPK pathway, but not through the ERK1/2 signaling pathway. Overall the results suggest that NLP effects NK cellular cytotoxicity by CD40-CD40L-mediated endogenous production of IL-12, which critically controls perforin-dependent tumor cell cytotoxicity.
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PMID:Natural killer cell mediated cytotoxicity of tumor cells initiated by neem leaf preparation is associated with CD40-CD40L-mediated endogenous production of interleukin-12. 1796 70

Dendritic cells (DC) are crucial for the induction of CD8(+) T cell responses. However, as DC present antigen, they may also be at risk for being killed by recent activated CD8+ T cells. Previously we have shown that lipopolysaccharide (LPS)- or CD40L-stimulated monocyte-derived DC express high levels of the granzyme B-inhibitory serpin proteinase inhibitor-9 (PI-9). Furthermore we found that its murine homolog serine protease inhibitor-6 (SPI-6) protected murine DC against cytotoxic T lymphocyte-induced apoptosis. These data suggest that PI-9/SPI-6 may regulate survival of DC when they are under attack by effector cells. We therefore analyzed how PI-9 is regulated upon stimulation with several Toll-like receptor ligands. We found that the expression of PI-9 correlated with maturation, as measured with CD86 levels, but not with the production of interleukin-12-p70. Using LPS as stimulus, we also showed that the induction of PI-9 is dependent on the p38 mitogen-activated protein kinase signaling pathway. The data suggest that PI-9 is tightly linked to maturation and may allow DC to exert their function in a potentially hostile environment.
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PMID:Proteinase inhibitor-9 expression is induced by maturation in dendritic cells via p38 MAP kinase. 1819 23

Tumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and the detection of anti-MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti-MAGE-3.A1 T-cells could initiate a tumor regression process. To understand the role of these T cells, we carried out a functional analysis of anti-MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti-MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced interleukin 10. Transcript profiling confirmed these results and indicated that approximately 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K, and granzyme H, were highly differentially expressed between the anti-MAGE-3.A1 CTL clones derived from patients vaccinated with either peptide-ALVAC or peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the antivaccine CD8 T-cells, which may have an effect on their capacity to trigger a tumor rejection response.
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PMID:Functions of Anti-MAGE T-cells induced in melanoma patients under different vaccination modalities. 1848 79


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