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)

Human bone marrow transplantation is becoming more common in the treatment of certain forms of cancer despite the scarcity of HLA matched donors. Because human umbilical cord blood (HUCB) has been used as a source for stem cells in bone marrow transplantation, and because NK cells appear to be important in graft versus leukemia response, we investigated the lytic activity of freshly isolated HUCB NK cells (HUCB-NK) against tumor targets and their ability to differentiate into LAK cells following stimulation with various cytokines. Although cytotoxicity mediated by fresh HUCB-NK was low compared to that of adult peripheral blood lymphocyte-derived NK cells (PBL-NK), the ability of HUCB-NK to bind to K562 target cells (TC) was similar to PBL-NK. In addition, the PBL-NK cytotoxicity of postpartum mothers was also low compared to that of normal adult PBL-NK. When we incubated HUCB for 18 hr in either IL-2 or IL-12, we boosted the level of HUCB-NK cytotoxicity to approximately the level observed in PBL-NK and increased the level of perforin, granzyme A, and granzyme B mRNA expression. In addition, when we incubated HUCB in IL-2, IL-4, IL-7, IL-12, TNF-alpha, IFN-alpha, IFN-gamma, or TGF-beta for 5 days, we observed that HUCB was capable of generating LAK cells only when incubated with either IL-2 or IL-12. In contrast, IL-2, IL-7, IL-12, TNF-alpha, and IFN-gamma all generated LAK cells from adult PBL. When we added to the medium low-dose IL-2 and irradiated K562 as feeder cells (mini-LAK), we were unable to generate LAK activity from HUCB-NK, whereas we could generate it with PBL-NK cells under the same conditions. Addition of serum derived from HUCB in a 4-hr 51Cr release assay with PBL-NK as the effector cells (EC) and K562 as the TC resulted in a 42% decrease in PBL-NK-mediated cytotoxicity. Although we detected no TGF-beta in HUCB serum, we did detect high concentrations of soluble class I MHC (sHLA). To our knowledge, sHLA has not previously been shown to inhibit NK cytotoxicity, although the expression of class I HLA on the surface of TC has been shown to inhibit NK cytotoxicity. To study further the effect of sHLA on cell-mediated cytotoxicity, we added various concentrations of sHLA to EC mediating NK, ADCC, and CTL activities. All were inhibited in a dose-dependent manner.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The lack of NK cytotoxicity associated with fresh HUCB may be due to the presence of soluble HLA in the serum. 799 57

To determine the immune processes involved in chronic liver allograft rejection (CR) we examined in situ cytokine production in tissue from 15 patients with both clinical and histopathological diagnoses of CR. Total RNA was isolated from liver samples, reverse-transcribed and analyzed by RT-PCR for the production of proinflammatory cytokines and immunoregulatory mediators. Transcripts for the Th1-like cytokines IL-2 and IFN-gamma were detected in 53.3% and 46.7% of CR grafts, while they were detected in only 16% and 0% of stable grafts, respectively. The cytotoxic T cell mediator granzyme B was expressed in the majority of liver grafts undergoing CR, but was expressed only in a minority of stable grafts (80% vs. 16%, P < 0.05). The T cell product IL-5 was also significantly upregulated in CR as compared with stable livers (80% vs. 16%, P < 0.01). Other Th2 cytokines--IL-4 and IL-10--and macrophage products--IL-1 beta, IL-6, IL-8, TGF-beta, and TNF-alpha--were not substantially upregulated in CR grafts as compared with stable grafts. PDGF-beta transcripts were detected in the majority of the CR grafts, but were not detected in stable liver grafts (73% vs. 0, P < 0.05). By immunohistochemical staining, we observed that CD3+CD4+, and CD3+CD4- T cells were detected in CR grafts along with CD20+ B cells and CD68+ macrophages. There was, however, a predominant infiltration of CD3+CD4+ lymphocytes. Taken together, these data suggest that infiltrating cells produce proinflammatory and immunoregulatory cytokines that have a role in mediating graft damage in CR.
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PMID:Expression of cytokines and immune mediators during chronic liver allograft rejection. 854 86

Chronic allograft nephropathy is a relentlessly progressive process and a major cause of long-term graft dysfunction and ultimate failure. Interstitial fibrosis, tubular atrophy, and glomerular and vascular lesions characterize this mechanistically unresolved disorder. Given the prominent role of TGF-beta 1 in tissue repair and in fibrosis, we have explored the hypothesis that fibrosis and chronic allograft nephropathy would be distinguished by intragraft TGF-beta 1 mRNA expression. This postulate was tested by mRNA phenotyping of RNA isolated from 127 human renal allograft biopsies. Reverse transcription assisted polymerase chain reaction was used to amplify and identify ingraft gene expression. Our investigation demonstrated a significant correlation between intragraft TGF-beta 1 mRNA display and renal allograft interstitial fibrosis and chronic allograft nephropathy. In contrast, intragraft expression of mRNA encoding immunoregulatory cytokines, IL-2, IFN-gamma, IL-4, IL-10, or cytotoxic attack molecules, granzyme B and perforin was not a correlate of interstitial fibrosis or chronic allograft nephropathy. Our studies identify, for the first time, a significant association between intragraft TGF-beta 1 mRNA expression and renal allograft interstitial fibrosis, and advance a candidate molecular mechanism for chronic allograft nephropathy.
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PMID:Intragraft TGF-beta 1 mRNA: a correlate of interstitial fibrosis and chronic allograft nephropathy. 873 Oct 94

Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify intrarenal expression of cytotoxic attack molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta 1) in 127 human renal allograft biopsies. The biopsies were classified using the Banff criteria, and intrarenal gene expression was correlated with the histological diagnosis. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10 or IL-2 is a correlate of acute rejection, and intrarenal expression of TGF beta 1 mRNA, of chronic rejection. These data, in addition to demonstrating differential and highly selective intragraft gene expression during rejection, suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing anti-rejection strategies.
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PMID:Molecular analyses of human renal allografts: differential intragraft gene expression during rejection. 906 37

This article explores the clinical usefulness of reverse transcriptase-polymerase chain reaction in organ graft recipients. In this study, reverse transcriptase-polymerase chain reaction was used to identify intrarenal expression of cytotoxic attack molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta 1) in human renal allograft biopsies. The biopsies (n = 127) were classified using the Banff criteria, and intrarenal gene expression was correlated with the histologic diagnosis. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10, or IL-2 is a correlate of acute rejection, and intrarenal expression of TGF beta 1 mRNA is a correlate of chronic rejection. In addition to demonstrating differential and highly selective intragraft gene expression during rejection, these data suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing antirejection strategies.
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PMID:Clinical application of molecular biology: a study of allograft rejection with polymerase chain reaction. 914 34

Multiple myeloma (MM) remains an incurable disease by conventional therapy. MM tumor cells evade the immune system and can induce immunosuppression by producing immunomodifying agents such as TGF-beta, FasL, vascular endothelial growth factor and Muc-1. In the present study, we show that bone marrow cells from a patient suffering from MM IgG/k type, stage IIIA, when cultured, expressed granzyme B and perforin, normally expressed exclusively by cytotoxic T cells (CTLs) and natural killer (NK) cells. In addition, phenotypic analysis revealed that the cultured cells were activated antigen-presenting cells with NK targeting capacity. We propose that expression of these cytolytic enzymes may constitute an additional adoptive mechanism by the tumor cells to actively destroy the host immune effector cells.
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PMID:Expression of granzyme B and perforin in multiple myeloma. 1146 84

Our previous study showed that PG490-88 effectively ameliorated both functional and histological changes of chronic rejection in the rat. In this experiment, we investigated the intragraft gene expression profiles of PG490-88 under successful prevention of chronic rejection in rat kidney allografts. Kidneys of F344 rats were transplanted into bilaterally nephrectomized LEW recipients. Recipients with a brief course of low-dose FK506 (1 mg/kg per day for 10 days) were dosed with PG490-88 0.5 mg/kg per day, which was predetermined and defined as the effective dose of preventing chronic allograft rejection in this model, for 90 days after grafting. Kidney grafts were harvested on day 90 after transplantation and subjected to gene expression analysis by real-time RT-PCR. Overall, the expression levels of all genes tested were upregulated in the brief course of low-dose FK506 control. PG490-88 treatment exhibited significant inhibition of intragraft m RNA levels of iNOS, IL-6, and perforin and marginal downregulation of IL-2, IFNgamma, IRF-1, TNFalpha, and TGFbeta. There was no change in IL-10, granzyme B, and PDGFalpha, when compared to the brief course of low-dose FK506 control. These results suggested that downregulation of multiple intragraft gene expression by mainly suppression of iNOS, IL-6, and perforin might be responsible for successful prevention of chronic kidney allograft nephropathy by PG490-88 in rats.
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PMID:Protective effects of PG490-88 on chronic allograft rejection by changing intragraft gene expression profiles. 1591 18

Tumors escape from immune surveillance by producing the immunosuppressive cytokine TGF-beta. However, the mechanism by which TGF-beta inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-beta acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products-namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma-which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-gamma involves binding of TGF-beta-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-beta/Smad pathway. Neutralization of systemic TGF-beta in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-beta suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression.
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PMID:TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. 1628 41

Cross-talk between TGF-beta and IL-6 has been shown to direct the differentiation of CD4(+) cells into special IL-17-secreting cells, which are termed Th17 cells. In this study, we demonstrated that TGF-beta and IL-6 could stimulate CD8(+) cells to differentiate into noncytotoxic, IL-17-producing cells in MLC. These IL-17-producing CD8(+) cells exhibit a unique granzyme B(-)IFN-gamma(-)IL-10(-) phenotype. The mRNA level of Th2/T cytotoxic 2 (Tc2) transcription factors GATA3 and Th1/Tc1 transcription factors T-box expressed in T cell (T-bet) as well as its target H2.O-like homeobox (Hlx) is decreased in CD8(+) cells from TGF-beta- and IL-6-treated MLC. In addition, these CD8(+) cells display a marked up-regulation of retinoic acid-related orphan receptor-gammat, a key IL-17 transcription factor. These results demonstrate that the existence of an IL-17-producing CD8(+) subset belongs to neither the Tc1 nor the Tc2 subset and can be categorized as a T noncytotoxic 17 (Tnc17) subset.
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PMID:Induction of a distinct CD8 Tnc17 subset by transforming growth factor-beta and interleukin-6. 1750 23

The first weeks of life are characterized by immune tolerance and increased susceptibility to intracellular pathogens. The neonatal adaptive response to HSV is attenuated compared with adult control models in humans and mice. T Regulatory cells (Tregs) control autoimmunity and excessive immune responses to infection. We therefore compared Treg responses in the draining lymph nodes (LN) of HSV-infected neonatal and adult C57BL/6 mice with the effect of Treg depletion/inactivation by anti-CD25 (PC61) treatment before infection on Ag-specific T cell effector responses at this site. There was a small, but significant increase in the frequency of CD4(+)Foxp3(+) Tregs at day 3 postinfection (p.i.) in the LN of neonatal and adult mice, compared with age-matched mock-infected controls. Depletion of Tregs before HSV infection significantly enhanced HSV-specific CD8(+) T cell cytotoxicity in vivo, cell number, activation, and granzyme B expression 4 days p.i. only in neonatal mice, and significantly enhanced CD8(+) and CD4(+) T cell IFN-gamma responses in both infected adults and neonates. Treg depletion also reduced the titer of infectious virus in the draining LN and nervous system of infected neonates on days 2 and 3 p.i. Treg suppression of the neonatal CTL response p.i. with HSV was associated with increased expression of TGF-beta in the draining LN at day 4 p.i. compared with uninfected neonates, but IL-10 was increased in infected adults alone. These experiments support the notion that the newborn primary T cell effector responses to HSV are suppressed by Tregs.
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PMID:T regulatory cells contribute to the attenuated primary CD8+ and CD4+ T cell responses to herpes simplex virus type 2 in neonatal mice. 1820 51


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