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)

Cytotoxic T lymphocytes are essential components of immune responses during chronic hepatitis B (CHB). It has been known that Fas ligand (FasL) and perforin/granzyme B-based mechanisms account for all T cell-mediated cytotoxicity. In the present work, we examined the correlation between injury of the hepatocytes and mRNA expression of FasL and perforin/granzyme B in liver tissue to investigate the roles of both the FasL and the perforin/granzyme B pathways in CHB. Reverse transcription-polymerase chain reaction was used to identify intrahepatic expression of FasL and perforin/granzyme B in liver biopsy specimens from 24 patients with hepatitis B virus (HBV) infection. In addition, the transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) method was used to determine the degree of apoptosis. The degree of mRNA expression and apoptosis were compared with the histologic activity index (HAI) and serology, including alanine aminotransferase (ALT). Intrahepatic mRNA expression rates of FasL, perforin and granzyme B were seen in 79.2, 62.5 and 33.3% of patients, respectively, and correlated with ALT levels (P < 0.05). Intrahepatic expression of FasL and perforin mRNA were significantly correlated with HAI (P < 0.05). Also, apoptosis documented by the TUNEL assay was correlated with HAI and intrahepatic mRNA expression of FasL and perforin (P < 0.05). Our results show that the T-cell mediated perforin death pathway as well as the Fas system play important roles in liver cell injury in HBV infection and that apoptosis mediated by the Fas/FasL system is closely correlated with HAI in chronic HBV infection.
 ...
PMID:Expression of FasL and perforin/granzyme B mRNA in chronic hepatitis B virus infection. 1499 47

In this study, we evaluated the expression of molecular markers of acute rejection in protocol biopsies of patients with and without subclinical acute rejection (SAR). Protocol biopsies were performed at 2 months (n = 21) and 12 months (n = 14) after kidney transplantation in patients with stable allograft function. After biopsy tissue RNA isolation, reverse transcription and polymerase chain reaction (RT-PCR) for the glyceraldehyde 3-phospate dehydrogenase (GAPDH), perforin, granzyme B and Fas ligand genes were performed. The Banff 97 classification was used for histological diagnosis. Creatinine concentrations at 2 months were significantly higher in patients with SAR (1.46 +/- 0.27 x 1.18 +/- 0.24; p < 0.02). Perforin transcripts were found in 15 biopsy specimens, 10 of which had histological signs of SAR (p = 0.06). Granzyme B expression was found in 10 specimens, nine of which had SAR (p < 0.01). Fas ligand was expressed in seven specimens, and six of them were classified as SAR (p < 0.01). Perforin expression had the highest sensitivity (81%) for the diagnosis of SAR. Granzyme B and Fas ligand had specificity of 90%. At 12 months, there was no significant difference in creatinine concentrations for patients with and without previous SAR (1.63 +/- 0.57 x 1.28 +/- 0.31; p = 0.10). Molecular analysis revealed that there was no statistically significant difference in the expression of perforin and granzyme B in patients with and without SAR. Fas ligand expression was observed in five samples, four of which had histological signs of SAR (p = 0.03). At 12 months, perforin expression had the highest sensitivity (83%), and Fas ligand, the highest specificity (88%) for the diagnosis of SAR. We concluded that the expression of genes that encode proteins involved in the cytolytic attack against the allograft is increased in kidneys with SAR. These findings support the understanding that SAR is an active immune process potentially deleterious to renal allografts.
 ...
PMID:Molecular markers in subclinical acute rejection of renal transplants. 1514 49

The host effector mechanisms against Mycobacterium tuberculosis infection are not well understood, and this remains a problem in the development of new vaccines and immunotherapies in tuberculosis (TB). Here, we studied the expression of genes for interferon gamma (IFN-gamma) and molecules involved in lymphocyte-mediated cytotoxicity [granzyme B (grzB), perforin, granulysin and Fas ligand (FasL)] against M. tuberculosis-infected macrophages. The kinetics of expression of these molecules were first established in peripheral blood mononuclear cells (PBMC) of healthy donors, and then investigated in TB patients with and without HIV-1 coinfection and appropriate control groups. We found that only IFN-gamma and grzB were induced by M. tuberculosis in PBMC from healthy purified protein derivative skin test reactive subjects. However, expression of neither gene nor IFN-gamma protein correlated with intracellular M. tuberculosis growth containment by macrophages. Mycobacterium tuberculosis induction of IFN-gamma, but not grzB, mRNA expression was significantly lower (P < 0.03) in TB patients as compared with healthy subjects.
 ...
PMID:Protective responses in tuberculosis: induction of genes for interferon-gamma and cytotoxicity by Mycobacterium tuberculosis and during human tuberculosis. 1532 Aug 88

Studies in nonhuman primates have demonstrated that elevation of the cytotoxic lymphocyte (CL) genes granzyme B, perforin, and Fas ligand in peripheral blood precedes islet allograft rejection. The purpose of this study was to determine whether this approach has utility for prediction of human islet allograft loss. We studied 13 patients who had long-term type 1 diabetes and were treated with steroid-free immunosuppression and given sequential islet cell infusions. All recipients became insulin independent, and eight of them experienced deterioration in glycemic control, followed by reinitiation of insulin therapy. Frequent peripheral blood samples were collected to monitor CL gene mRNA levels with real-time PCR. For the eight back-to-insulin patients, there was a clear elevation of CL gene mRNA levels 25-203 days before the onset of frequent hyperglycemia. Granzyme B was the most reliable indicator of ongoing graft loss. Additional correlations with infection were noted; however, evidence of sensitization in antidonor mixed lymphocyte reaction was observed in seven of eight patients who experienced partial graft loss, whereas this was not seen when upregulated CL gene expression was associated with infection. The results suggest that, when taken into consideration with other clinical parameters, elevated CL gene levels may enable prediction of islet allograft loss.
 ...
PMID:Assessment of cytotoxic lymphocyte gene expression in the peripheral blood of human islet allograft recipients: elevation precedes clinical evidence of rejection. 1533 37

Acute hepatitis and recovery from woodchuck hepatitis virus (WHV) infection involves increased intrahepatic expression of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) mRNAs. In the present study, recovery correlated with increased intrahepatic expression of mRNAs for major histocompatibility complex class 1 (MHC1), beta(2)-microglobulin, 2'5'-oligoadenylate synthetase (2'5'-OAS), and indoleamine dioxygenase (IDO). By comparison, acute WHV infection progressing to chronicity was associated with diminished expression of these IFN-gamma-associated mRNAs in liver. Transfection of WHV-infected primary hepatocytes (WPH) from WHV carriers with an IFN-gamma-expressing plasmid (pIFN-gamma) resulted in dose-dependent accumulations of MHC1, TNF-alpha, 2'5'-OAS, and IDO mRNAs within 96 h. Markers of T cells and immune-mediated cytotoxicity that accumulate in recovering liver were not apparent in WPH based on the relative lack of CD3, CD4, Fas ligand, perforin, and granzyme B mRNAs. Expression of pIFN-gamma, and TNF-alpha-expressing plasmid (pTNF-alpha), did not affect total WHV RNA, or fully double-stranded WHV DNA in WPH, but each reduced some of the replicative intermediate (RI) species of WHV DNA synthesis. WPH treated with recombinant IFN-alpha protein had a higher fold induction of 2'5'-OAS mRNA associated with partial reductions in WHV RNAs and the major RI species. Thus, IFN-gamma expression in carrier WPH induced several host responses often observed in liver of recovering woodchucks, and impaired a stage of WHV DNA synthesis by a non-cytolytic mechanism mediated by TNF-alpha. Local enhancement of IFN-gamma-associated responses in chronic WHV-infected hepatocytes may promote therapeutic antiviral effects, but additional effector mechanisms evident during recovery appear necessary for more complete clearance of WHV infection.
 ...
PMID:Interferon-gamma-associated responses to woodchuck hepatitis virus infection in neonatal woodchucks and virus-infected hepatocytes. 1535 45

Fractalkine (CX3CL1) and its receptor CX3CR1 play an important role in natural killer (NK) cell- and cytotoxic T cell-mediated endothelium damage. Here we describe the cytotoxicity of myelodysplastic syndrome (MDS)-derived T cell line, K2-MDS, through the fractalkine-CX3CR1 system. K2-MDS cells induced apoptosis against CD34(+) cells from normal bone marrow (BM) in a direct cell contact manner. K2-MDS cells expressed perforin and granzyme B, but they lacked Fas ligand expression. A specific inhibitor for perforin, concanamycin A, blocked K2-MDS-dependent cytotoxicity. Furthermore, a CX3C-chemokine, fractalkine, was expressed in CD34(+) cells, and its receptor, CX3CR1, was expressed on K2-MDS cells. The neutralizing monoclonal antibody (MoAb) for fractalkine and soluble fractalkine significantly inhibited K2-MDS-dependent cytotoxicity. K2-MDS cells also induced the cytotoxicity against human umbilical cord endothelial cells (HUVECs) expressing fractalkine. These data indicate that K2-MDS may be a perforin-granzyme-positive T cell line that exerts a cytotoxic effect on CD34(+) cells mediated through the fractalkine-CX3CR1 system.
 ...
PMID:A perforin/granzyme-positive MDS-derived T cell line, K2-MDS, induces apoptosis in CD34+ cells through the fractalkine-CX3CR1 system. 1538 May 36

Intestinal parasite infections induce thymus-dependent villus atrophy, but the effector mechanisms directly responsible for the development of villus atrophy are not thoroughly understood. In this study, we analyzed the expression of cytotoxic factors or ligands in athymic nude rnu/rnu rats and their littermate euthymic rnu/+ rats infected with the nematode Nippostrongylus brasiliensis. Morphometric analyses showed that partial villus atrophy developed 10 days after infection in euthymic but not in athymic rats, whereas crypt hyperplasia occurred in both types of animal. Reverse transcription-polymerase chain reaction analyses of the isolated jejunal epithelial fraction showed that the development of villus atrophy in euthymic rats was positively correlated with an increase of granzyme B transcript levels but not with Fas ligand or tumor necrosis factor-alpha expression. In addition, the number of granzyme B-immunoreactive cells was increased significantly in euthymic rat villus epithelium and the propria mucosa after infection. The CD8+ cell number did not change significantly. Collectively, these findings showed that significant increases in the number of cells that express the cytotoxic factor granzyme B occur in the nematode-infected small intestine of immunocompetent hosts. The type of cells that express granzyme B and their role in the progression of enteropathy remain to be elucidated.
 ...
PMID:Villus epithelial injury induced by infection with the nematode Nippostrongylus brasiliensis is associated with upregulation of granzyme B. 1556 1

Cytotoxic T-cells (CTL) play a central role in the recovery of mammalian hosts from retroviral infections. However, the molecular pathways that mediate the antiretroviral activity of CTL are still elusive. Here we explore the protective role of the two main cytolytic pathways of CTL, that is, granule exocytosis and Fas/Fas ligand (FasL), in acute and persistent Friend retrovirus (FV) infection of mice. For this purpose, we have used mutant mouse strains with targeted gene defects in one or more components of the two cytolytic pathways including perforin, granzyme A, granzyme B, Fas, and FasL. The important function of CTL in resistance of C57BL/6 (B6) mice to FV is emphasized by the finding that depletion of CD8+ T-cells prior to virus infection resulted in severe splenomegaly and high viral loads in blood and spleen tissue. Analysis of primary FV infection in knockout mice revealed that acute infection was readily controlled in the absence of functional Fas. Most notably in the presence of Fas/FasL each of the three effector molecules of the exocytosis pathway (i.e., perforin, granzyme A, and granzyme B) was capable on its own to mediate suppression of virus replication and protection from leukemia. However, triple knockout mice lacking perforin and the two granzymes were fully susceptible to FV-induced leukemia. In contrast to acute infection the Fas/FasL pathway was mandatory for effective control of FV replication during persistent infection. These findings suggest novel pathways of CTL-mediated viral defense and contribute towards a better understanding of the molecular mechanisms of CTL activity in retroviral infections.
 ...
PMID:Independent roles of perforin, granzymes, and Fas in the control of Friend retrovirus infection. 1556 31

The factors that influence the relative contribution of the T cell subsets to allograft rejection remain unclear. We compared skin and heart rejection in CD4 Knockout (KO), and CD8 KO mice across full-, minor-, and class II histocompatibility antigen (HA) mismatches. Skin allografts were rejected by either CD4+ or CD8+ T cells alone at any degree of antigenic mismatch. However, either the absence of CD4+ cells or a lesser degree of HA mismatch resulted in prolongation of graft survival. In contrast, fully allogeneic heart grafts were accepted in CD4 KO recipients, and minor HA mismatched heart grafts were accepted by both CD4 KO and CD8 KO mice. Thus, the T cell subsets required for allograft rejection are determined by the immunogenicity of the tissue transplanted. In the absence of CD8+ T cells, perforin and Fas ligand (FasL) but not granzyme B mRNA were detected in rejecting grafts. Thus, granzyme B is a CD8+ cytotoxic T lymphocyte (CTL)-specific effector molecule.
 ...
PMID:Role of CD4+ and CD8+ T cells in murine skin and heart allograft rejection across different antigenic desparities. 1558 43

Treatment of animals or certain cells with carbon monoxide (CO), a product of heme degradation by heme oxygenase-1 (HO-1), has potent anti-inflammatory and antiapoptotic effects that contribute to the survival of transplanted organs. We report here that inducing HO-1 in, or administering CO to, only the donor can be used in a therapeutic manner to sustain the survival of transplanted allogeneic islets. Similar treatments of only the islets or only the recipient are also salutary. Administering CO only to the donor frequently leads to long-term survival of those islets in untreated allogeneic recipients, which are then antigen-specifically tolerant. Several proinflammatory and proapoptotic genes that are strongly induced in islets after transplantation in the untreated situation were significantly suppressed after administering CO to the donor without further treatment. These included tumor necrosis factor-alpha, inducible nitric oxide synthase, monocyte chemoattractant protein-1, granzyme B, and Fas/Fas ligand, all of which contribute to the pathogenesis of the rejection of transplanted islets. This correlated with a lesser infiltration of recipient macrophages into the transplanted islets. Our present findings show that induction of HO-1 in, or administration of CO to, only the donor, islets, or the recipient or combinations of such treatments improve allogeneic islet survival.
 ...
PMID:Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. 1585 26


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