Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a novel single-chain Ep-CAM-/CD3-bispecific single-chain antibody construct designated MT110. MT110 redirected unstimulated human peripheral T cells to induce the specific lysis of every Ep-CAM-expressing tumor cell line tested. MT110 induced a costimulation independent polyclonal activation of CD4- and CD8-positive T cells as seen by de novo expression of CD69 and CD25, and secretion of interferon gamma, tumor necrosis factor alpha, and interleukins 2, 4 and 10. CD8-positive T cells made the major contribution to redirected tumor cell lysis by MT110. With a delay, CD4-positive cells could also contribute presumably as consequence of a dramatic upregulation of granzyme B expression. MT110 was highly efficacious in a NOD/SCID mouse model with subcutaneously growing SW480 human colon cancer cells. Five daily doses of 1 microg MT110 on days 0-4 completely prevented tumor outgrowth in all mice treated. The bispecific antibody construct also led to a durable eradication of established tumors in all mice treated with 1 microg doses of MT110 on days 8-12 after tumor inoculation. Finally, MT110 could eradicate patient-derived metastatic ovarian cancer tissue growing under the skin of NOD/SCID mice. MT110 appears as an attractive bispecific antibody candidate for treatment of human Ep-CAM-overexpressing carcinomas.
Mol Immunol 2006 Mar
PMID:MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. 1613 92

Long-term success in lung transplantation is limited by obliterative bronchiolitis, whereas T cell effector mechanisms in this process remain incompletely understood. Using the mouse heterotopic allogeneic airway transplant model, we studied T cell effector responses during obliterative airways disease (OAD). Allospecific CD8+ IFN-gamma+ T cells were detected in airway allografts, with significant coexpression of TNF-alpha and granzyme B. Therefore, using IFN-gamma as a surrogate marker, we assessed the distribution and kinetics of extragraft allo-specific T cells during OAD. Robust allospecific IFN-gamma was produced by draining the lymph nodes, spleen, and lung mononuclear cells from allograft, but not isograft recipients by Day 14, and significantly decreased by Day 28. Although the majority of allospecific T cells were CD8+, allospecific CD4+ T cells were also detected in these compartments, with each employing distinct allorecognition pathways. An influx of pluripotent CD8+ effector cells with a memory phenotype were detected in the lung during OAD similar to those seen in the allografts and secondary lymphoid tissue. Antibody depletion of CD8+ T cells markedly reduced airway lumen obliteration and fibrosis at Day 28. Together, these data demonstrate that allospecific CD8+ effector T cells play an important role in OAD and traffic to the lung after heterotopic airway transplant, suggesting that the lung is an important immunologic site, and perhaps a reservoir, for effector cells during the rejection process.
Am J Respir Cell Mol Biol 2006 Jan
PMID:Pluripotent allospecific CD8+ effector T cells traffic to lung in murine obliterative airway disease. 1619 40

During granule-mediated killing by cytotoxic T lymphocytes or natural killer cells, the serine protease granzyme B enters the target cell by endocytosis and induces apoptosis. Previous studies suggested a role for the mannose 6-phosphate receptor, but further experiments with purified granzyme B indicated this was not essential. Additionally, it is now clear that grB is exocytosed from killer cells in a high-molecular-weight complex with the proteoglycan serglycin. Here granzyme B was delivered as a purified monomer, or in complex with either glycosaminoglycans or serglycin, and killing was evaluated. When granzyme B was a monomer, soluble mannose 6-phosphate had a limited impact, whereas apoptosis induced by the complexed grB was effectively inhibited by mannose 6-phosphate. Most importantly, when granzyme B and perforin were delivered together from granules, inhibition by mannose 6-phosphate was also observed. In pulldown assays mediated by the cation-independent mannose 6-phosphate receptor, granzyme B bound to the receptor more intensely in the presence of immobilized heparan sulfate. We therefore propose the model that under physiological conditions serglycin-bound granzyme B is critically endocytosed by a mannose 6-phosphate receptor, and receptor binding is enhanced by cell surface heparan sulfate.
Mol Biol Cell 2006 Feb
PMID:Granule-mediated killing by granzyme B and perforin requires a mannose 6-phosphate receptor and is augmented by cell surface heparan sulfate. 1628 Mar 58

Pentoxifylline (PTX) is an unspecific inhibitor of phosphodiesterase activity that increases intracellular concentration of cyclic nucleotides, mainly cAMP. Since PTX improves microcirculatory blood flow, it is commonly and often chronically used in peripheral vascular diseases. On the other hand PTX also displays a variety of immunomodulatory activities. PTX inhibits natural cytotoxicity and it has previously been suggested that it could partially act also through its influence on perforin/granzyme-dependent pathways. However, the underlying mechanisms are obscure and it remains unknown whether PTX inhibits natural cytotoxicity influencing only leukocytes or also acting on target cells. In this study, we show that PTX inhibits expression of granzyme A in human leukocytes probably due to suppression of phosphodiesterase activity. Contrary, PTX does not affect expression of granzyme B and H. On the other hand we hypothesized that PTX could inhibit natural cytotoxicity not only affecting leukocytes but also due to generation of resistance to leukocyte-mediated cytotoxicity in target cells e.g. through overexpression of PI-9, a specific granzyme B inhibitor. We found that at the mRNA level, PTX stimulates expression of PI-9 in K562 cells. However, we did not observe such an influence at the protein level, in either K562 cells or in human leukocytes. It may suggest that other PTX-triggered molecular events may interfere with PI-9 overexpression in these cells at the further, post-transcriptional levels. According to these results, PTX did not affect resistance of target cells to natural cytotoxicity. Altogether, PTX inhibits natural cytotoxicity affecting mainly effector but not target cells and in case of the effector cells, besides previously reported mechanisms, it can also inhibit granzyme A expression.
Int J Mol Med 2006 Jan
PMID:Influence of pentoxifylline on natural cytotoxicity and expression of granzymes and PI-9, a specific granzyme B inhibitor. 1632 22

Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B-induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only-treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma. Moreover, we predict that SAGA will be useful therapeutically in any human cancer that expresses Survivin.
Mol Cancer Ther 2006 Mar
PMID:Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy. 1654 84

Granzyme A (GzmA) activates a caspase-independent cell death pathway with morphological features of apoptosis. Single-stranded DNA damage is initiated when the endonuclease NM23-H1 becomes activated to nick DNA after granzyme A cleaves its inhibitor, SET. SET and NM23-H1 reside in an endoplasmic reticulum-associated complex (the SET complex) that translocates to the nucleus in response to superoxide generation by granzyme A. We now find the 3'-to-5' exonuclease TREX1, but not its close homolog TREX2, in the SET complex. TREX1 binds to SET and colocalizes and translocates with the SET complex. NM23-H1 and TREX1 work in concert to degrade DNA. Silencing NM23-H1 or TREX1 inhibits DNA damage and death of cells treated with perforin (PFN) and granzyme A, but not of cells treated with perforin and granzyme B (GzmB). After granzyme A activates NM23-H1 to make single-stranded nicks, TREX1 removes nucleotides from the nicked 3' end to reduce the possibility of repair by rejoining the nicked ends.
Mol Cell 2006 Jul 07
PMID:The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. 1681 37

Dendritic cells (DC) resident in draining lymph nodes (LN) of patients with lung cancer are proposed to have a critical role in stimulating anti-tumor immunity. CpG oligodeoxynucleotides are undergoing clinical trials in patients with lung cancer and are likely to target plasmacytoid-DC. The present study, therefore, investigated the capacity of plasmacytoid-DC from human lung cancer draining LN to respond to CpG for activation of T cell responses relevant to anti-tumor immunity. The phenotype of DC was examined by flow cytometry, and cytokine production by cytometric bead array (CBA) and ELISA. Plasmacytoid-DC, purified by cell sorting, were immature but expressed the toll-like receptor, TLR9. Plasmacytoid-DC responded to the CpG oligodeoxynucleotide, CpG 2216, by production of the proinflammatory cytokines, IFN-alpha and IL-6. DC were cocultured with normal, allogeneic T cells, and cytokine production determined by CBA and immunophenotyping. CpG 2216 enhanced IFN-gamma production and induced intracellular production of IFN-gamma by CD8(+) and CD4(+), granzyme B by CD8(+), and IL-2 by CD4(+) T cells, respectively. Ligation of CD40 on plasmacytoid-DC combined with exposure to CpG 2216 also strongly enhanced IFN-gamma production. There was no significant difference between the responses of plasmacytoid-DC from patients with lung cancer and patients with benign carcinoid tumors with no pathologic LN involvement. These results indicate that plasmacytoid DC from the draining LN of patients with lung cancer effectively induce Tc1 immunity and could, therefore, represent a novel and attractive target for immunotherapeutic intervention.
Am J Respir Cell Mol Biol 2007 Mar
PMID:Plasmacytoid dendritic cells from human lung cancer draining lymph nodes induce Tc1 responses. 1702 87

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.
Mol Immunol 2007 Mar
PMID:Comparison of gene expression by co-cultured WC1+ gammadelta and CD4+ alphabeta T cells exhibiting a recall response to bacterial antigen. 1708 9

Cytotoxic lymphocytes such as Natural Killer (NK) cells can result in leukemias and lymphomas with aggressive clinical course. The cytoplasmic granules of NK cells contain molecules that cause apoptosis of their target cells. In this study, we examined changes of the cytotoxic granules of the Natural Killer cell line YT during Etoposide-induced apoptosis. Etoposide treatment resulted in an early upregulation of Fas and cytoplasmic release of mitochondrial cytochrome c. The cytotoxic granules remain intact in the early stages of apoptosis induction with no significant cytoplasmic release of granzyme B, which is one of the components of the cytotoxic granules. These results suggest that disruption of the cytotoxic granules is not involved in the induction stage of Etoposide-induced apoptosis in the NK cell line YT.
Exp Mol Pathol 2007 Aug
PMID:Cytotoxic granule disruption is a late event in chemotherapy-induced apoptosis in natural killer YT cells. 1717 51

Mast cells are widely distributed throughout the body and express effector functions in allergic reactions, inflammatory diseases, and host defense. Activation of mast cells results in exocytosis of preformed chemical mediators and leads to novel synthesis and secretion of lipid mediators and cytokines. Here, we show that human mast cells also express and release the cytotoxic lymphocyte-associated protease, granzyme B. Granzyme B was active and localized in cytoplasmic granules, morphologically resembling those present in cytotoxic lymphocytes. Expression and release of granzyme B by mast cell-lines HMC-1 and LAD 2 and by cord blood- and mature skin-derived human mast cells depended on the mode of activation of these cells. In mast cell lines and cord blood-derived mast cells, granzyme B expression was mainly induced by non-physiological stimuli (A23187/PMA, Compound 48/80) and substance P. In contrast, mature skin-derived mast cells only produced granzyme B upon IgE-dependent stimulation. We conclude that granzyme B is expressed and released by human mast cells upon physiologic stimulation. This suggests a role for granzyme B as a novel mediator in mast cell biology.
Mol Immunol 2007 Jul
PMID:Human mast cells produce and release the cytotoxic lymphocyte associated protease granzyme B upon activation. 1748 16


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