Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B16F10 melanoma is a tumor derived from C57BL/6 mice that has been found to be poorly immunogenic and highly aggressive. Here we have shown that vaccination of mice with irradiated B16F10 cells followed by treatment with a combination of staphylococcal enterotoxins A and B (SEA/SEB) leads to significant and specific protection against subsequent challenge with viable B16F10 cells (at least 25-fold greater than a lethal dose). Also, 75% of mice surviving over 150 days remained tumor-free after rechallenge with viable B16F10 cells, evidence of the development of strong immunologic memory. Additional studies showed increases in CD4(+) and CD8(+) T-cell populations, cytotoxic T-lymphocyte activity and interferon-gamma production, all of which may contribute to enhanced survival. Furthermore, failure to produce protection in either CD4(-/-) or CD8(-/-) T-cell knockout mice is evidence that CD4(+) and CD8(+) T cells play an essential role in induction of immunity. These results show that superantigen administration subsequent to vaccination with inactivated tumor cells results in protective antitumor immunity. Thus, prophylactic vaccination against cancer is a feasible method for arming the immune system prior to the incidence of cancer.
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PMID:Superantigen enhanced protection against a weak tumor-specific melanoma antigen: implications for prophylactic vaccination against cancer. 1174 86

This report describes induction of HIV-1 resistance and synthesis of resistance factors in immortal CD4-positive T lymphocytes. SupT1 cells were infected by NL4-3 attenuated by a defect in the vif gene through coculture with infected primary lymphocytes. Cell lines from this infection, termed R1, expressed CD4 and CXCR4, carried low levels of HIV-1 DNA, but expressed no other detectable viral products and were resistant to infection by wild-type HIV-1. Investigation of challenge infection in resistant R1 lines demonstrated entry, reverse transcription, and integration by incoming HIV-1 but no synthesis of viral RNA. By assay of marker gene expression, we found that Tat was unable to activate LTR-driven transcription in R1 lines. HIV-1-resistant R1 lines secreted soluble factors that inhibited productive infection of primary lymphocytes by several strains of HIV-1 and blocked viral RNA synthesis in newly infected cells. Resistance factors also blocked the induction of HIV-1 transcription in ACH-2 cells as assayed by viral antigen expression and Northern blot of viral RNA. Soluble factors produced by HIV-1-resistant, immortal R1 cells may form the basis of new approaches to control HIV-1 infection.
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PMID:Induction of secreted human immunodeficiency virus type 1 (HIV-1) resistance factors in CD4-positive T lymphocytes by attenuated HIV-1 infection. 1188 60

Substance P (SP), a potent modulator of neuroimmunoregulation, is expressed in human immune cells. We observed elevated plasma SP levels in HIV-infected men compared with uninfected subjects. In the present study, we investigated the possible cellular source of the increased SP level caused by HIV infection. Using real-time reverse transcriptase-polymerase chain reaction, we demonstrated that monocyte-derived macrophages (MDM) and lymphocytes from both placental cord blood and adult peripheral blood expressed SP mRNA, which was significantly increased by HIV infection. HIV-induced SP expression was positively related to virus replication in the infected MDM. Purified recombinant HIV envelope glycoprotein 120 (gp120) derived from both the macrophage-tropic strain (MN) and the T lymphocyte-tropic strain (IIIB), when added to MDM cultures, enhanced SP mRNA expression. The gp120-induced SP expression was abrogated by pretreating the cells with soluble CD4. Furthermore, the activation of HIV in the latently infected promonocytic cell line (U1) and T-cell line (ACH-2) up-regulated SP mRNA expression. These data support the hypothesis that interaction of HIV and SP may have significant in vivo relevance to the immunopathogenesis of HIV infection and AIDS.
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PMID:HIV enhances substance P expression in human immune cells. 1191 72

1. IL-13 is an important mediator in inflammatory diseases such as asthma. IL-13 is mainly produced by T cells. However, signalling pathways leading to induction of this cytokine are not well-characterized. We analysed the regulation of IL-13 in human peripheral blood mononuclear cells and CD4(+) T cells. 2. Cyclosporine (CsA) and FK-506 inhibited IL-13 synthesis, when cells were stimulated by TPA/ionomycin. However, stimulation by alpha-CD3/alpha-CD28 led to an enhanced IL-13 synthesis. 3. NF-kappa B inhibitor N-tosyl-L-lysine chloromethylketone (TLCK) inhibited IL-13 synthesis more effectively after TPA/ionomycin stimulation. After alpha-CD3/alpha-CD28 stimulation, only 300 microM TLCK inhibited IL-13 synthesis. Dexamethasone inhibited IL-13 equally effective after alpha-CD3/alpha-CD28 and TPA/ionomycin stimulation. 4. p38 MAPK inhibitor SB203580 inhibited IL-13 synthesis only partially. MEK inhibitor U0126 inhibited TPA/ionomycin induced IL-13 synthesis very effectively, whereas alpha-CD3/alpha-CD28 stimulated IL-13 induction was resistant to this drug. 5. These results were confirmed in purified CD4(+) T cells. In difference to PBMCs alpha-CD3/alpha-CD28 stimulated IL-13 synthesis was effectively inhibited by CsA, FK-506 and U0126. 6. Therefore U0126 was tested in an animal model of allergic asthma. We could demonstrate for the first time that inhibition of the MEK - ERK cascade is a therapeutic option for asthma. Intraperitoneal administration of 10 mg kg(-1) U0126 reduced lung eosinophilia in ovalbumin-challenged Brown Norway rats by 44%. 7. These results demonstrate that different signalling pathways are involved in regulating IL-13 synthesis in primary human T cells. Characterizing highly potent inhibitors of IL-13 synthesis can be exploited to identify new drugs to treat immunological diseases such as asthma.
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PMID:Regulation of IL-13 synthesis in human lymphocytes: implications for asthma therapy. 1195 94

Recognition of the essential role of dendritic cells (DCs) as professional antigen-presenting cells has prompted investigators to search for methods to use DCs as natural adjuvants in immunotherapy. A number of antigenic oligopeptides, recognized by CD8(+) cytotoxic T lymphocytes (CTLs) specific for cancer cells, have been applied in clinical trials using DCs. Such a monovalent vaccine with a single epitope for a particular type of HLA class 1 molecule would be effective. However, a polyvalent vaccine might be more potent. We designed a novel protein delivery system consisting of hydrophobized polysaccharides complexed with target proteins. The truncated HER2 protein encompassing 147 N-terminal amino acids, including the 9-mer HER2p63-71 peptide (HER2p63), TYLPTNASL, the human homologue of an antigenic murine tumor rejection peptide, was prepared. We report here that HLA-A2402(+) DCs could incorporate hydrophobized polysaccharide-truncated HER2 protein complexes and process the protein to present major histocompatibility complex class 1-binding HER2p63 peptide. The complexes enter DCs by phagocytosis, and then the truncated protein is processed through a pathway similar to that for endogenous proteins. DCs sensitized by these complexes primed and boosted HER2p63-specific CD8(+) T cells in the context of HLA-A2402. Vaccination with DCs incorporating these complexes completely suppressed lung metastases in a HER2-expressing murine tumor model. We also generated 3 CD4(+) clones reactive with different HER2- derived 25-mer peptides from lymph node cells in mice treated with CHP/HER2-147. Thus, hydrophobized polysaccharide-protein complexes are promising candidates for the construction of polyvalent vaccines.
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PMID:Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy. 1198 28

Natural antigen processing and presentation of antigen is thought to be important for the generation of a broad functional repertoire of antigen-specific T cells. In this study, the T-cell repertoire to an immunodominant human leukocyte antigen A2 (HLA-A2) binding peptide epitope of HER-2/neu, p369-377, was examined in a patient following immunization with a peptide-based vaccine consisting of helper peptides encompassing HLA-A2 peptide epitopes. The responding T-cell repertoire generated was both phenotypically and functionally diverse. A total of 21 p369-377 clones were generated from this patient. With the exception of two clones, all clones were CD3(+). Sixteen of the clones were CD8(+)/CD4(-). Five of the clones were CD4(+)/CD8(-), despite being generated with an HLA-A2 binding peptide. Nineteen of 21 of clones expressed the alpha beta-T-cell receptor (TCR). The remaining two clones expressed the gamma delta T-cell response (TCR). Selected alpha beta-TCR clones, both CD8(+) and CD4(+), could lyse HLA-A2 transfected HER2 overexpressing tumor cells and p369-377-loaded B-lymphoblastic cell line. In addition to their lytic capabilities these clones could be induced to produce interferon-gamma (IFN-gamma) specifically in response to p369-377 peptide stimulation. The 2 gamma delta-TCR clones expressed CD8 and lysed HLA-A2(+) HER-2/neu(+) tumor cells, but not HLA-A2(-) HER-2/neu(+) tumor cells. One of gamma delta-TCR clones also released IFN-gamma directly in response to p369-377 stimulation. These results suggest that a tumor antigen TCR, directed against a specific epitope, can be markedly polyclonal at multiple levels including CD4/CD8 and TCR.
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PMID:Clonal diversity of the T-cell population responding to a dominant HLA-A2 epitope of HER-2/neu after active immunization in an ovarian cancer patient. 1207 90

HER2/neu is a compelling cancer vaccine candidate because it is overexpressed on some cancer cells relative to normal tissues, it is known to be immunogenic in both animal models and in humans, and it is already known to be targetable by the antibody component of the immune system in the form of monoclonal antibody therapy with trastuzumab. Vaccines offer the theoretical advantage of being able to elicit T-cell responses in addition to antibody responses. HER2 vaccines have been shown to provide benefit in animal models and to be immunogenic in humans. However, the optimal vaccine formulation is not yet known and the therapeutic efficacy of the vaccines in humans has not yet been evaluated. HER2 vaccine approaches currently being tested include peptide-based, DNA plasmid-based, and protein-based vaccines. Our group has developed and started testing a protein-based vaccine composed of both the extracellular domain of HER2 and the carboxyl terminal autophosphorylation portion of the intracellular domain. The extracellular domain was retained to provide for antibody targeting. The kinase domain of the intracellular domain was excluded because of its high degree of homology to other human kinases. The carboxyl terminal autophosphorylation domain was retained because it is the most unique and possibly most immunogenic portion of the HER2 molecule with the least homology to other members of the HER family. The vaccine, termed dHER2, is immunogenic in mice and primates. In animal models it can elicit CD8 and CD4 T-cell responses as well as antibody responses that suppress the growth of HER2-positive cancer cells in vitro and in vivo. Vaccine trials are contemplated in patients with breast cancer that will determine whether the vaccine construct is similarly immunogenic in humans.
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PMID:Designing HER2 vaccines. 1213 98

Early growth response gene 1 (Egr1) codes for a transcriptional regulator that contains a zinc-finger DNA binding domain. Egr1 expression is induced by a variety of extracellular stimuli including TCR-ligand interactions. Its pattern of expression in the thymus and dependence on ERK activation have led to speculation that it has a role in T cell development, but the exact nature of this role has been undefined. To more clearly define the role of Egr1 in thymocyte development, we have analyzed thymocytes from Egr1-deficient mice. We find that thymuses from Egr1-deficient mice contain twice as many cells as age-matched controls, and the increase in thymocyte number is apparent at the early CD4/CD8 double negative stage of development. Subsequent maturation to the CD4/CD8 double positive stage and survival of the double positive cells both appear normal in Egr1-deficient animals. We also find that Egr1 promotes positive selection of both CD4 and CD8 single positive cells without playing a major role in negative selection. Egr1 influences positive selection by enhancing expression of the helix-loop-helix inhibitor Id3 and the anti-apoptosis molecule bcl-2. Thus, Egr1 translates developmental signals into appropriate changes in gene expression at multiple stages of thymocyte development.
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PMID:Thymocyte development in early growth response gene 1-deficient mice. 1216 91

Chronic engagement of the T cell receptor mediates the induction of T lymphocyte unresponsiveness called clonal anergy. The development of such unresponsiveness has been suggested as one of the mechanisms that regulate peripheral tolerance to self-antigens and hamper the capacity of tumor antigen-specific T cells to eliminate cancerous cells. In the attempt to enhance the effector function of CD4(+) T lymphocytes and their resistance to clonal anergy induction, we have transduced primary T cells with a retroviral vector encoding active p21(ras) (Ras(Leu61)). Here we show that Ras(Leu61) elicited TCR-independent activation of the Ras-Raf-ERK pathway and conferred primary T cells with the ability to secrete IL-2 in response to stimulation with a Ca(2+) ionophore alone, without altering antigen-, CD3/CD28- and PMA/ionomycin-driven IL-2 secretion and T cell proliferation in vitro. However, chronic engagement of the TCR onthe surface of Ras(Leu61) T cells still led to an inability of the cells to produce IL-2 upon restimulation. These results indicate that enforced p21(ras) functionality enhances primary T cells responses to calcium-generated signals, but is insufficient to prevent TCR-driven T cell unresponsiveness and suggest that additional biochemical mechanisms, independent of p21(ras), negatively regulate IL-2 production in unresponsive T cells.
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PMID:Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. 1220 34

Dendritic cells (DCs) are the major cells responsible for the uptake and the transport of antigens to regional lymphoid tissues and for the presentation of antigenic peptides to T cells. They are highly effective in immunotherapy. However, in lymphoid and other tissues, DCs constitute only a small population and are difficult to isolate in large numbers. Our objective was to devise a method with which to rapidly expand splenic DCs in vivo. We accomplished this by intramuscular injection of plasmids encoding mouse granulocyte-macrophage colony stimulating factor (GM-CSF) and fms-like tyrosine kinase 3-ligand (FLT3-L). Gene transfer was amplified by electroporation. Both cytokine vectors significantly increased DC numbers, but they were more effective in combination. When either control plasmid (Blank), or FLT3-L or GM-CSF expression plasmids were injected individually, the mean numbers of CD11c(+)/MHC II(+) DCs in spleen cell suspensions were, respectively, 6, 11, and 23 million. When FLT3-L and GM-CSF plasmids were codelivered, this increased to 36 million. Peak levels occurred 7 days postinjection of DNA. To further characterize these DCs, we stained them with myeloid (CD11b, F4/80)- and lymphoid (CD8alpha)-related markers. FLT3-L cDNA favored lymphoid DC expansion and GM-CSF cDNA favored myeloid DC expansion, whereas combined treatment expanded both types with a myeloid predominance. We confirm the ability of these DCs to present antigen to CD4(+) T cells and to stimulate in mixed lymphocyte cultures. We demonstrate that DCs can be rapidly expanded by this simple gene transfer method, which has numerous potential applications.
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PMID:In vivo generation of dendritic cells by intramuscular codelivery of FLT3 ligand and GM-CSF plasmids. 1223 Nov 78


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