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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study describes the distinct roles of B7 and LFA-3 in the regulation of T cell responses. Activation of CD4+ T cells with Chinese hamster ovary (CHO)-DR4/B7 and CHO-DR4/LFA-3 cells that present the superantigen staphylococcal enterotoxin A resulted in significant T cell proliferation and substantial production of TNF and IFN-gamma. Strong IL-2 production was recorded in B7-costimulated, but not LFA-3-costimulated, cultures. The presence of B7 induced a more vigorous and prolonged proliferative T cell response compared with LFA-3 costimulation. In contrast, LFA-3 was more efficient than B7 in mediating cell adhesion of CD4+ T cells. Costimulation with the CHO-DR4/B7/LFA-3 triple transfectant resulted in enhanced cell adhesion, proliferation, and cytokine production compared with either DR4/B7 or DR4/LFA-3 alone. Optimal production of IL-2 by naive and memory CD4+ T cells was seen only when cells were costimulated with B7, whereas IFN-gamma production was induced in memory cells by both LFA-3 and B7. The Jurkat T cell line responded to CHO-DR4/B7/LFA-3 in a manner similar to peripheral blood CD4+ T cells. Reverse transcriptase-PCR analysis of Jurkat cells stimulated with staphylococcal enterotoxin E and the different CHO transfectants revealed that the cooperative effect of B7 and LFA-3 on IL-2 production was also seen at the mRNA level. The large amounts of IL-2 produced by B7 costimulation indicate a paracrine function of the B7/CD28 pathway, whereas the LFA-3/CD2 pathway provides strong adhesion and may facilitate autocrine T cell expansion. Combined expression of the B7 and LFA-3 molecules seems to provide an optimal Ag-presenting function that ensures strong adhesion and optimal signal transduction.
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PMID:Costimulation of human CD4+ T lymphocytes with B7 and lymphocyte function-associated antigen-3 results in distinct cell activation profiles. 752 63

The murine B7-1 (mB7-1) molecule expressed on APCs delivers a costimulatory signal for T cell activation through its T cell counter-receptor CD28, resulting in T cell proliferation and IL-2 production. Signaling through the TCR in the absence of CD28 signaling results in T cell anergy. We have analyzed the genomic structure of mB7-1 and here describe the identification of a previously unrecognized sixth exon at the far 3' end of the locus, which encodes an alternative cytoplasmic domain. Reverse transcriptase-PCR amplification of mB7-1 transcripts demonstrates that exon 6 is functionally spliced to the transmembrane-encoding exon 4. Furthermore, using 5' rapid amplification of cDNA ends, we determined that the 5'-untranslated region extends over 1505 bp beyond the previously reported transcriptional start site. In addition, we report the chromosomal location of mB7-1 to chromosome 16, band B5.
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PMID:Characterization of the murine B7-1 genomic locus reveals an additional exon encoding an alternative cytoplasmic domain and a chromosomal location of chromosome 16, band B5. 752 22

Ku protein is a relatively abundant DNA-binding nuclear protein complex composed of two polypeptide subunits, p70 and p80. Ku has been recently identified as the regulatory component of the DNA-dependent protein kinase that phosphorylates RNA polymerase II. To further characterize in vivo regulation of Ku protein, we studied the expression of the transcripts coding for the Ku p70 and p80 subunits in different human cell lines and normal tissues by Northern blot hybridization, using specific cDNA probes. The expression level of both genes was approximately 10-fold higher in established cell lines than in normal tissues. However, mRNA expression levels in permanent cell lines correlated more strongly with their proliferative state than with their level of malignant transformation. In purified T lymphocytes induced to proliferate by the combined action of monoclonal antibodies directed against the CD2 and CD28 adhesion molecules, Ku p70 and p80 mRNA steady-state levels increased as soon as 6 h after activation and lasted at least 72 h. The human genes coding for the Ku p70 and p80 subunits were localized by cytogenetic mapping, using fluorescence in situ hybridization, to 22q13 and 2q33-->q35, respectively.
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PMID:Chromosomal location and expression of the genes coding for Ku p70 and p80 in human cell lines and normal tissues. 825 94

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.
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PMID:Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. 860 41

Allograft rejection is dependent on T cell activation, which requires both the engagement of the T cell receptor by antigen in the context of the MHC molecules and costimulatory signals delivered by cell surface molecules such as B7-CD28/CTLA4 pathway. CTLA4-Ig is a fusion protein that blocks this pathway and has previously been shown to prolong both allograft and xenograft survival. The current study demonstrates markedly prolonged murine cardiac allograft survival and specific prolongation of secondary skin grafts using a combination of CTLA4-Ig plus donor bone marrow. A role for hematopoietic chimerism in the establishment of CTLA4-Ig-induced transplantation tolerance was investigated using reverse transcriptase polymerase chain reaction analysis of recipient tissues. Expression of donor-specific MHC class II transcripts in both peripheral and lymphoid tissues was demonstrated at greater than 200 days after transplant. To investigate the functional significance of this observation, heart donors, and donor bone marrow were irradiated before transplantation in CTLA4-Ig-treated recipients. A reduction in allograft survival was associated with irradiation of both the donor heart and the bone marrow. These results suggest that there may be a donor-derived radiosensitive element that enhances allograft survival in this model. Reverse transcriptase polymerase chain reaction analysis of allografts of tolerant and control animals at days 5, 8, and 12 after transplantation failed to demonstrate a dramatic difference in the expression of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma message. Cytotoxicity effector transcripts were largely intact in CTLA4-Ig + bone marrow-treated recipients as they showed no decrease in intragraft granzyme, perforin, Fas, or Fas ligand transcripts during thr first 8 days after transplant. These results imply that complex mechanisms may be important for the induction and maintenance of transplantation tolerance in the CTLA4-Ig plus bone marrow murine cardiac allograft model.
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PMID:CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model. Evidence for hematopoietic chimerism. 862 6

Ischemia/reperfusion injury associated with organ retrieval and storage influences the development of chronic graft dysfunction, the major clinical problem in solid organ transplantation. The potential role of mononuclear cells (T cells and monocyte/macrophages) in this type of injury is unknown. Inbred male Lewis rats were uninephrectomized and the left kidney perfused in situ with 10 ml of iced University of Wisconsin solution. Immunohistological studies showed mononuclear cell infiltration of the ischemic organs associated with the upregulation of MHC class II antigen expression. Reverse transcriptase-PCR indicated that T cell associated cytokines and monocyte/macrophage activation markers/products are upregulated early after the ischemic insult. B7 expression occurred within 24 h and peaked at 3 d. Plasma creatinine levels rose transiently with complete recovery of renal function by 5 d. Animals began to develop progressive proteinuria after 8-12 wk, indicative of the long-term functional consequences of early ischemia/reperfusion injury. Blockade of T cell CD28-B7 costimulation with CTLA4Ig resulted in significant inhibition of T cell and macrophage infiltration and activation in situ. Treated animals did not exhibit transient renal dysfunction, nor developed proteinuria over time. This is the first demonstration that blocking T cell costimulatory activation in the absence of alloantigen can prevent the early and late consequences of ischemia/reperfusion injury.
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PMID:The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury. 927 37

Substance P (SP) is an immunoregulatory tachykinin which augments antigen- and mitogen-induced lymphocyte proliferation via signaling through the neurokinin-1 receptor (NK1-R). Non-neuronal cells of the immune system such as monocytes, T lymphocytes and eosinophils can be a source of SP. We have investigated if antigen-presenting dendritic cells (DC) produce SP. DC were grown from bone marrow precursors using a cocktail of GM-CSF, IL-4 and Flt-3 ligand. Reverse transcriptase-PCR amplification using primers for the mouse preprotachykinin-A gene and direct DNA sequencing of amplified products from purified DC demonstrated the presence of the gamma-transcript of the gene, coding for SP and neurokinin A. At the protein level, mouse DC expressed SP as determined by an enzyme immunoassay and confirmed by immunostaining. The functional role of endogenous SP release was determined. During the interaction with syngeneic or allogeneic DC, the addition of a specific NK1-R antagonist partly reduced proliferation in responding T lymphocytes. This was confirmed by using responders derived from NK1-R-deficient mice. In the absence of DC, proliferation of T cells induced by direct TCR ligation and soluble CD28 was partly dependent on signaling through NK1-R, revealing an autocrine effect of SP production by T cells. In conclusion, these results demonstrate that endogenously produced SP contributes to T cell proliferation induced by DC or TCR / CD28 stimulation.
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PMID:Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. 1060 89

Intraoperative lymphatic mapping and sentinel lymphadenectomy (LM/SL) provides a unique opportunity for assessing potential immunologic interactions between the primary tumor and regional lymph node basin. We performed LM/SL in 24 patients with early-stage melanoma and resected an additional nonsentinel node (non-SN) in each case. Sentinel nodes (SNs) and non-SNs were evaluated by routine pathologic analysis, and a portion of each node was processed for expression of three dendritic markers of activation (CD80, CD86, CD40) and their corresponding T-cell receptors (CTLA-4 and CD28). Twenty (83%) patients had matched SNs and non-SNs. A total of 26 nodal pairs were obtained because one patient had three pairs and two other patients each had two pairs. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of paired SNs and non-SNs demonstrated a marked reduction in semiquantitative expression of CD80 (77%), CD86 (77%), and CD40 (85%), as well as CTLA-4 (88%) and CD28 (85%) in SNs. The diminished expression appeared to be unrelated to B-cell (CD20) and T-cell (CD2) expression. A quantitative reduction in dendritic cell markers in SNs may be important in the immunologic interaction between the primary site and regional lymph node basin and may also provide useful criteria for identifying SNs.
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PMID:Surgical and molecular approaches to the sentinel lymph nodes. 1159 94

The helper (Th)2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are ligands for the chemokine receptor CCR4. A number of cellular sources of TARC and MDC have been identified, including not only macrophages, dendritic cells, and natural killer cells, but also bronchial epithelial cells. Recent studies report that TARC and MDC may serve as pivotal chemokines for the development of Th2-dominated experimental allergen-induced asthma. This study was designed to assess TARC and MDC production by CD4+ T cells, including naive T cells and memory/effector T cells, purified from peripheral blood mononuclear cells in patients with asthma. Asthmatic subjects included in this study had mild asthmatic symptoms, positive skin test responses to house dust mite allergen, and elevated level of Dermatophagoides farinae immunoglobulin E in the sera. CD4+ T cells--CD45RA+ CD4+ T cells--as naive T cells and CD45RO+ CD4+ T cells--as memory/effector T cells--were purified by negative selection from peripheral blood mononuclear cells obtained from asthmatic patients (n = 6) and healthy controls (n = 6). These cells and established Th1/Th2 cell lines were then cultured in the presence of both anti-CD3 and -CD28 antibodies. After 48 hr of incubation, concentrations of TARC, MDC, interleukin (IL)-4, IL-5, and interferon-gamma in the supernatants were measured by enzyme-linked immunoadsorbent assay. Reverse transcriptase-polymerase chain reaction was performed to analyze mRNA expression of TARC and MDC. Our results clearly showed that TARC and MDC were produced by activated CD45RA+ CD4+ T cells rather than by activated CD45RO+ CD4+ T cells, and the levels of these chemokines in the asthmatic patients were higher than those in the healthy controls. Furthermore, these chemokines production by Th2 cell lines were greater than those by Th1 cell lines, but the level were smaller than those by naive T cells. Our studies suggest that TARC and MDC are produced by naive T cells rather than by memory/effector T cells, including Th2 cells, in asthmatic patients, and these chemokines were produced at modest levels in any T-cell populations from healthy controls. Taken together, naive T cells in asthma have a peculiar function to produce TRAC and MDC, which contribute to local migration of Th2 cells into lung and lymphoid tissues, along with a function as precursor for memory/effector T cell. This novel function of naive T cells may be implicated in the development of asthma.
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PMID:Production of TARC and MDC by naive T cells in asthmatic patients. 1264 58

We compared immune restoration in patients who suppressed human immunodeficiency virus type 1 replication after treatment with a protease inhibitor (PI) plus nevirapine or with 3 nucleoside reverse-transcriptase inhibitors (NRTIs) plus nevirapine. Changes in total and memory CD4 and CD8 cells were similar in the groups, as were decreases in immune activation (e.g., CD38 and HLA-DR) and increases in CD28 expression. Increases in naive CD4 and CD8 cells tended to be greater in the NRTI-treated group, with differences in naive CD4 cells significant at weeks 8 and 12 (P<.05) but not at week 48. Lymphocyte apoptosis decreased in both groups, but the week-1 decrease was greater in the PI-treated group (P<.02). Lymphocyte proliferation and skin-test responses were comparable. We find little evidence for differences in the major direct immunologic effect of PI versus NRTI regimens and propose that effects observed elsewhere were indirect, mediated through antiviral activity or adaptation of the virus to selection pressure.
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PMID:Immune reconstitution is comparable in antiretroviral-naive subjects after 1 year of successful therapy with a nucleoside reverse-transcriptase inhibitor- or protease inhibitor-containing antiretroviral regimen. 1462 69


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