Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because UV-induced epidermal macrophages (UV-Mph) preferentially activate CD4+ T suppressor-inducer cells and induce tolerance, we hypothesized that they differentially up-regulate T cell early activation genes compared with constitutive epidermal APC, Langerhans cells. We used epidermal cells from UV-exposed (UV-EC) and control (C-EC) human skin to stimulate allogeneic CD4+ T lymphocytes. Reverse transcriptase-PCR revealed that both C-EC (Langerhans cells) and UV-EC (UV-Mph) induced 10(3)- to 10(6)-fold increases in IL-2 mRNA. However, while T cells stimulated by C-EC for 48 h showed a greater than 10(3)-fold increase in IL-2R alpha mRNA, those stimulated by UV-EC did not (n = 5, p = 0.004). Flow cytometry demonstrated that 4.1 +/- 2.3% of unstimulated CD4+ lymphocytes expressed cell surface IL-2R alpha, which increased to 15.7 +/- 1.8% upon stimulation by C-EC for 48 h, but stimulation by UV-EC failed to increase the IL-2R alpha+ population (n = 3, p = 0.038). The addition of neutralizing anti-TGF-beta Abs to UV-EC-stimulated cultures restored CD4+ cell surface IL-2R alpha expression to 12.9 +/- 0.2%. CD4+ T cell activation by UV-Mph is distinct from previously described models of tolerance such as Th2 activation (IFN-gamma mRNA was induced and IL-4 mRNA was not) and Th1 anergy (IL-2 mRNA levels induced by UV-EC and C-EC were similar). Furthermore, costimulatory signals were provided by UV-Mph; CTLA4-Ig and LFA-3-Ig fusion proteins and Abs to CD2, LFA-3, LFA-1, and ICAM-1 inhibited UV-Mph-induced T cell proliferation. Thus, the altered immune outcome induced by UV-Mph (tolerization) compared with Langerhans cells (sensitization) is reflected as a novel mechanism of initial CD4+ T cell early activation gene expression characterized by TGF-beta-dependent deficient IL-2R alpha expression.
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PMID:Suppressor T cell-activating macrophages in ultraviolet-irradiated human skin induce a novel, TGF-beta-dependent form of T cell activation characterized by deficient IL-2r alpha expression. 749 43

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

Polymorphonuclear neutrophils (PMN) are part of the innate immune system and are first-line effector cells in acute inflammatory responses. On activation PMNs secrete cytokines and oxygen metabolites that might be involved in the regulation of the acquired immune response. We show here that peripheral blood PMNs constitutively express a B7-1-like molecule as detected by immunostaining with several B7-1 antibodies. Reverse transcriptase-polymerase chain reaction using three sets of primers spanning different regions of B7-1 indicate dissimilarities at the mRNA level. B7-1 mRNA is expressed in bone marrow cells and lipopolysaccharide (LPS)-stimulated but not in unstimulated PMNs. The B7-1-like molecule is localized to the cytoplasmic granules and translocated to the cell surface after stimulation with LPS or interleukin-12 in some donors. Binding of CTLA4-Ig suggests that the B7-1-like molecule can interact with functional B7 ligand and might be important in the immunobiology of PMNs.
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PMID:Human polymorphonuclear neutrophils express a B7-1-like molecule. 1061 76

Costimulatory pathways have a pivotal role in the T-cell response to alloantigen. The role of costimulatory blockade with anti-CD154 in orthotopic liver transplantation (OLT) has not been examined previously. This study aims to investigate effects of anti-CD154 and CTLA4-immunoglobulin (Ig) in the early post-OLT period using a major histocompatibility complex-disparate fully arterialized OLT model in the rat. Lewis rats underwent OLT with Dark Agouti liver allografts. Recipients were randomized to receive (1) isotype control, (2) anti-CD154, (3) CTLA4-Ig, or (4) cyclosporine A (CyA). Rats were killed day 8, and specimens were obtained for histological examination, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, immunohistochemistry, and quantitative reverse-transcriptase polymerase chain reaction. An additional five transplant recipients were treated with anti-CD154 for 14 days postoperatively to assess long-term allograft survival. All isotype control animals died on or before day 6 of acute rejection. Apart from four deaths caused by nonimmunologic causes, all treated recipients survived to day 8. The median survival of rats treated for 14 days with anti-CD154 was greater than 150 days. Serum aspartate aminotransferase and bilirubin levels normalized by day 3 in the CyA group and day 5 in transplant recipients treated with costimulatory blockade. Histologically, there was no difference between isotype controls and CTLA4-Ig-treated animals, whereas anti-CD154-treated transplant recipients had a lower Banff score. CD4+ and CD8+ T-cell infiltrates were prominent in transplant recipients treated with costimulatory blockade. Intragraft analysis showed an increase in lymphocyte apoptosis, Fas ligand messenger RNA expression, and reduction in interleukin-6 gene expression in transplant recipients treated with costimulatory blockade. Costimulatory blockade did not alter intragraft gene expression of other mediators of T-cell priming, differentiation, and effector function compared with isotype control animals. In conclusion, costimulatory blockade prevented acute rejection, enabled long-term survival, and increased intragraft lymphocyte apoptosis in a high-responding rat OLT model.
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PMID:Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin-6 in an orthotopic liver transplant model in the rat. 1200 46

Regulatory T cells (Tregs) support pregnancy maintenance by suppressing placental inflammation, while diminished Treg function may accompany reproductive failure. Experimental FIV infection frequently results in vertical transmission and increased pregnancy failure in the cat. The mechanism of reproductive compromise is unknown. We hypothesized that FIV infection alters endometrial Treg population dynamics and function, potentiating vertical transmission and reproductive failure. RNA collected from early and late gestation reproductive tissue and fetuses from FIV infected and control cats was probed for expression of FIV gag and Treg markers CD25, FOXP3, and CTLA4, using real time reverse-transcriptase (RT)-PCR. Frequent placental and fetal infection and reproductive failure were detected at early and late pregnancy. Expression of FOXP3 and CTLA4 was higher in early gestation tissues from control cats. FIV infection significantly reduced expression of FOXP3 and CTLA4 at early, but not late pregnancy. At late pregnancy, CTLA4 was expressed to higher levels in infected tissues. The number of tissues with decreased co-expression of FOXP3 and CTLA4 was significant in infected cats at early pregnancy. No significant changes in CD25 expression occurred between FIV-infected and control animals at early or late pregnancy. Differences in Treg marker expression were not significant between viable and non-viable pregnancies in infected cats. The detection of Treg markers in these feline tissues provides the first evidence of feline endometrial Tregs and suggests that such cells diminish as pregnancy progresses. These cells may be depleted or rendered less functional by viral infection, but understanding their role in pregnancy requires further study.
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PMID:Expression of regulatory T cell (Treg) activation markers in endometrial tissues from early and late pregnancy in the feline immunodeficiency virus (FIV)-infected cat. 2067 72