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CCR5 Expression (ccr5 + expression)
Selected AbstractsCCR5 deficiency exacerbates T-cell,mediated hepatitis in mice,HEPATOLOGY, Issue 4 2005Christophe Moreno Experimental T-cell,mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A,induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5+ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5,/,) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5,/, mice also exhibited increased production of interleukin 4, tumor necrosis factor ,, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1+. In vivo neutralization of CCR5 ligands in CCR5,/, mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell,mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immunomediated liver injury. (HEPATOLOGY 2005;42:854,862.) [source] Optimization of in vitro expansion of macaque CD4+ T cells using anti-CD3 and co-stimulation for autotransfusion therapyJOURNAL OF MEDICAL PRIMATOLOGY, Issue 4-5 2006Nattawat Onlamoon Abstract Background, Our laboratory has previously shown that adoptive transfer of in vitro -expanded autologous purified polyclonal CD4+ T cells using anti-CD3/CD28-coated beads induced antiviral responses capable of controlling SIV replication in vivo. Methods, As CD4+ T cells comprise several phenotypic and functional lineages, studies were carried out to optimize the in vitro culture conditions for maximal CD4+ T-cell expansion, survival and delineate the phenotype of these expanded CD4+ T cells to be linked to maximal clinical benefit. Results and Conclusions, The results showed that whereas anti-monkey CD3,/, was able to induce T-cell proliferation and expansion in combination with antibodies against multiple co-stimulatory molecules, monkey CD3, cross reacting antibodies failed to induce proliferation of macaque CD4+ T cells. Among co-stimulatory signals, anti-CD28 stimulation was consistently superior to anti-4-1BB, CD27 or ICOS while the use of anti-CD154 failed to deliver a detectable proliferation signal. Increasing the relative anti-CD28 co-stimulatory signal relative to anti-CD3 provided a modest enhancement of expansion. Additional strategies for optimization included attempts to neutralize free radicals, enhancement of glucose uptake by T cells or addition of T-cell stimulatory cytokines. However, none of these strategies provided any detectable proliferative advantage. Addition of 10 autologous irradiated feeder cells/expanding T cell provided some enhancement of expansion; however, given the high numbers of T cell needed, this approach was deemed impractical and costly, and lower ratios of feeder to expanding T cells failed to provide such benefit. The most critical parameter for efficient expansion of purified CD4+ T cells from multiple monkeys was the optimization of space and culture conditions at culture inception. Finally, anti-CD3/28-expanded CD4+ T cells uniformly exhibited a central memory phenotype, absence of CCR5 expression, marked CXCR4 expression in vitro, low levels of caspase 3 but also of Bcl-2 expression. [source] Expression of CCL5 (RANTES) and CCR5 in prostate cancer,THE PROSTATE, Issue 2 2006Gayle G. Vaday Abstract Background Expression of the inflammatory chemokine CCL5 (RANTES) by tumor cells is thought to correlate with the progression of several cancers. CCL5 was shown to induce breast cancer cell migration, mediated by the receptor CCR5. A CCR5 antagonist was demonstrated to inhibit experimental breast tumor growth. Recently, CCL5 and CCR5 mRNA expression was reported in prostate cancer (PCa) tissues. Herein, we characterized CCL5 and CCR5 expression in cultures of PCa cells and explored possible functions of CCL5 in PCa progression. Methods Quantitative RT-PCR, ELISA, and immunohistochemical staining were performed to examine CCL5 expression in prostate cell lines. CCR5 expression was measured by flow cytometry. Proliferation and invasion assays were performed to determine potential functions of CCL5 and CCR5 in PCa. Results Expression of CCL5 mRNA and protein was found in human PCa cell lines (PC-3; DU-145; LNCaP) and primary prostate adenocarcinoma cells. CCL5 and CCR5 were also detected in human PCa tissues. CCR5 expression was demonstrated on the cell surface of PCa cells, as well as in intracellular pools. Incubation with CCL5 (10,100 ng/ml) induced PCa cell proliferation, and the CCR5 antagonist TAK-779 inhibited CCL5-induced proliferation. CCL5 was found to stimulate PCa cell invasion, and TAK-779 blocked the effects of CCL5. Conclusions In light of evidence that inflammation influences the pathogenesis of PCa, these results suggest that inflammatory chemokines, such as CCL5, expressed by prostate cells may act directly on the growth and survival of PCa cells. Chemokine receptor antagonists may thus block autocrine mechanisms of PCa progression. Published 2005 Wiley-Liss, Inc. [source] CCR5 Is Required for Regulation of Alloreactive T-Cell Responses to Single Class II MHC-Mismatched Murine Cardiac GraftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009T. Nozaki The effector CD4 T-cell response in wild-type C57BL/6 recipients of single class II MHC-disparate B6.H-2bm12 cardiac allografts is restricted by CD4+CD25+ regulatory T cells (Tregs) resulting in long-term allograft survival. To investigate the role chemokine receptors might play in Treg function, this study tested the requirement for CCR5 on Tregs to suppress the alloimmune response in C57BL/6 recipients of B6.H-2bm12 cardiac allografts. In contrast to the long-term survival of B6.H-2bm12 allografts in wild-type recipients (>100 days), the allografts were acutely rejected within 25 days in CCR5,/, recipients with intense infiltration of CD4 T cells. Numbers and duration of donor-reactive CD4 T cells producing IFN-, and IL-4 were markedly increased in spleens of B6.CCR5,/, versus wild-type recipients. Wild-type and B6.CCR5,/, mice had equivalent numbers of splenic FoxP3+ Tregs before and following transplantation, and these Tregs were equivalently suppressive in vitro. However, diminished numbers of FoxP3+ Tregs infiltrated B6.H-2bm12 allografts in B6.CCR5,/, recipients. Adoptive transfer of wild-type, but not CCR5-deficient, CD4+CD25+ Tregs to CCR5,/, recipients restored long-term survival of B6.H-2bm12 cardiac grafts. Collectively, these results indicate that CCR5 expression is required for the regulatory functions of Tregs that restrict alloreactive CD4 T-cell responses to single class II MHC-mismatched cardiac allografts. [source] CCR5 is involved in resolution of inflammation in proteoglycan-induced arthritisARTHRITIS & RHEUMATISM, Issue 10 2009Paul D. Doodes Objective CCR5 and its ligands (CCL3, CCL4, and CCL5) may play a role in inflammatory cell recruitment into the joint. However, it was recently reported that CCR5 on T cells and neutrophils acts as a decoy receptor for CCL3 and CCL5 to assist in the resolution of inflammation. The aim of this study was to determine whether CCR5 functions as a proinflammatory or antiinflammatory mediator in arthritis, by examining the role of CCR5 in proteoglycan (PG),induced arthritis (PGIA). Methods Arthritis was induced by immunizing wild-type (WT) and CCR5-deficient (CCR5,/,) BALB/c mice with human PG in adjuvant. The onset and severity of PGIA were monitored over time. Met-RANTES was used to block CCR5 in vivo. Arthritis was transferred to SCID mice, using spleen cells from arthritic WT and CCR5,/, mice. The expression of cytokines and chemokines was measured by enzyme-linked immunosorbent assay. Results In CCR5,/, mice and WT mice treated with the CCR5 inhibitor Met-RANTES, exacerbated arthritis developed late in the disease course. The increase in arthritis severity in CCR5,/, mice correlated with elevated serum levels of CCL5. However, exacerbated arthritis was not intrinsic to the CCR5,/, lymphoid cells, because the arthritis that developed in SCID mouse recipients was similar to that in WT and CCR5,/, mice. CCR5 expression in the SCID mouse was sufficient to clear CCL5, because serum levels of CCL5 were the same in SCID mouse recipients receiving cells from either WT or CCR5,/, mice. Conclusion These data demonstrate that CCR5 is a key player in controlling the resolution of inflammation in experimental arthritis. [source] The impact of cytokines on the expression of drug transporters, cytochrome P450 enzymes and chemokine receptors in human PBMCBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009NJ Liptrott Mandarin translation of abstract Background and purpose:, The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC. Experimental approach:, Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes. Key results:, We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 ± 11961) and protein (% control 200 ± 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-, (IFN,) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFN, respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r2 = 0.545). Conclusions and implications:, These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells. Mandarin translation of abstract [source] | ||||||||||