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991.
Inducing antitumor T cell immunity: comparative functional analysis of interstitial versus Langerhans dendritic cells in a human cell line model 总被引:1,自引:0,他引:1
Santegoets SJ Bontkes HJ Stam AG Bhoelan F Ruizendaal JJ van den Eertwegh AJ Hooijberg E Scheper RJ de Gruijl TD 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(7):4540-4549
Dendritic cells (DC) are increasingly applied as a cellular adjuvant in immunotherapy of cancer. Two major myeloid DC subsets are recognized: interstitial DC (IDC) that infiltrate connective tissues and Langerhans cells (LC) that line epithelial surfaces. Yet, functional differences between IDC and LC remain to be defined. We recently showed that the CD34(+) acute myeloid leukemia cell line MUTZ-3 supports differentiation of both DC-SIGN(+) IDC and Langerin-positive Birbeck granule-expressing LC. By comparative functional characterization of MUTZ-3 IDC and MUTZ-3 LC, we aimed to elucidate the relative abilities of these two DC subsets to induce a specific T cell response and reveal the more suitable candidate for use as a clinical vehicle of tumor vaccines. Although mature LC and IDC displayed comparable lymph node-homing potential, mature LC showed higher allogeneic T cell stimulatory capacity. Nevertheless, IDC supported the induction of tumor Ag-specific CD8(+) T cells at an overall higher efficiency. This might be related to the observed inability of LC to release T cell stimulatory cytokines such as IL-12p70, IL-23, and IL-15. Although this inability did not result in a detectable deviation in the cytokine expression profile of primed T cells, transduction with IL-12p70 significantly improved priming efficiency of LC, and ensured a functional equivalence with IDC in this regard. In conclusion, except for the inability of LC to release distinct type 1 T cell stimulatory cytokines, in vitro function of LC and IDC suggests comparable abilities of both subsets for the in vivo induction of antitumor T cells. 相似文献
992.
Moreno M Molling JW von Mensdorff-Pouilly S Verheijen RH Hooijberg E Kramer D Reurs AW van den Eertwegh AJ von Blomberg BM Scheper RJ Bontkes HJ 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(4):2446-2454
CD1d-restricted invariant NKT (iNKT) cells can enhance immunity to cancer or prevent autoimmunity, depending on the cytokine profile secreted. Antitumor effects of the iNKT cell ligand alpha-galactosylceramide (alphaGC) and iNKT cell adoptive transfer have been demonstrated in various tumor models. Together with reduced numbers of iNKT cells in cancer patients, which have been linked to poor clinical outcome, these data suggest that cancer patients may benefit from therapy aiming at iNKT cell proliferation and activation. Herein we present results of investigations on the effects of human iNKT cells on Ag-specific CTL responses. iNKT cells were expanded using alphaGC-pulsed allogeneic DC derived from the acute myeloid leukemia cell line MUTZ-3, transduced with CD1d to enhance iNKT cell stimulation, and with IL-12 to stimulate type 1 cytokine production. Enhanced activation and increased IFN-gamma production was observed in iNKT cells, irrespective of CD4 expression, upon stimulation with IL-12-overexpressing dendritic cells. IL-12-stimulated iNKT cells strongly enhanced the MART-1 (melanoma Ag recognized by T cell 1)-specific CD8(+) CTL response, which was dependent on iNKT cell-derived IFN-gamma. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as alphaGC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN-gamma-producing iNKT cells, which may be more effective against tumors in vivo. Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with alphaGC. 相似文献
993.
Attenuation of recombinant vesicular stomatitis virus-human immunodeficiency virus type 1 vaccine vectors by gene translocations and g gene truncation reduces neurovirulence and enhances immunogenicity in mice 下载免费PDF全文
Cooper D Wright KJ Calderon PC Guo M Nasar F Johnson JE Coleman JW Lee M Kotash C Yurgelonis I Natuk RJ Hendry RM Udem SA Clarke DK 《Journal of virology》2008,82(1):207-219
Recombinant vesicular stomatitis virus (rVSV) has shown great potential as a new viral vector for vaccination. However, the prototypic rVSV vector described previously was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates. Here, we describe the attenuation, neurovirulence, and immunogenicity of rVSV vectors expressing human immunodeficiency virus type 1 Gag. These rVSV vectors were attenuated by combinations of the following manipulations: N gene translocations (N4), G gene truncations (CT1 or CT9), noncytopathic M gene mutations (Mncp), and positioning of the gag gene into the first position of the viral genome (gag1). The resulting N4CT1-gag1, N4CT9-gag1, and MncpCT1-gag1 vectors demonstrated dramatically reduced neurovirulence in mice following direct intracranial inoculation. Surprisingly, in spite of a very high level of attenuation, the N4CT1-gag1 and N4CT9-gag1 vectors generated robust Gag-specific immune responses following intramuscular immunization that were equivalent to or greater than immune responses generated by the more virulent prototypic vectors. MncpCT1-gag1 also induced Gag-specific immune responses following intramuscular immunization that were equivalent to immune responses generated by the prototypic rVSV vector. Placement of the gag gene in the first position of the VSV genome was associated with increased in vitro expression of Gag protein, in vivo expression of Gag mRNA, and enhanced immunogenicity of the vector. These findings demonstrate that through directed manipulation of the rVSV genome, vectors that have reduced neurovirulence and enhanced immunogenicity can be made. 相似文献
994.
995.
A series of structurally related 2,5-disubstituted 6-(1-naphthylmethyl)-pyrimidin-4(3H)-ones, compounds 6a-6r, were synthesized and evaluated for their in vitro anti-HIV activities in MT-4 cells. Most of the new compounds investigated showed moderate-to-good activities against wild-type HIV-1, with IC(50) values in the range 5.64-0.21 microM. Compound 6d was the most potent congener (IC(50)=0.21 microM, SI=724) in inhibiting HIV-1 replication, which is ca. 25 times more effective than the reference compound 2',3'-dideoxyinosine (DDI). Preliminary structure-activity relationship (SAR) studies revealed that both modulation of the amino function at C(2) and of the alkyl group at C(5) of the pyrimidine ring are crucial for high anti-HIV-1 activity. 相似文献
996.
Background
Across all sequenced bacterial genomes, the number of domains n c in different functional categories c scales as a power-law in the total number of domains n, i.e. , with exponents α c that vary across functional categories. Here we investigate the implications of these scaling laws for the evolution of domain-content in bacterial genomes and derive the simplest evolutionary model consistent with these scaling laws. 相似文献997.
998.
Hemmingsson E Hellénius ML Ekelund U Bergström J Rössner S 《Obesity (Silver Spring, Md.)》2008,16(6):1308-1313
Objective: There are few established methods for promoting physical activity (PA) in the severely obese. Because social support is a potential method for promoting PA, we compared mean steps/day during 18 weeks in severely obese outpatients receiving either standard support (SS) or added support (AS). Methods and Procedures: Eighty severely obese outpatients from an obesity clinic were invited; 66 provided written consent, 55 were randomized, and 42 were included in final analyses (9 men, 33 women; age 44.4 ± 13.1 years; BMI 41.9 ± 5.5 kg/m2). All participants received a pedometer and a walking promotion booklet. In addition to SS, the AS group received ten 2‐h group counseling sessions aimed at increasing weekly accumulated steps, every second week during the study. Each participant was asked to complete a 7‐day walking diary every second week (10 observations). Results: Baseline steps/day was 6,912 for the AS group and 5,311 for the SS group (P = 0.023). Data at 18 weeks showed that the AS group recorded 10,136 steps/day and the SS group 6,118 steps/day (P = 0.024). There was no allocation × time interaction (P = 0.46). During the follow‐up period as a whole, the AS group recorded 1,794 more steps/day than the SS group (P = 0.0074). Discussion: The AS group recorded more steps/day than the SS group, reaching a mean level of ~10,000 steps/day. However, the nonsignificant interaction between allocation × time suggests that this difference was present already at baseline and did not increase during follow‐up. 相似文献
999.
Objective: To assess whether the long‐term effects of childhood television viewing on BMI and cardiorespiratory fitness are mediated by adult viewing. Methods and Procedures: This prospective study included an unselected birth cohort of 1,037 participants (535 men) born in Dunedin, New Zealand in 1972/1973. Hours of television viewing on weekdays were reported at ages 5, 7, 9, 11, 13, 15, and 32 years. BMI and cardiorespiratory fitness were measured at age 32 years. Results: Both childhood and adult television viewing times were significantly associated with higher BMI and lower cardiorespiratory fitness at age 32 years. Childhood television viewing was a better predictor of adult BMI and fitness than adult viewing and remained a significant predictor of these outcomes after adjusting for adult viewing time. After adjusting for adult viewing, the odds (95% confidence interval) of adult obesity increased by a factor of 1.25 (1.01, 1.53) and poor fitness increased by a factor of 1.40 (1.16, 1.70) for each hour of mean weekday television viewing during childhood. Discussion: The association between childhood television viewing and obesity and poor fitness in adulthood is not mediated by adult viewing. The detrimental health effects of watching too much television during childhood persist into adulthood. Attempts to reduce adult obesity and poor fitness by modifying television viewing habits need to begin in childhood. 相似文献
1000.