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31.
Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation 总被引:32,自引:0,他引:32
Hwu P Du MX Lapointe R Do M Taylor MW Young HA 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(7):3596-3599
Dendritic cells (DCs) play a key role in the activation and regulation of B and T lymphocytes. Production of indoleamine 2, 3-dioxygenase (IDO) by macrophages has recently been described to result in inhibition of T cell proliferation through tryptophan degradation. Since DCs can be derived from monocytes, we sought to determine whether DCs could produce IDO which could potentially regulate T cell proliferation. Northern blot analysis of RNA from cultured monocyte-derived human DC revealed that IDO mRNA was induced upon activation with CD40 ligand and IFN-gamma. IDO produced from activated DCs was functionally active and capable of metabolizing tryptophan to kynurenine. Activated T cells were also capable of inducing IDO production by DCs, which was inhibited by a neutralizing Ab against IFN-gamma. DC production of IDO resulted in inhibition of T cell proliferation, which could be prevented using the IDO inhibitor 1-methyl-dl -tryptophan. These results suggest that activation of DCs induces the production of functional IDO, which causes depletion of tryptophan and subsequent inhibition of T cell proliferation. This may represent a potential mechanism for DCs to regulate the immune response. 相似文献
32.
Lapointe R Royal RE Reeves ME Altomare I Robbins PF Hwu P 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(8):4758-4764
Involvement of tumor-Ag specific CD4(+) and CD8(+) T cells could be critical in the generation of an effective immunotherapy for cancer. In an attempt to optimize the T cell response against defined tumor Ags, we previously developed a method allowing transgene expression in human dendritic cells (DCs) using retroviral vectors. One advantage of using gene-modified DCs is the potential ability to generate CD8(+) T cells against multiple class I-restricted epitopes within the Ag, thereby eliciting a broad antitumor immune response. To test this, we generated tumor-reactive CD8(+) T cells with DCs transduced with the melanoma Ag gp100, for which a number of HLA-A2-restricted epitopes have been described. Using gp100-transduced DCs, we were indeed able to raise T cells recognizing three distinct HLA-A2 epitopes within the Ag, gp100(154-162), gp100(209-217), and gp100(280-288). We next tested the ability of transduced DCs to raise class II-restricted CD4(+) T cells. Interestingly, stimulation with gp100-transduced DCs resulted in the generation of CD4(+) T cells specific for a novel HLA-DRbeta1*0701-restricted epitope of gp100. The minimal determinant of this epitope was defined as gp100(174-190) (TGRAMLGTHTMEVTVYH). These observations suggest that retrovirally transduced DCs have the capacity to present multiple MHC class I- and class II-restricted peptides derived from a tumor Ag, thereby eliciting a robust immune response against that Ag. 相似文献
33.
34.
Binzak BA Wevers RA Moolenaar SH Lee YM Hwu WL Poggi-Bach J Engelke UF Hoard HM Vockley JG Vockley J 《American journal of human genetics》2001,68(4):839-847
Dimethylglycine dehydrogenase (DMGDH) (E.C. number 1.5.99.2) is a mitochondrial matrix enzyme involved in the metabolism of choline, converting dimethylglycine to sarcosine. Sarcosine is then transformed to glycine by sarcosine dehydrogenase (E.C. number 1.5.99.1). Both enzymes use flavin adenine dinucleotide and folate in their reaction mechanisms. We have identified a 38-year-old man who has a lifelong condition of fishlike body odor and chronic muscle fatigue, accompanied by elevated levels of the muscle form of creatine kinase in serum. Biochemical analysis of the patient's serum and urine, using (1)H-nuclear magnetic resonance NMR spectroscopy, revealed that his levels of dimethylglycine were much higher than control values. The cDNA and the genomic DNA for human DMGDH (hDMGDH) were then cloned, and a homozygous A-->G substitution (326 A-->G) was identified in both the cDNA and genomic DNA of the patient. This mutation changes a His to an Arg (H109R). Expression analysis of the mutant cDNA indicates that this mutation inactivates the enzyme. We therefore confirm that the patient described here represents the first reported case of a new inborn error of metabolism, DMGDH deficiency. 相似文献
35.
To understand how information flows and is used in the human brain, we must map neural structures at all levels, providing visualizations similar to those of Google Earth for continents, countries, cities, and streets. Unfortunately, the imaging and processing techniques currently used in connectomics projects cannot achieve complete mapping for the brains of large animals within the timespan of a typical research career. However, feasible improvements in x-ray imaging would change this situation. This Q&A discusses synchrotron x-ray tomography, an exciting new approach for in situ mapping of whole-brain wiring diagrams at multiple levels of spatial resolution. 相似文献
36.
Wen-Jen Chen Feng-Chia Hsieh Fu-Chiun Hsu Yi-Fang Tasy Je-Ruei Liu Ming-Che Shih 《PLoS pathogens》2014,10(8)
Pseudomonas taiwanensis is a broad-host-range entomopathogenic bacterium that exhibits insecticidal activity toward agricultural pests Plutella xylostella, Spodoptera exigua, Spodoptera litura, Trichoplusia ni and Drosophila melanogaster. Oral infection with different concentrations (OD = 0.5 to 2) of wild-type P. taiwanensis resulted in insect mortality rates that were not significantly different (92.7%, 96.4% and 94.5%). The TccC protein, a component of the toxin complex (Tc), plays an essential role in the insecticidal activity of P. taiwanensis. The ΔtccC mutant strain of P. taiwanensis, which has a knockout mutation in the tccC gene, only induced 42.2% mortality in P. xylostella, even at a high bacterial dose (OD = 2.0). TccC protein was cleaved into two fragments, an N-terminal fragment containing an Rhs-like domain and a C-terminal fragment containing a Glt symporter domain and a TraT domain, which might contribute to antioxidative stress activity and defense against macrophagosis, respectively. Interestingly, the primary structure of the C-terminal region of TccC in P. taiwanensis is unique among pathogens. Membrane localization of the C-terminal fragment of TccC was proven by flow cytometry. Sonicated pellets of P. taiwanensis ΔtccC strain had lower toxicity against the Sf9 insect cell line and P. xylostella larvae than the wild type. We also found that infection of Sf9 and LD652Y-5d cell lines with P. taiwanensis induced apoptotic cell death. Further, natural oral infection by P. taiwanensis triggered expression of host programmed cell death-related genes JNK-2 and caspase-3. 相似文献
37.
Chia-Chi Chien Ivan M. Kempson Cheng Liang Wang H.H. Chen Yeukuang Hwu N.Y. Chen T.K. Lee Kelvin K.-C. Tsai Ming-Sheng Liu Kwang-Yu Chang C.S. Yang G. Margaritondo 《Biotechnology advances》2013
Complete profiling would substantially facilitate the fundamental understanding of tumor angiogenesis and of possible anti-angiogenesis cancer treatments. We developed an integrated synchrotron-based methodology with excellent performances: detection of very small vessels by high spatial resolution (~ 1 μm) and nanoparticle contrast enhancement, in vivo dynamics investigations with high temporal resolution (~ 1 ms), and three-dimensional quantitative morphology parametrization by computer tracing. The smallest (3–10 μm) microvessels were found to constitute > 80% of the tumor vasculature and exhibit many structural anomalies. Practical applications are presented, including vessel microanalysis in xenografted tumors, monitoring the effects of anti-angiogenetic agents and in vivo detection of tumor vascular rheological properties. 相似文献
38.
Jessica Ann Chacon Richard C. Wu Pariya Sukhumalchandra Jeffrey J. Molldrem Amod Sarnaik Shari Pilon-Thomas Jeffrey Weber Patrick Hwu Laszlo Radvanyi 《PloS one》2013,8(4)
Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the “rapid expansion protocol” (REP) were not designed to enhance the generation of optimal effector-memory CD8+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8+ T cells, on the yield, phenotype, and functional activity of expanded CD8+ T cells during the REP. We found that CD8+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients. 相似文献
39.
Huai-Hsuan Tseng Sue-Huei Chen Chih-Min Liu Oliver Howes Yu-Lien Huang Ming H. Hsieh Chen-Chung Liu Jia-Chi Shan Yi-Ting Lin Hai-Gwo Hwu 《PloS one》2013,8(6)
Background
Patients with schizophrenia perform significantly worse on emotion recognition tasks than healthy participants across several sensory modalities. Emotion recognition abilities are correlated with the severity of clinical symptoms, particularly negative symptoms. However, the relationships between specific deficits of emotion recognition across sensory modalities and the presentation of psychotic symptoms remain unclear. The current study aims to explore how emotion recognition ability across modalities and neurocognitive function correlate with clusters of psychotic symptoms in patients with schizophrenia.Methods
111 participants who met the DSM-IV diagnostic criteria for schizophrenia and 70 healthy participants performed on a dual-modality emotion recognition task, the Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW), and selected subscales of WAIS-III. Of all, 92 patients received neurocognitive evaluations, including CPT and WCST. These patients also received the PANSS for clinical evaluation of symptomatology.Results
The emotion recognition ability of patients with schizophrenia was significantly worse than healthy participants in both facial and vocal modalities, particularly fearful emotion. An inverse correlation was noted between PANSS total score and recognition accuracy for happy emotion. The difficulty of happy emotion recognition and earlier age of onset, together with the perseveration error in WCST predicted total PANSS score. Furthermore, accuracy of happy emotion and the age of onset were the only two significant predictors of delusion/hallucination. All the associations with happy emotion recognition primarily concerned happy prosody.Discussion
Deficits in emotional processing in specific categories, i.e. in happy emotion, together with deficit in executive function, may reflect dysfunction of brain systems underlying severity of psychotic symptoms, in particular the positive dimension. 相似文献40.