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911.
You S Chen C Lee WH Brusko T Atkinson M Liu CP 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(11):6777-6785
Immunization of NOD mice with autoantigens such as glutamic acid decarboxylase (GAD) 221-235 peptide (p221) can induce Ag-specific CD4(+) T regulatory (Tr) cells. However, it is unclear whether these Tr cells acquire their regulatory capacity due to immunization or whether they are constitutively harbored in unimmunized naive mice. To address this question, we used an I-Ag7 tetramer to isolate p221-specific T cells from naive NOD mice (N221(+) cells) after peptide-specific in vitro expansion. The N221(+) T cells produced IFN-gamma and IL-10, but very little IL-4, in response to p221 stimulation. These T cells could function as regulatory cells and inhibit in vitro proliferation of diabetogenic BDC2.5 cells. This suppressive activity was cell contact-independent and was abrogated by Abs to IL-10 or IL-10R. Interestingly, IL-2 produced by other T cells present in the cell culture induced unactivated N221(+) T cells to exhibit regulatory activities involving production of IL-10. In vivo, N221(+) cells inhibited diabetes development when cotransferred with NOD splenocytes into NOD/scid recipients. Together, these results demonstrate that p221-specific IL-10-dependent Tr cells, including Tr type 1 cells, are present in naive NOD mice. The use of spontaneously arising populations of GAD peptide-specific Tr cells may represent a promising immunotherapeutic approach for preventing type 1 diabetes. 相似文献
912.
Berglez J Iliades P Sirawaraporn W Coloe P Macreadie I 《International journal for parasitology》2004,34(1):95-100
Mutations in Plasmodium falciparum dihydropteroate synthase have been linked to resistance to the antimalarial drug, sulfadoxine, which competes with the dihydropteroate synthase substrate, p-aminobenzoate. In an effort to evaluate the role of these mutations in a simple model system, we have expressed six relevant alleles of the P. falciparum dihydropteroate synthase gene in Escherichia coli. When each construct was produced in a dihydropteroate synthase disrupted E. coli strain that required thymidine, the thymidine requirement was lost, indicating heterologous complementation had occurred. In the presence of sulfadoxine, the growth of the strain with the wild-type dihydropteroate synthase allele was inhibited while those containing each of the five mutant alleles grew, indicating that these mutations can confer sulfadoxine resistance in E. coli. When tested against twelve additional 'sulfa' drugs a variety of responses were obtained. All strains were resistant to sulfadiazine, but the wild-type allele conferred sensitivity to all other sulfa drugs. Three alleles conferred resistance to dapsone, a drug that is to be targetted for a new regime of malaria treatment in Africa. All mutant alleles remained sensitive to sulfachloropyridazine and sulfacetamide. These results suggest new drugs that could be tried for effective malaria treatment. 相似文献
913.
Smyth LM Bobalova J Mendoza MG Lew C Mutafova-Yambolieva VN 《The Journal of biological chemistry》2004,279(47):48893-48903
Chemical signaling in autonomic neuromuscular transmission involves agents that function as neurotransmitters and/or neuromodulators. Using high performance liquid chromatography techniques with fluorescence and electrochemical detection we observed that, in addition to ATP and norepinephrine (NE), electrical field stimulation (EFS, 4-16 Hz, 0.1-0.3 ms, 15 V, 60-120 s) of isolated vascular and non-vascular preparations co-releases a previously unidentified compound with apparent nucleotide or nucleoside structure. Extensive screening of more than 25 nucleotides and nucleosides followed by detailed peak identification revealed that beta-nicotinamide adenine dinucleotide (beta-NAD) is released in tissue superfusates upon EFS of canine mesenteric artery (CMA), canine urinary bladder, and murine urinary bladder in the amounts of 7.1 +/- 0.7, 26.5 +/- 4.5, and 15.1 +/- 3.2 fmol/mg of tissue, respectively. Smaller amounts of the beta-NAD metabolites cyclic adenosine 5'-diphosphoribose (cADPR) and ADPR were also present in the superfusates collected during EFS of CMA (2.5 +/- 0.9 and 5.8 +/- 0.8 fmol/mg of tissue, respectively), canine urinary bladder (1.8 +/- 0.5 and 9.0 +/- 6.0 fmol/mg of tissue, respectively), and murine urinary bladder (1.4 +/- 0.1 and 6.2 +/- 2.4 fmol/mg of tissue, respectively). The three nucleotides were also detected in the samples collected before EFS (0.2-1.6 fmol/mg of tissue). Exogenous beta-NAD, cADPR, and ADPR (all 100 nm) reduced the release of NE in CMA at 16 Hz from 27.8 +/- 6.0 fmol/mg of tissue to 15.5 +/- 5.0, 12 +/- 3.0, and 10.0 +/- 4.0 fmol/mg of tissue, respectively. In conclusion, we detected constitutive and nerve-evoked overflow of beta-NAD, cADPR, and ADPR in vascular and non-vascular smooth muscles, beta-NAD being the prevailing compound. These substances modulate the release of NE, implicating novel nucleotide mechanisms of autonomic nervous system control of smooth muscle. 相似文献
914.
Sills ES Ghulmiyyah LM Wehbe SA Atkinson PF Perloe M Tucker MJ 《Histology and histopathology》2004,19(4):1241-1244
The frequency of triplet gestation is low in humans, estimated at 1:6400 deliveries. Monochorionic gestations represent a subpopulation of approximately 10% of these triplet pregnancies. Hypertensive complications are known to occur with greater frequency in the context of multiple gestation. In this report we describe microscopic placental changes associated with pre-eclampsia and proteinuria in the setting of an uncommon monochorionic-triamniotic triplet pregnancy achieved via in vitro fertilization. Histologic features observed in this case include placental stromal fibrosis and increased syncytial nodularity (Tenney-Parker change). In this triplet delivery resulting from two consecutive fissions of a single embryo, chorion and amnion configuration are also characterized with a review of the literature discussing the potential relationship between in vitro culture conditions and monozygotic multiple gestation. 相似文献
915.
Card KF Price-Schiavi SA Liu B Thomson E Nieves E Belmont H Builes J Jiao JA Hernandez J Weidanz J Sherman L Francis JL Amirkhosravi A Wong HC 《Cancer immunology, immunotherapy : CII》2004,53(4):345-357
Antibody-based targeted immunotherapy has shown promise as an approach to treat cancer. However, many known tumor-associated antigens are not expressed as integral membrane proteins and cannot be utilized as targets for antibody-based therapeutics. In order to expand the limited target range of antibodies, we have constructed a soluble single-chain T-cell receptor (TCR) fusion protein designated 264scTCR/IL-2. This fusion protein is comprised of a three-domain HLA-A2-restricted TCR specific for a peptide epitope of the human p53 tumor suppressor protein, which is overexpressed in a broad range of human malignancies. The 264scTCR/IL-2 fusion protein has been expressed at high levels in mammalian cells, and milligram quantities have been purified. MHC-restricted antigen-specific binding properties are maintained in the single-chain, three-domain TCR portion of the fusion protein, and the IL-2 portion retains bioactivity similar to that of free recombinant IL-2. Moreover, this fusion protein is capable of conjugating target and effector cells, remains intact in the blood and substantially increases the half life of the IL-2 portion of the molecule. Finally, the 264scTCR/IL-2 fusion protein can be used to stain tumor cells and is capable of reducing lung metastases in an experimental model of metastasis. Thus, TCR-based fusion proteins may provide a novel class of targeted immunotherapeutics for cancer. 相似文献
916.
The term vitamin E denotes a family of tocopherols and tocotrienols, plant lipids that are essential for vertebrate fertility and health. The principal form of vitamin E found in humans, RRR-alpha-tocopherol (TOH), is thought to protect cells by virtue of its ability to quench free radicals, and functions as the main lipid-soluble antioxidant. Regulation of vitamin E homeostasis occurs in the liver, where TOH is selectively retained while other forms of vitamin E are degraded. Through the action of tocopherol transfer protein (TTP), TOH is then secreted from the liver into circulating lipoproteins that deliver the vitamin to target tissues. Presently, very little is known regarding the intracellular transport of vitamin E. We utilized biochemical, pharmacological, and microscopic approaches to study this process in cultured hepatocytes. We observe that tocopherol-HDL complexes are efficiently internalized through scavenger receptor class B type I. Once internalized, tocopherol arrives within approximately 30 min at intracellular vesicular organelles, where it co-localizes with TTP, and with a marker of the lysosomal compartment (LAMP1), before being transported to the plasma membrane in a TTP-dependent manner. We further show that intracellular processing of tocopherol involves a functional interaction between TTP and an ABC-type transporter. 相似文献
917.
Mosquera LA Card KF Price-Schiavi SA Belmont HJ Liu B Builes J Zhu X Chavaillaz PA Lee HI Jiao JA Francis JL Amirkhosravi A Wong RL Wong HC 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(7):4381-4388
We have constructed a protein composed of a soluble single-chain TCR genetically linked to the constant domain of an IgG1 H chain. The Ag recognition portion of the protein binds to an unmutated peptide derived from human p53 (aa 264-272) presented in the context of HLA-A2.1, whereas the IgG1 H chain provides effector functions. The protein is capable of forming dimers, specifically staining tumor cells and promoting target and effector cell conjugation. The protein also has potent antitumor effects in an in vivo tumor model and can mediate cell killing by Ab-dependent cellular cytotoxicity. Therefore, single-chain TCRs linked to IgG1 H chains behave like Abs but possess the ability to recognize Ags derived from intracellular targets. These fusion proteins represent a novel group of immunotherapeutics that have the potential to expand the range of tumors available for targeted therapies beyond those currently addressed by the conventional Ab-based approach. 相似文献
918.
Krych-Goldberg M Hauhart RE Porzukowiak T Atkinson JP 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(7):4528-4535
The extracellular domain of the complement receptor type 1 (CR1; CD35) consists entirely of 30 complement control protein repeats (CCPs). CR1 has two distinct functional sites, site 1 (CCPs 1-3) and two copies of site 2 (CCPs 8-10 and CCPs 15-17). In this report we further define the structural requirements for decay-accelerating activity (DAA) for the classical pathway (CP) C3 and C5 convertases and, using these results, generate more potent decay accelerators. Previously, we demonstrated that both sites 1 and 2, tandemly arranged, are required for efficient DAA for C5 convertases. We show that site 1 dissociates the CP C5 convertase, whereas the role of site 2 is to bind the C3b subunit. The intervening CCPs between two functional sites are required for optimal DAA, suggesting that a spatial orientation of the two sites is important. DAA for the CP C3 convertase is increased synergistically if two copies of site 1, particularly those carrying DAA-increasing mutations, are contained within one protein. DAA in such constructs may exceed that of long homologous repeat A (CCPs 1-7) by up to 58-fold. To explain this synergy, we propose a dimeric structure for the CP C3 convertase on cell surfaces. We also extended our previous studies of the amino acid requirements for DAA of site 1 and found that the CCP 1/CCP 2 junction is critical and that Phe82 may contact the C3 convertases. These observations increase our understanding of the mechanism of DAA. In addition, a more potent decay-accelerating form of CR1 was generated. 相似文献
919.
Muthurangu V Atkinson D Sermesant M Miquel ME Hegde S Johnson R Andriantsimiavona R Taylor AM Baker E Tulloh R Hill D Razavi RS 《American journal of physiology. Heart and circulatory physiology》2005,289(3):H1301-H1306
Pulmonary hypertensive disease is assessed by quantification of pulmonary vascular resistance. Pulmonary total arterial compliance is also an indicator of pulmonary hypertensive disease. However, because of difficulties in measuring compliance, it is rarely used. We describe a method of measuring pulmonary arterial compliance utilizing magnetic resonance (MR) flow data and invasive pressure measurements. Seventeen patients with suspected pulmonary hypertension or congenital heart disease requiring preoperative assessment underwent MR-guided cardiac catheterization. Invasive manometry was used to measure pulmonary arterial pressure, and phase-contrast MR was used to measure flow at baseline and at 20 ppm nitric oxide (NO). Total arterial compliance was calculated using the pulse pressure method (parameter optimization of the 2-element windkessel model) and the ratio of stroke volume to pulse pressure. There was good agreement between the two estimates of compliance (r = 0.98, P < 0.001). However, there was a systematic bias between the ratio of stroke volume to pulse pressure and the pulse pressure method (bias = 61%, upper level of agreement = 84%, lower level of agreement = 38%). In response to 20 ppm NO, there was a statistically significant fall in resistance, systolic pressure, and pulse pressure. In seven patients, total arterial compliance increased >10% in response to 20 ppm NO. As a population, the increase did not reach statistical significance. There was an inverse relation between compliance and resistance (r = 0.89, P < 0.001) and between compliance and mean pulmonary arterial pressure (r = 0.72, P < 0.001). We have demonstrated the feasibility of quantifying total arterial compliance using an MR method. 相似文献
920.
Many attempts have been made to quantify Africa's malaria burden but none has addressed how urbanization will affect disease transmission and outcome, and therefore mortality and morbidity estimates. In 2003, 39% of Africa's 850 million people lived in urban settings; by 2030, 54% of Africans are expected to do so. We present the results of a series of entomological, parasitological and behavioural meta-analyses of studies that have investigated the effect of urbanization on malaria in Africa. We describe the effect of urbanization on both the impact of malaria transmission and the concomitant improvements in access to preventative and curative measures. Using these data, we have recalculated estimates of populations at risk of malaria and the resulting mortality. We find there were 1,068,505 malaria deaths in Africa in 2000 - a modest 6.7% reduction over previous iterations. The public-health implications of these findings and revised estimates are discussed. 相似文献