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Biomedical subjects

Hideki Harada

Publications and source records attributed to Hideki Harada.

At least 19 recordsLinked to original sources

Identification and cultivation of anaerobic, syntrophic long-chain fatty acid-degrading microbes from mesophilic and thermophilic methanogenic sludges.

We investigated long-chain fatty acid (LCFA)-degrading anaerobic microbes by enrichment, isolation, and RNA-based stable isotope probing (SIP). Primary enrichment cultures were made with each of four LCFA substrates (palmitate, stearate, oleate, or linoleate, as the sole energy source) at 55 degrees C or 37 degrees C with two sources of anaerobic granular sludge as the inoculum. After several transfers, we obtained seven stable enrichment cultures in which LCFAs were converted to methane. The bacterial populations in these cultures were then subjected to 16S rRNA gene-based cloning, in situ hybridization, and RNA-SIP. In five of seven enrichment cultures, the predominant bacteria were affiliated with the family Syntrophomonadaceae. The other two enrichment cultures contained different bacterial populations in which the majority of members belonged to the phylum Firmicutes and the class Deltaproteobacteria. After several attempts to isolate these dominant bacteria, strain MPA, belonging to the family Syntrophomonadaceae, and strain TOL, affiliated with the phylum Firmicutes, were successfully isolated. Strain MPA converts palmitate to acetate and methane in syntrophic association with Methanospirillum hungatei. Even though strain TOL assimilated [(13)C]palmitate in the original enrichment culture, strain TOL has not shown the ability to degrade LCFAs after isolation. These results suggest that microbes involved in the degradation of LCFAs under methanogenic conditions might not belong only to the family Syntrophomonadaceae, as most anaerobic LCFA-degrading microbes do, but may also be found in phylogenetically diverse bacterial groups.

Bacteria, Anaerobic↗

Effective partial nitrification to nitrite by down-flow hanging sponge reactor under limited oxygen condition.

Combining the processes of partial nitrification and anaerobic ammonium oxidation (ANAMMOX) is an attractive wastewater-treatment technology for nitrogen removal. In this study we investigated partial nitrification by implementing a closed down-flow hanging sponge (DHS) reactor operated at controlled oxygen concentrations. Basic concept of DHS process is similar to that of trickling filter, in which oxygen concentration can be easily manipulated by controlling airflow to the reactor. The closed reactor was fed with artificial wastewater containing NH(4)Cl and operated with an HRT of 1.5h at 30 degrees C. Oxygen inside the reactor was maintained below 3% (1.2mgDO x L(-1)) (DO-dissolved oxygen) except during the startup periods. Five months of continuous operation showed that there was a strong relationship between oxygen concentration and nitrite production. The ratio of nitrite produced relative to ammonium oxidized increased by decreasing oxygen concentration. Partial nitrification was satisfactorily accomplished under oxygen limitation at around 0.5% in the gas phase (0.2mgDOL(-1)). The system showed a high ammonium-removal rate, at a maximum of 1.46kg NH(4)(+)-Nm(-3)day(-1), even at limited oxygen concentration. We also found that oxygen concentration played an important role in the production of nitrous oxide, which increased with decreasing oxygen concentration.

Air Movements↗

Moderate cerebral venous congestion induces rapid cerebral protection via adenosine A1 receptor activation.

Stroke is a devastating complication in cardiovascular surgery, and neuronal damage is worsened by intracranial pressure elevation caused by cerebral venous circulatory disturbances (CVCD). However, we have previously reported that CVCD before cerebral ischemia decreases the infarct area. In the present study, focal cerebral ischemia was induced in spontaneously hypertensive rats by filament insertion through the carotid artery. Rats were divided into the following four groups: sham-operated, mild or severe venous congestion (VC), and DPCPX. The DPCPX group received the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) prior to mild VC. Behavior, infarct volume, edema and S-100 protein were evaluated among the four groups. The infarct volume rates in mild VC and severe VC groups were significantly less than that in sham-operated and DPCPX groups. However, the mortality of the severe VC group worsened in a time-dependent manner. We observed a significant decrease in edema in the mild VC group compared to the DPCPX group. Behavioral scores also indicated that the mild VC group had fewer neurological deficits than the other three groups, including the DPCPX group. We were able to induce rapid cerebral protection via adenosine A1 receptor activation by administering an appropriate degree of VC prior to cerebral ischemia produced by middle cerebral artery occlusion. Our work suggests possible mechanisms by which such effective VC may lead to cerebral protection and adenosine A1 receptor activation.

Adenosine A1 Receptor Antagonists↗

Economic evaluation of sewage treatment processes in India.

This paper evaluates the total annual cost including capital and operation and maintenance (O&M) costs for the up-flow anaerobic sludge blanket (UASB) and waste stabilization pond (WSP) systems operated in India. It also compares UASB and WSP systems with the activated sludge process (ASP) and biological aerated filter (BAF) systems in terms of total annual cost and chemical oxygen demand (COD) removal cost by assuming various annual interest rates and land prices. It was found that the relationship between capital and O&M costs per unit size of a UASB or WSP system and its treatment capacity can be established by a first-order equation. The relation between the cost of organic removal and capital or O&M cost for various sewage treatment systems at various annual interest rates revealed that, for the Indian context, UASB could be the most suitable option in terms of expenses and treatment efficiency.

Costs and Cost Analysis↗

Visualization of mcr mRNA in a methanogen by fluorescence in situ hybridization with an oligonucleotide probe and two-pass tyramide signal amplification (two-pass TSA-FISH).

Two-pass tyramide signal amplification-fluorescence in situ hybridization (two-pass TSA-FISH) with a horseradish peroxidase (HRP)-labeled oligonucleotide probe was applied to detect prokaryotic mRNA. In this study, mRNA of a key enzyme for methanogenesis, methyl coenzyme M reductase (mcr), in Methanococcus vannielii was targeted. Applicability of mRNA-targeted probes to in situ hybridization was verified by Clone-FISH. It was observed that sensitivity of two-pass TSA-FISH was significantly higher than that of TSA-FISH, which was further increased by the addition of dextran sulphate in TSA working solution. Signals from two-pass TSA-FISH were more reliable compared to the weak, spotty signals yielded by TSA-FISH.

DNA, Bacterial↗

Pelotomaculum terephthalicum sp. nov. and Pelotomaculum isophthalicum sp. nov.: two anaerobic bacteria that degrade phthalate isomers in syntrophic association with hydrogenotrophic methanogens.

An anaerobic phthalate isomer-degrading strain (JT(T)) that we previously isolated was characterized. In addition, a strictly anaerobic, mesophilic, syntrophic phthalate isomer-degrading bacterium, designated strain JI(T), was isolated and characterized in this study. Both were non-motile rods that formed spores. In both strains, the optimal growth was observed at temperatures around 37 degrees C and neutral pH. In syntrophic co-culture with the hydrogenotrophic methanogen Methanospirillum hungatei, both strains could utilize two or three phthalate isomers for growth, and produce acetate and methane as end products. Strain JT(T) was able to grow on isophthalate, terephthalate, and a number of low-molecular weight aromatic compounds, such as benzoate, hydroquinone, 2-hydroxybenzoate, 3-hydroxybenzoate, 2,5-dihydroxybenzoate, 3-phenylpropionate in co-culture with M. hungatei. It could also grow on crotonate, hydroquinone and 2,5-dihydroxybenzoate in pure culture. Strain JI(T) utilized all of the three phthalate isomers as well as benzoate and 3-hydroxybenzoate for growth in co-culture with M. hungatei. No substrates were, however, found to support the axenic growth of strain JI(T). Neither strain JT(T) nor strain JI(T) could utilize sulfate, sulfite, thiosulfate, nitrate, fumarate, Fe (III) or 4-hydroxybenzoate as electron acceptor. Phylogenetically, strains JT(T) and JI(T) were relatively close to the members of the genera Pelotomaculum and Cryptanaerobacter in 'Desulfotomaculum lineage I'. Physiological and chemotaxonomic characteristics indicated that the two isolates should be classified into the genus Pelotomaculum, creating two novel species for them. Here, we propose Pelotomaculum terephthalicum sp. nov. and Pelotomaculum isophthalicum sp. nov. for strain JT(T) and strain JI(T), respectively. The type strains are strains JT(T) (= DSM 16121(T )= JCM 11824(T )= NBRC 100523(T)) and JI(T) (= JCM 12282(T) = BAA-1053(T)) for P. terephthalicum and P. isophthalicum, respectively.

Anaerobiosis↗

Tepidanaerobacter syntrophicus gen. nov., sp. nov., an anaerobic, moderately thermophilic, syntrophic alcohol- and lactate-degrading bacterium isolated from thermophilic digested sludges.

Three anaerobic, moderately thermophilic, syntrophic primary alcohol- and lactate-degrading microbes, designated strains JL(T), JE and OL, were isolated from sludges of thermophilic (55 degrees C) digesters that decomposed either municipal solid wastes or sewage sludge. The strains were strictly anaerobic organisms. All three strains grew at 25-60 degrees C and pH 5.5-8.5 and optimum growth was observed at 45-50 degrees C and pH 6.0-7.0. The three organisms grew chemo-organotrophically on a number of carbohydrates in the presence of yeast extract. In co-culture with the hydrogenotrophic methanogen Methanothermobacter thermautotrophicus, all strains could utilize ethanol, glycerol and lactate syntrophically for growth, although these compounds were not metabolized in pure culture without additional external electron acceptors. All strains could reduce thiosulphate. Quinones were not detected. The DNA G+C contents of strains JL(T), JE and OL were 38.0, 37.3 and 37.7 mol%, respectively. Major cellular fatty acids of the strains were iso-C(15 : 0), C(16 : 0) and unsaturated species of C(15 : 1). Phylogenetic analyses based on 16S rRNA gene sequences revealed that the strains belong to a deeply branched lineage of the phylum Firmicutes; the most closely related species was Thermovenabulum ferriorganovorum (16S rRNA gene sequence similarity of 88 %). The three strains were phylogenetically very closely related to each other (99-100 % 16S rRNA gene sequence similarity) and were physiologically and chemotaxonomically similar. These genetic and phenotypic properties suggest that the strains should be classified as representatives of a novel species and genus; the name Tepidanaerobacter syntrophicus gen. nov., sp. nov. is proposed. The type strain of Tepidanaerobacter syntrophicus is strain JL(T) (=JCM 12098(T)=NBRC 100060(T)=DSM 15584(T)).

Alcohols↗

Anaerolinea thermolimosa sp. nov., Levilinea saccharolytica gen. nov., sp. nov. and Leptolinea tardivitalis gen. nov., sp. nov., novel filamentous anaerobes, and description of the new classes Anaerolineae classis nov. and Caldilineae classis nov. in the bacterial phylum Chloroflexi.

One thermophilic (strain IMO-1(T)) and two mesophilic (strains KIBI-1(T) and YMTK-2(T)) non-spore-forming, non-motile, Gram-negative, multicellular filamentous micro-organisms, which were previously isolated as members of the tentatively named class 'Anaerolineae' of the phylum Chloroflexi, were characterized. All isolates were strictly anaerobic micro-organisms. The length of the three filamentous isolates was greater than 100 microm and the width was 0.3-0.4 microm for strain IMO-1(T), 0.4-0.5 microm for strain KIBI-1(T) and thinner than 0.2 microm for strain YMTK-2(T). Strain IMO-1(T) could grow at pH 6.0-7.5 (optimum growth at pH 7.0). The optimal temperature for growth of strain IMO-1(T) was around 50 degrees C (growth occurred between 42 and 55 degrees C). Growth of the mesophilic strains KIBI-1(T) and YMTK-2(T) occurred at pH 6.0-7.2 with optimal growth at pH 7.0. Both of the mesophilic strains were able to grow in a temperature range of 25-50 degrees C with optimal growth at around 37 degrees C. Yeast extract was required for growth of all three strains. All the strains could grow with a number of carbohydrates in the presence of yeast extract. The G + C contents of the DNA of strains IMO-1(T), KIBI-1(T) and YMTK-2(T) were respectively 53.3, 59.5 and 48.2 mol%. Major fatty acids for thermophilic strain IMO-1(T) were anteiso-C(17 : 0), iso-C(15 : 0), C(16 : 0) and anteiso-C(15 : 0), whereas those for mesophilic strains KIBI-1(T) and YMTK-2(T) were branched C(14 : 0), iso-C(15 : 0), C(16 : 0) and branched C(17 : 0), and branched C(17 : 0), C(16 : 0), C(14 : 0) and C(17 : 0), respectively. Detailed phylogenetic analyses based on their 16S rRNA gene sequences indicated that the isolates belong to the class-level taxon 'Anaerolineae' of the bacterial phylum Chloroflexi, which for a long time had been considered as a typical uncultured clone cluster. Their morphological, physiological, chemotaxonomic and genetic traits strongly support the conclusion that these strains should be described as three novel independent taxa in the phylum Chloroflexi. Here, Anaerolinea thermolimosa sp. nov. (type strain IMO-1(T) = CM 12577(T) = DSM 16554(T)), Levilinea saccharolytica gen. nov., sp. nov. (type strain KIBI-1(T) = JCM 12578(T) = DSM 16555(T)) and Leptolinea tardivitalis gen. nov., sp. nov. (type strain YMTK-2(T) = JCM 12579(T) = DSM 16556(T)) are proposed. In addition, we formally propose to subdivide the tentative class-level taxon 'Anaerolineae' into Anaerolineae classis nov. and Caldilineae classis nov. We also propose the subordinate taxa Anaerolineales ord. nov., Caldilineales ord. nov., Anaerolineaceae fam. nov. and Caldilineaceae fam. nov.

Chloroflexi↗

Improved in situ hybridization efficiency with locked-nucleic-acid-incorporated DNA probes.

Low signal intensity due to poor probe hybridization efficiency is one of the major drawbacks of rRNA-targeted in situ hybridization. There are two major factors affecting the hybridization efficiency: probe accessibility and affinity to the targeted rRNA molecules. In this study, we demonstrate remarkable improvement in in situ hybridization efficiency by applying locked-nucleic-acid (LNA)-incorporated oligodeoxynucleotide probes (LNA/DNA probes) without compromising specificity. Fluorescently labeled LNA/DNA probes with two to four LNA substitutions exhibited strong fluorescence intensities equal to or greater than that of probe Eub338, although these probes did not show bright signals when they were synthesized as DNA probes; for example, the fluorescence intensity of probe Eco468 increased by 22-fold after three LNA bases were substituted for DNA bases. Dissociation profiles of the probes revealed that the dissociation temperature was directly related to the number of LNA substitutions and the fluorescence intensity. These results suggest that the introduction of LNA residues in DNA probes will be a useful approach for effectively enhancing probe hybridization efficiency.

Bacteria↗

Non-sulfate-reducing, syntrophic bacteria affiliated with desulfotomaculum cluster I are widely distributed in methanogenic environments.

The classical perception of members of the gram-positive Desulfotomaculum cluster I as sulfate-reducing bacteria was recently challenged by the isolation of new representatives lacking the ability for anaerobic sulfate respiration. For example, the two described syntrophic propionate-oxidizing species of the genus Pelotomaculum form the novel Desulfotomaculum subcluster Ih. In the present study, we applied a polyphasic approach by using cultivation-independent and culturing techniques in order to further characterize the occurrence, abundance, and physiological properties of subcluster Ih bacteria in low-sulfate, methanogenic environments. 16S rRNA (gene)-based cloning, quantitative fluorescence in situ hybridization, and real-time PCR analyses showed that the subcluster Ih population composed a considerable part of the Desulfotomaculum cluster I community in almost all samples examined. Additionally, five propionate-degrading syntrophic enrichments of subcluster Ih bacteria were successfully established, from one of which the new strain MGP was isolated in coculture with a hydrogenotrophic methanogen. None of the cultures analyzed, including previously described Pelotomaculum species and strain MGP, consumed sulfite, sulfate, or organosulfonates. In accordance with these phenotypic observations, a PCR-based screening for dsrAB (key genes of the sulfate respiration pathway encoding the alpha and beta subunits of the dissimilatory sulfite reductase) of all enrichments/(co)cultures was negative with one exception. Surprisingly, strain MGP contained dsrAB, which were transcribed in the presence and absence of sulfate. Based on these and previous findings, we hypothesize that members of Desulfotomaculum subcluster Ih have recently adopted a syntrophic lifestyle to thrive in low-sulfate, methanogenic environments and thus have lost their ancestral ability for dissimilatory sulfate/sulfite reduction.

Culture Media↗

Reconstruction and regulation of the central catabolic pathway in the thermophilic propionate-oxidizing syntroph Pelotomaculum thermopropionicum.

Obligate anaerobic bacteria fermenting volatile fatty acids in syntrophic association with methanogenic archaea share the intermediate bottleneck step in organic-matter decomposition. These organisms (called syntrophs) are biologically significant in terms of their growth at the thermodynamic limit and are considered to be the ideal model to address bioenergetic concepts. We conducted genomic and proteomic analyses of the thermophilic propionate-oxidizing syntroph Pelotomaculum thermopropionicum to obtain the genetic basis for its central catabolic pathway. Draft sequencing and subsequent targeted gap closing identified all genes necessary for reconstructing its propionate-oxidizing pathway (i.e., methylmalonyl coenzyme A pathway). Characteristics of this pathway include the following. (i) The initial two steps are linked to later steps via transferases. (ii) Each of the last three steps can be catalyzed by two different types of enzymes. It was also revealed that many genes for the propionate-oxidizing pathway, except for those for propionate coenzyme A transferase and succinate dehydrogenase, were present in an operon-like cluster and accompanied by multiple promoter sequences and a putative gene for a transcriptional regulator. Proteomic analysis showed that enzymes in this pathway were up-regulated when grown on propionate; of these enzymes, regulation of fumarase was the most stringent. We discuss this tendency of expression regulation based on the genetic organization of the open reading frame cluster. Results suggest that fumarase is the central metabolic switch controlling the metabolic flow and energy conservation in this syntroph.

Acyl Coenzyme A↗

Effects of systemic deep hypothermia and subarachnoid block on the longitudinally conducting evoked spinal cord potentials in man.

The present study reports the effects of systemic deep hypothermia (SDH) and subarachnoid block (SAB) on the longitudinally conducting evoked spinal cord potential (conducting ESCP) in man. Before induction of anesthesia, a pair of bipolar catheter electrodes was introduced to the epidural space: one at the level of the cervical enlargement and the other at the lumbosacral enlargement. The conducting ESCP was produced by electrical stimulation through the upper electrode and recorded through the lower electrode, and vice versa. SDH Study: Subjects were 6 patients who underwent replacement surgery of an aortic aneurysm with deep hypothermia anesthesia. The peak latency of the ESCP was gradually prolonged and the duration was widened with cooling via extracorporeal circulation. The amplitude of ESCP showed a biphasic change over the course of cooling with a turning point of around 30 degrees C in esophageal temperature. The ESCP was well observed until blood temperatures as low as near 10 degrees C. The result shows that ESCP is available as an intra-operative monitoring parameter of the spinal function even under SDH. SAB Study: Subjects were 7 patients, 6 of whom had SAB and the remaining 1 intravenous application of a local anesthetic. The conducting ESCP was markedly depressed or disappeared completely even after SAB with clinical doses of various local anesthetics, while it was hardly affected by the intravenous application. The result implies that SAB causes, at least partially, the conduction block within the spinal cord.

Adult↗

The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats.

OBJECT: The use of human umbilical cord blood (HUCB) cells has been reported to improve functional recovery in cases of central nervous system injuries such as stroke, traumatic brain injury, and spinal cord injury (SCI). The authors investigated the effects of hemopoietic stem cells that were derived from HUCB and transplanted into the injured spinal cords of rats. METHODS: One week after injury, an HUCB fraction enriched in CD34-positive cells was transplanted into the experimental group. In control animals, vehicle (Matrigel) was transplanted. Recovery of motor functions was assessed using the Basso-Beattie-Bresnahan Locomotor Scale, and immunohistochemical examinations were performed. Cells from HUCB that were CD34 positive improved functional recovery, reduced the area of the cystic cavity at the site of injury, increased the volume of residual white matter, and promoted the regeneration or sparing of axons in the injured spinal cord. Immunohistochemical examination revealed that transplanted CD34-positive cells survived in the host spinal cord for at least 3 weeks after transplantation but had disappeared by 5 weeks. The transplanted cells were not positive for neural markers, but they were positive for hemopoietic markers. There was no evidence of an immune reaction at the site of injury in either group. CONCLUSIONS: These results suggest that transplantation of a CD34-positive fraction from HUCB may have therapeutic effects for SCI. The results of this study provide important preclinical data regarding HUCB stem cell-based therapy for SCI.

Animals↗

[Intra-operative monitoring of EEG].

The fundamentals and clinical applications of intra-operative EEG monitoring are described. EEG monitored on line at bedside is useful for the evaluation of the depth of anesthesia and sedation, and also for the early detection of cerebral ischemia and seizure. However, EEG monitoring is not easy in the operating room, where a number of electrical machines and medical personnel are working. The authors have introduced a basal lead for the recording of brain-stem electrical activity and a fiberoptic EEG instrument for the exclusion of electrical noises. Recently, EEG instruments with computer-processing function, which are small in size and easy to manage, have been developed one after another. Computer-processed EEG is sequentially expressed as a digitalized value. Today, computer-processed EEG is more popular than raw EEG as an intra-operative monitoring of cerebral function, while raw EEG is superior to computer-processed EEG in the detection of seizure waves. The authors recommend multi-modality monitoring including non-invasive measurements of oxygen saturation and blood flow for the safe maintenance of cerebral

Anesthesia↗

Prospects for a self-sustainable sewage treatment system: a case study on full-scale UASB system in India's Yamuna River Basin.

The government of India decided to launch a project to implement 16 full-scale Upflow Anaerobic Sludge Blanket (UASB) reactors (with a total capacity of 598,000 m(3)/d) in the Yamuna River basin under its Yamuna Action Plan (YAP). A polishing pond called the Final Polishing Unit (FPU) was utilized for post-treatment. This paper evaluates the sewage treatment efficiency of the combined system of full-scale UASB reactors and polishing ponds under Indian climatic conditions. Results have shown that the effluent from the sewage treatment plants (STPs) investigated failed to comply with applicable discharge standards in terms of BOD, SS, and fecal coliform removal. Therefore, it is proposed that such proper operation and maintenance as removing excess sludge and scum be conducted in order to increase treatment efficiency. Moreover, trained and experienced workers are also required to operate and maintain the systems, along with a scientific approach.

Ammonia↗

Creating oral squamous cancer cells: a cellular model of oral-esophageal carcinogenesis.

Immortalization and malignant transformation are important steps in tumor development. The ability to induce these processes from normal human epithelial cells with genetic alterations frequently found in the corresponding human cancer would significantly enhance our understanding of tumor development. Alterations in several key intracellular regulatory pathways (the pRB, p53, and mitogenic signaling pathways and the telomere maintenance system) appear to be sufficient for the neoplastic transformation of normal human cells. Nevertheless, in vitro transformation models to date depend on viral oncogenes, most prominently the simian virus 40 early region, to induce immortalization and malignant transformation of normal human epithelial cells. Here, we demonstrate a transformation model creating oral-esophageal cancer cells by using a limited set of genetic alterations frequently observed in the corresponding human cancer. In a stepwise model, cyclin D1 overexpression and p53 inactivation led to immortalization of oral keratinocytes. Additional ectopic epithelial growth factor receptor overexpression followed by c-myc overexpression as well as consecutive reactivation of telomerase induced by epithelial growth factor receptor sufficed to transform oral epithelial cells, truly recapitulating the development of the corresponding human disease.

Carcinoma, Squamous Cell↗

Hyperthermia suppresses the cytotoxicity of NK cells via down-regulation of perforin/granzyme B expression.

Hyperthermia, which is used as an adjunctive therapy for cancer, is known to modulate the activity of natural killer (NK) cells in vitro, but its effect in vivo is unclear. In the present study, we used a whole body hyperthermia (WBH) device heated by infrared rays to evaluate the effect of WBH on mice models. We demonstrate here that wild type C57BL/6J mice exposed to 42 degrees C for 60min had reduced NK cell cytolytic activity against YAC-1 target cells as determined by cytolytic assay. This result was confirmed using Rag-2 knockout mice, which possess functional NK but not cytolytic T or NK-T cells. Moreover, WBH decreased the mRNA expression of perforin and granzyme B in spleens of mice. But the expression of TNF cytokines (Fas ligand and TRAIL) was unchanged. These data suggest that the suppression of NK cell activity induced by WBH could be mediated through the perforin/granzyme pathway.

Animals↗

Selective expansion and engraftment of human CD16+ NK cells in NOD/SCID mice.

NK cells are large granular lymphocytes that represent a critical component of the innate immunity. Investigations of human NK cell function are largely based on in vitro assays because of the lack of suitable animal models. Here we have established conditions leading to the development of human NK cells in NOD/SCID (severe combined immunodeficiency) mice receiving grafts of cord blood mononuclear cells (CBMC), and GFP-transduced HFWT inducing NK cells (GHINK-1), which have been shown to support the selective expansion of NK cells from human PBMC and CBMC in vitro. Significant numbers of CD56dimCD16+ cytotoxic and CD56-CD16+ immature NK cells appeared in peripheral blood (PB), peritoneal cavity, spleen, bone marrow and liver of the mice. The newly generated NK cells did not express activation markers such as CD25, CD69 and NKp44, the expression of which was augmented by IL-2 in vitro. The NOD/SCID mice engrafted with human NK cells exhibited antitumor activity against K562 erythroleukemia in vitro and in vivo. Thus, we succeeded in developing a CD56dimCD16+ cytotoxic NK cell populations in NOD/SCID mice closely resembling the main NK fraction in human PB and CD56-CD16+ immature NK cells. Our model provides not only information about the development and dynamics of physiological human NK cells but also an important pre-clinical system for immunotherapeutic strategies.

Animals↗