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Toshio Heike

Publications and source records attributed to Toshio Heike.

34 records · Page 2Linked to original sources
PubMed2004

Differential requirement for the CD40-CD154 costimulatory pathway during Th cell priming by CD8 alpha+ and CD8 alpha- murine dendritic cell subsets.

Dendritic cells (DCs) regulate the development of distinct Th populations and thereby provoke appropriate immune responses to various kinds of Ags. In the present work, we investigated the role CD40-CD154 interactions play during the process of Th cell priming by CD8 alpha(+) and CD8 alpha(-) murine DC subsets, which have been reported to differently regulate the Th response. Adoptive transfer of Ag-pulsed CD8 alpha(+) DCs induced a Th1 response and the production of IgG2a Abs, whereas transfer of CD8 alpha(-) DCs induced Th2 cells and IgE Abs in vivo. Induction of distinct Th populations by each DC subset was also confirmed in vitro. Although interruption of CD80/CD86-CD28 interactions inhibited Th cell priming by both DC subsets, disruption of CD40-CD154 interactions only inhibited the induction of the Th1 response by CD8 alpha(+) DCs in vivo. CD40-CD154 interactions were not required for the proliferation of Ag-specific naive Th cells stimulated by either DC subset, but were indispensable in the production of IL-12 from CD8 alpha(+) DCs and their induction of Th1 cells in vitro. Taken together, in our immunization model of Ag-pulsed DC transfer, CD40-CD154 interactions play an important role in the development of CD8 alpha(+) DC-driven Th1 responses but not CD8 alpha(-) DC-driven Th2 responses to protein Ags.

Animals↗
PubMed2004

Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice.

OBJECTIVE: Arterial injury results in vascular remodeling associated with proliferation and migration of smooth muscle cells (SMCs) and the development of intimal hyperplasia, which is a critical component of restenosis after angioplasty of human coronary arteries and an important feature of atherosclerotic lesions. However, the origin of SMCs and other cells in the development of vascular remodeling is not yet fully understood. METHODS AND RESULTS: We utilized a cuff-induced vascular injury model after transplantation of the bone marrow (BM) from green fluorescent protein (GFP)-transgenic mice. We found that macrophages were major cells recruited to the adventitia of the vascular injury lesion along with SMCs and endothelial cells (ECs). While investigating whether those cells are derived from the donor, we found that most of the macrophages were GFP-positive, and some of the SMCs and ECs were also GFP-positive. Administration of the anti-c-fms antibody resulted in a marked decrease in macrophages and a relative increase of SMCs, while administration of antibodies against the platelet-derived growth factor receptor-beta caused a prominent decrease in SMCs and a relative increase in macrophages. CONCLUSIONS: The current study indicates that BM-derived cells play an important role in vascular injury, and that differentiation of macrophages and SMCs might be dependent on each other.

Animals↗
PubMed2004

X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival.

X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID) is an X-linked recessive disease caused by a mutation in the nuclear factor-kappaB (NF-kappaB) essential modulator (NEMO). Here we report an XL-EDA-ID patient with atypical features of very few naive-phenotype T cells and defective mitogen-induced proliferation of peripheral blood mononuclear cells (PBMCs). The patient's NEMO defect was diagnosed by flow cytometric analysis of intracellular NEMO staining. Specific cell lineages (monocytes and neutrophils) expressed reduced levels of NEMO, but 2 populations of T, B, and NK cells were detected with normal and reduced expression of NEMO. Genomic analysis revealed that duplication of a 4.4-kb sequence ranging from intron 3 to exon 6 caused the reduced expression of NEMO. Polymorphism analysis showed that the patient's B- and T-cell lines with reduced and normal expression of NEMO had the same X chromosome, indicating that the somatic mosaicism was not due to fetomaternal transfusion but was most likely due to postzygotic reversion. This XLEDA-ID case adds to our understanding of NEMO biology, indicating that NEMO is critical for T-cell development and/or survival in humans as well as in mice.

Animals↗
PubMed2004

Stem cell plasticity in the hematopoietic system.

Bone marrow (BM) contains hematopoietic stem cells, which differentiate into all mature blood cells, and marrow stromal cells that provide the microenvironment for hematopoietic stem/progenitor cells along with the capability to differentiate into mature cells of multiple mesenchymal tissues including fat, bone, and cartilage. Recent studies indicate that adult BM also contains cells that can differentiate into nonhematopoietic cells of ectodermal, mesodermal, and endodermal tissues other than hematopoietic tissues, including liver, pancreas, kidney, lung, skin, gastrointestinal tract, heart, skeletal muscles, and neural tissues. Studies reporting the multipotentiality of BM cells have become a focus of interest because they suggest that clinical applications could be at hand using easily obtainable cells in the treatment of tissue damage or degenerative diseases. Presently, however, definitive evidence explaining the mechanism of this multipotentiality of BM stem cells is lacking. In this review, we summarize recent progress and controversies in investigation of the multipotentiality of adult BM-derived stem cells to differentiate into nonhematopoietic tissues.

Adult↗
PubMed2004

Development of primitive and definitive hematopoiesis from nonhuman primate embryonic stem cells in vitro.

Although information about the development of primitive and definitive hematopoiesis has been elucidated in murine embryos and embryonic stem (ES) cells, there have been few in vitro studies of these processes in primates. In this study, we investigated hematopoietic differentiation from cynomolgus monkey ES cells grown on OP9, a stromal cell line deficient in macrophage colony-stimulating factor. Primitive erythrocytes (EryP) and definitive erythrocytes (EryD) developed sequentially from ES cells in the culture system; this was confirmed by immunostaining and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of embryonic, fetal and adult globin genes. EryP were detected on day 8 without exogenous erythropoietin (EPO), whereas EryD appeared on day 16 and had an indispensable requirement for exogenous EPO. RT-PCR analysis of the cultures revealed a sequential expression of genes associated with primitive and definitive hematopoietic development that was equivalent to that seen during primate ontogeny in vivo. Vascular endothelial growth factor (VEGF) increased, in a dose-dependent manner, not only the number of floating hematopoietic cells, but also the number of adherent hematopoietic cell clusters containing CD34-positive immature progenitors. In colony assays, exogenous VEGF also had a dose-dependent stimulatory effect on the generation of primitive erythroid colonies. More efficient primitive and definitive erythropoiesis was induced by re-plating sorted CD34-positive cells. Thus, this system reproduces early hematopoietic development in vitro and can serve as a model for analyzing the mechanisms of hematopoietic development in primates.

Animals↗
PubMed2004

[Changes in food allergen sensitization rates of Japanese allergic children during the last 15 years].

In order to evaluate the changes in food allergen sensitization rates of allergic children, serum samples from 85 patients about 15 years ago (past group) and those from 90 current patients (present group) were randomly selected, and the specific IgE for six food allergens (wheat, peanuts, sesame, mackerel, ovomucoid, and kiwi) were measured with the CAP-RAST system. Sensitivity rates (class 2 or higher) for wheat and peanuts were significantly higher in the present than in the past group. Although there was no statistical difference in sensitivity rates (class 2 or higher) for kiwi between the groups, sensitivity rates (class 1 or higher) of the present group were significantly higher than those of the past group, indicating that the number of cases mildly sensitized to kiwi has been increasing. This trend was especially marked among children aged 6 or younger, and there was no statistical difference in sensitivity rates among those aged 7 or older. For the management of food allergy, special attention should therefore be paid not only to an increase in the number of patients, but also to changes in the kinds of causative foods.

Allergens↗
PubMed2004

[Changes in Japanese cedar sensitization rates of Japanese allergic children during the last 15 years].

In order to evaluate the changes in Japanese Cedar (JC) sensitization rates of allergic children, serum samples from 88 patients about 15 years ago (past group) and those from 91 current patients (present group) were randomly selected, and their JC specific IgE were measured with the CAP-RAST system. Sensitivity rate (class 2 or more) for JC of the present group was 65.9%, which was significantly higher than that of the past group, which was 46.6%. However, there was no significant difference between these two groups for children aged 6 or younger. For children aged 7 or older, the sensitivity rate of the present group was significantly higher than that of the past group. Thus, protection against JC sensitization, especially during early childhood, should be given serious attention.

Allergens↗
PubMed2003

Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body.

The transplantation of primitive human cells into sublethally irradiated immune-deficient mice is the well-established in vivo system for the investigation of human hematopoietic stem cell function. Although mast cells are the progeny of hematopoietic stem cells, human mast cell development in mice that underwent human hematopoietic stem cell transplantation has not been reported. Here we report on human mast cell development after xenotransplantation of human hematopoietic stem cells into nonobese diabetic severe combined immunodeficient (NOD/SCID)/gamma(c)(null) (NOG) mice with severe combined immunodeficiency and interleukin 2 (IL-2) receptor gamma-chain allelic mutation. Supported by the murine environment, human mast cell clusters developed in mouse dermis, but they required more time than other forms of human cell reconstitution. In lung and gastric tract, mucosal-type mast cells containing tryptase but lacking chymase located on gastric mucosa and in alveoli, whereas connective tissue-type mast cells containing both tryptase and chymase located on gastric submucosa and around major airways, as in the human body. Mast cell development was also observed in lymph nodes, spleen, and peritoneal cavity but not in the peripheral blood. Xenotransplantation of human hematopoietic stem cells into NOG mice can be expected to result in a highly effective model for the investigation of human mast cell development and function in vivo.

Animals↗
PubMed2003

Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice.

Severe congenital neutropenia (SCN) is a hematopoietic disorder characterized by neutropenia in peripheral blood and maturation arrest of neutrophil precursors in bone marrow. Patients with SCN may evolve to have myelodysplastic syndrome or acute myelocytic leukemia. In approximately 20% of SCN cases, a truncation mutation is found in the cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR). We then generated mice carrying murine wild-type G-CSFR and its mutants equivalent to truncations at amino acids 718 and 731 in human G-CSFR, those were reported to be related to leukemic transformation of SCN. Although numbers of peripheral white blood cells, red blood cells, and platelets did not differ among mutant and wild-type G-CSFR transgenic (Tg) mice, both of the mutant receptor Tg mice had one third of peripheral neutrophil cell counts compared with wild-type receptor Tg mice. The mutant receptor Tg mice also showed impaired resistance to the infection with Staphylococcus aureus. Moreover, bone marrow of these Tg mice had an increased percentage of immature myeloid cells, a feature of SCN. This maturation arrest was also observed in in vitro cultures of bone marrow cells of truncated G-CSFR Tg mice under G-CSF stimulation. In addition, clonal culture of bone marrow cells of the truncated G-CSFR Tg mice showed the hypersensitivity to G-CSF in myeloid progenitors. Our Tg mice may be useful in the analysis of the role of truncated G-CSFR in SCN pathobiology.

Acute Disease↗
PubMed2003

Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model.

Establishment of an assay capable of generating all classes of human lymphocytes from hematopoietic stem cells (HSCs) will provide new insight into the mechanism of human lymphopoiesis. We report ontogenic, functional, and histologic examination results of reconstituted human lymphocytes in NOD/SCID/ gammacnull mice after the transplantation of human cord blood (CB) CD34+ cells. After transplantation, human B, natural killer (NK), and T cells were invariably identified in these mice, even though no human tissues were cotransplanted. Immature B cells resided mainly in bone marrow (BM), whereas mature B cells with surface immunoglobulins were preferentially found in spleen. NK cells were identified in BM and spleen. T cells were observed in various lymphoid organs, but serial examinations after transplantation confirmed human T lymphopoiesis occurring in the thymus. These human lymphocytes were also functionally competent. Human immunoglobulin M (IgM), IgA, and IgG were detected in the sera of these mice. T cells showed a diverse repertoire of T-cell-receptor Vbeta (TCR Vbeta) chains, proliferated in response to phytohemagglutinin, and were cytotoxic against cell lines. NK activity was demonstrated using the K562 cell line. Immunohistochemical analysis revealed that human lymphocytes formed organized structures in spleen and thymus that were analogous to those seen in humans. In the thymus, CD4 and CD8 double-positive T cells were predominant and coexpressed CD1a and Ki-67, thereby supporting the notion that T lymphopoiesis was taking place. NOD/SCID/ gammacnull mice provide a unique model to investigate human lymphopoiesis without the cotransplantation of human tissues.

Animals↗
PubMed2003

Direct visualization of transplanted hematopoietic cell reconstitution in intact mouse organs indicates the presence of a niche.

OBJECTIVE: The temporal and spatial behavior of transplanted hematopoietic stem cells (HSCs) within bones remains to be clarified. Our goal is to examine in vivo reconstitution processes and candidate niches in all bones in the mouse body using a new visualization method. MATERIALS AND METHODS: Using bone marrow cells from green fluorescent protein (GFP) transgenic mice, the reconstitution processes of transplanted hematopoietic cells (HCs) under myeloablative or nonmyeloablative conditions were observed sequentially from outside the bones with a fluorescent stereomicroscope. RESULTS: In case of myeloablative transplantation, GFP(+) spots were first detected at the epiphysis of femurs, and in some ribs and vertebrae among all intact bones. Thereafter, engrafted cells proliferated and spread into other bones. In case of nonmyeloablative transplantation with lin(-)Sca-1(+)c-kit(+) cells into W/Wv neonates, characterized by vacant niches because of stem cell defects, GFP(+) cells localized at the epiphysis of femurs and in some vertebrae and ribs, but not in all bones even 4 months after transplantation. CONCLUSION: Our findings show that transplanted HSCs or their immature progenies engraft preferentially at the epiphysis of the femurs or short and flat bones such as ribs and vertebrae. The transplanted cells remain quiescent for at least 4 months under nonmyloablative conditions, which implies the presence of stem cells in a niche. Our approach for the first time graphically demonstrates the kinetics of HCs in vivo and should facilitate analysis of HSC behavior in a three-dimensional mode.

Animals↗
PubMed2002

NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells.

To establish a more appropriate animal recipient for xenotransplantation, NOD/SCID/gamma(c)(null) mice double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2Rgamma (IL-2Rgamma) allelic mutation (gamma(c)(null)) were generated by 8 backcross matings of C57BL/6J-gamma(c)(null) mice and NOD/Shi-scid mice. When human CD34+ cells from umbilical cord blood were transplanted into this strain, the engraftment rate in the peripheral circulation, spleen, and bone marrow were significantly higher than that in NOD/Shi-scid mice treated with anti-asialo GM1 antibody or in the beta2-microglobulin-deficient NOD/LtSz-scid (NOD/SCID/beta2m(null)) mice, which were as completely defective in NK cell activity as NOD/SCID/gamma(c)(null) mice. The same high engraftment rate of human mature cells was observed in ascites when peripheral blood mononuclear cells were intraperitoneally transferred. In addition to the high engraftment rate, multilineage cell differentiation was also observed. Further, even 1 x 10(2) CD34+ cells could grow and differentiate in this strain. These results suggest that NOD/SCID/gamma(c)(null) mice were superior animal recipients for xenotransplantation and were especially valuable for human stem cell assay. To elucidate the mechanisms involved in the superior engraftment rate in NOD/SCID/gamma(c)(null) mice, cytokine production of spleen cells stimulated with Listeria monocytogenes antigens was compared among these 3 strains of mice. The interferon-gamma production from dendritic cells from the NOD/SCID/gamma(c)(null) mouse spleen was significantly suppressed in comparison with findings in 2 other strains of mice. It is suggested that multiple immunological dysfunctions, including cytokine production capability, in addition to functional incompetence of T, B, and NK cells, may lead to the high engraftment levels of xenograft in NOD/SCID/gamma(c)(null) mice.

Animals↗
PubMed2002

Tool-use learning induces BDNF expression in a selective portion of monkey anterior parietal cortex.

Learning but not execution of tool-use induced expression of brain-derived neurotrophic factor (BDNF). The expression was highest in the anterior bank of the intraparietal sulcus, especially in the region posteriorly adjacent to the somatosensory shoulder and forearm region in area 3b, suggesting that BDNF plays a role in altering the body image of the hand to include the repeatedly used tool as its extension.

Animals↗
PubMed2002

Tool-use learning selectively induces expression of brain-derived neurotrophic factor, its receptor trkB, and neurotrophin 3 in the intraparietal multisensorycortex of monkeys.

When humans repeatedly use a tool, our body image alters until the tool finally becomes a part or an extension of the body. This alteration of body image perhaps results from re-integration of somatosensory and visual signals. We trained Japanese monkeys to use a rake-shaped tool to retrieve a distant food pellet, then used a novel tissue-sampling method to suction brain tissue from the anterior bank of their intraparietal sulcus, where somatosensory and visual signals converge. Examination of the messenger RNA expression levels of neurotrophins and their receptors using real-time quantitative polymerase chain reaction revealed learning-selective induction in the expression of brain-derived neurotrophic factor, its receptor trkB, and NT-3 during, but not after, the learning. These results suggest that these factors are involved in the reorganization of the somatosensory and visual signals in the anterior bank of the intraparietal sulcus when monkeys are learning the use of the tool.

Animals↗
PubMed2002

Maturational sequence of neuroblastoma revealed by molecular analysis on cDNA microarrays.

Neuroblastoma (NB), one of the most common solid tumors among children, is histologically classified by the degree of maturation. To elucidate the mechanisms underlying its maturational sequence, we analyzed gene-expression profiles of 14 NB tumors on cDNA microarrays consisting of 23,040 genes. Computational analysis identified 78 genes whose expression levels were significantly different between differentiating NB tumors and poorly differentiated NB tumors. This group included genes associated with cell maturation and apoptosis. Among them we identified 15 that were up-regulated in Stage IV NB tumors; these included genes encoding cell adhesion molecules and cytoskeleton proteins. The set of genes we report here should contribute to a better understanding of NB tumor maturation and could lead to development of new therapeutic strategies.

Apoptosis↗