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Biomedical subjects

S Suematsu

Publications and source records attributed to S Suematsu.

At least 19 recordsLinked to original sources
PubMed2001

Manual control in space--research on perceptual-motor functions under zero gravity condition.

Microgravity effects on human factor were studied through a series of manual control experiments conducted in the First Material Processing Test. The Japanese Payload Specialist operated a finger stick for 130 seconds to maintain a light spot movement around the center of a vertical LED array display. The stick angle is doubly integrated to make the controlled element motion. The light spot position indicates the difference between the motion and pseudo-random wave patterns which drives the man-machine tracking system. 24 runs were conducted in each of 2 months before launch, immediately pre-flight, and post-flight experiments. During the flight experiments, the PS felt pain in fast eye movement. He was obliged to fix his line of sight at the center of display and to watch the displayed error movement using peripheral view. He also felt difficulty in supporting his body against reaction force of his hand movement. During a few days after landing, disturbance was observed in the PS's posture. The operator describing function analysis revealed the disappearance of the "regression" phenomenon and increment of the effective time delay. As the result, the flight describing function showed better fit to the simplified model of lead with pure time delay.

Adaptation, Physiological↗
PubMed2000

Activation of self-reactive B cells and autoimmune diseases.

The development of antigen-specific cells of the immune system, the T and B lymphocytes, creates a dilemma. On the one hand, survival of the organism depends upon the generation of a nearly limitless repertoire of potential antigen-binding specificities so that cells able to respond to pathogens are present prior to contact. However, by devising genetic strategies to maximize receptor diversity, the generation of T and B cells with autoreactive receptors is inevitable. B cells have an even greater opportunity than T cells to become autoreactive, since they may randomly alter the amino acid sequence and hence the specificity of their receptors during an immune response. Observing the system, one might wonder not why autoimmune diseases occasionally develop, but rather why they are not more frequent or even unavoidable. In this review, we examine the generation of B cells and their repertoire of antigen receptors, describe mechanisms that have evolved to prevent self-reactive B cells from causing autoimmune diseases, and discuss scenarios that may lead to a breakdown of self tolerance.

Animals↗
PubMed1999

Response in Patients with Chronic HCV Hepatitis to Treatment with Interferon-alpha.

Twelve patients with chronic hepatitis C received interferon-alpha at doses of 3 million units (11 patients) or 6 millions units (1 patient) 3 times per week for 52 weeks. The patients were evaluated for clinical response, and total blood cell count, B and T lymphocyte count, subtyping of CD4+ and CDS+ lymphocytes, blastic transformation of lymphocytes after stimulation with phytohemagglutinin and concanavalin-A, and liver function tests. Liver biopsies with immunohistochemical methods were done before and after treatment in 7 patients. Blood tests were done every 4 weeks in all 12 patients. Serum beta-2-microglobulin was measured before treatment and after 32 and 52 weeks. Patients with liver disease due to other causes (autoimmune disease and HIV infection) were excluded. The following results were obtained: 1) Four patients improved with treatment (4/12 = 33%) during the 52 week treatment period; 3 of them responding completely and one partially. Two others who were not considered responders maintained ALT levels below 1.5x the normal range after the end of therapy. One of these had received the higher dose of interferon-alpha. Histopathologically, 10 patients improved (10/12 = 83%), one presented progression of the disease and one did not show significant changes with treatment; 2) Immunological evaluation before and after treatment did not show significant differences except for total blood lymphocyte count, which was decreased after treatment; 3) T and CD4+ lymphocyte counts in liver tissue were significantly decreased after treatment, but there was no change in the pattern of their distribution within the hepatic parenchyma. These findings confirm that interferon-alpha is effective in patients with hepatitis C, and suggest that the drug has a predominantly antiviral effect in chronic hepatitis caused by C virus, and that the hepatocellular damage observed in these cases is mainly due to the cytopathic effect of the virus rather than immunopathologic processes.

Journal Article↗
PubMed1998

Transgenic expression of Fas in T cells blocks lymphoproliferation but not autoimmune disease in MRL-lpr mice.

Fas is a member of the TNF receptor family. Binding of Fas ligand to Fas induces apoptosis in Fas-bearing cells. Fas is expressed in various cells, including thymocytes, peripheral T cells, and activated B cells. The mouse lpr mutation is a loss of function mutation of Fas. MRL-lpr/lpr mice develop lymphadenopathy and splenomegaly, and produce multiple autoantibodies, which results in autoimmune disease. In this report, we describe the establishment of a line of Fas transgenic MRL-lpr mice in which mouse Fas cDNA was expressed using the T cell-specific murine lck promoter. The transgenic mice expressed functional Fas in thymocytes and peripheral T cells, but not in B cells. The transgenic mice did not accumulate abnormal T cells (Thy-1+ B220+), but still accumulated B cells (Thy-1- B220+); they produced a large quantity of Igs (IgG1 and IgG2a), including anti-DNA Abs, and developed glomerulonephritis. These results suggest that autoreactive or activated B cells must be killed through Fas expressed in the B cells by the Fas ligand expressed in activated T cells.

Animals↗
PubMed1997

Interleukin-6 overexpression cannot generate serious disorders in severe combined immunodeficiency mice.

C57BL/6 human interleukin-6 (IL-6) transgenic mice develop mesangial proliferative glomerulonephritis with massive IgG1 plasmacytosis and die of renal failure in early life. To test whether the IL-6 overexpression could cause development of mesangial proliferative glomerulonephritis without plasmacytosis or promote proliferation of immature B cells that have not undergone immunoglobulin gene rearrangement, the IL-6 transgene was introduced into mice with severe combined immunodeficiency (SCID). In the immunocompetent littermate IL-6 transgenic mice, there were various symptoms such as plasmacytosis, nephropathy, anemia, and thrombocytosis, accompanied by marked increases in serum IL-6 levels as they aged. All these mice died by 25 weeks of age. In contrast, the SCID-IL-6 transgenic mice had no such abnormalities, except certain hematological changes, although the transgene was expressed in various tissues. In these mice, the serum IL-6 levels were 10- to 15-fold higher than those in the nontransgenic mice, and they remained constant throughout their lives. Furthermore, there were no signs of lymphoid development. This study demonstrates that deregulation of IL-6 expression does not stimulate cell growth or differentiation of immature B cells, and thus does not result in plasmacytosis and age-related increases in IL-6 production, and also does not generate mesangial proliferative glomerulonephritis.

Animals↗
PubMed1997

Possible involvement of calcium/calmodulin-dependent protein kinase in ACTH-induced expression of the steroidogenic acute regulatory (StAR) protein in bovine adrenal fasciculata cells.

Steroidogenic acute regulatory (StAR) protein plays a crucial role in the regulation of cholesterol transport from the outer mitochondrial membrane to the inner membrane, where P450scc participates in a rate-limiting step of adrenal steroidogenesis. We have already reported that both of cAMP- and protein kinase C-dependent processes may play a crucial role in the regulation of expression of StAR protein when bovine fasciculata cells are stimulated with ACTH. In the present study, ACTH increased cytosolic calcium movement and activated expression of StAR protein, resulting in enhancing cortisol production by bovine adrenal fasciculata cells. The role of the calcium/calmodulin-dependent protein kinase process in the regulation of expression of the StAR protein by ACTH was studied. The activating effects of ACTH on the StAR protein and cortisol production were inhibited by pretreatment with KN-93, a specific inhibitor of calcium/calmodulin-dependent protein kinase II. These findings suggest that ACTH can enhance expression of the StAR protein as well as cortisol synthesis in bovine adrenal fasciculata cells, in part via a calcium/calmodulin-dependent protein kinase process.

Adrenocorticotropic Hormone↗
PubMed1996

Regulation of expression of the steroidogenic acute regulatory (StAR) protein by ACTH in bovine adrenal fasciculata cells.

Immunocytochemical studies and immunoblotting analysis demonstrated that there exists the StAR protein in bovine adrenal fasciculata cells, and ACTH activated expression of the StAR protein. Then roles of intracellular signal transduction systems in the regulation of expression of the StAR protein were studied. The addition of Bt2cAMP and forskolin, or phorbol ester plus calcium ionophore 23187 activated expression of the StAR protein as well as cortisol production, suggesting that cyclic AMP- or protein kinase C-dependent process plays a crucial role in the regulation of expression of the StAR protein. Activating effects of ACTH which activates cyclic AMP formation on the StAR protein and cortisol production were inhibited by pretreatment with calphostin C which is a protein kinase C inhibitor, suggesting that ACTH enhances expression of the StAR protein possibly via both of two signal transduction systems such as cyclic AMP- and protein kinase C-dependent processes.

Adrenocorticotropic Hormone↗
PubMed1996

Enhanced and accelerated lymphoproliferation in Fas-null mice.

Fas is a 45-kDa membrane protein that transduces an apoptotic signal. The mouse lymphoproliferation (lpr) mutation is a leaky mutation of Fas. In this study, we examined lymphocyte development in Fas-null mice generated by gene targeting. The Fas-/- mice progressively accumulated abnormal T cells (Thy1+, B220+, CD4-, and CD8-) and developed lymphadenopathy and splenomegaly, which were much more accelerated and pronounced than those in lpr mice. In addition, the Fas-null mice showed lymphocytosis, accompanied by lymphocytic infiltration in the lungs and liver. The number of apparently normal B cells also increased, and large amounts of immunoglobulins, including anti-DNA antibodies, were produced. Thymic clonal deletion, assessed by deletion of T cells reactive to mouse endogenous superantigens, was apparently normal in the Fas-/- mice, whereas the peripheral clonal deletion of mature T cells against a bacterial superantigen was impaired. These results suggested that Fas plays a decisive role in peripheral clonal deletion but not in negative selection in the thymus.

Animals↗
PubMed1996

Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders.

gp130 is a ubiquitously expressed signal-transducing receptor component shared by interleukin 6, interleukin 11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1. To investigate physiological roles of gp130 and to examine pathological consequences of a lack of gp130, mice deficient for gp130 have been prepared. Embryos homozygous for the gp130 mutation progressively die between 12.5 days postcoitum and term. On 16.5 days postcoitum and later, they show hypoplastic ventricular myocardium without septal and trabecular defect. The subcellular ultrastructures in gp130-/- cardiomyocytes appear normal. The mutant embryos have greatly reduced numbers of pluripotential and committed hematopoietic progenitors in the liver and differentiated lineages such as T cells in the thymus. Some gp130-/- embryos show anemia due to impaired development of erythroid lineage cells. These results indicate that gp130 plays a crucial role in myocardial development and hematopoiesis during embryogenesis.

Animals↗
PubMed1995

Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages.

To investigate the role of NF-IL6 in vivo, we have generated NF-IL6 (-/-) mice by gene targeting. NF-IL6 (-/-) mice were highly susceptible to infection by Listeria monocytogenes. Electron microscopic observation revealed the escape of a larger number of pathogens from the phagosome to the cytoplasm in activated macrophages from NF-IL6 (-/-) mice. Furthermore, the tumor cytotoxicity of macrophages from NF-IL6 (-/-) mice was severely impaired. However, cytokines involved in macrophage activation, such as TNF and IFN gamma, were induced normally in NF-IL6 (-/-) mice. Nitric oxide (NO) formation was induced to a similar extent in macrophages from both wild-type and NF-IL6 (-/-) mice. These results demonstrate the crucial role of NF-IL6 in macrophage bactericidal and tumoricidal activities as well as the existence of a NO-independent mechanism of these activities. We also demonstrate that NF-IL6 is essential for the induction of G-CSF in macrophages and fibroblasts.

Animals↗
PubMed1995

An interleukin-6 transgene expressed in B lymphocyte lineage cells overcomes the T cell-dependent establishment of normal levels of switched immunoglobulin isotypes.

Long-term proliferating, stromal cell/interleukin (IL)-7-reactive precursor B cell lines established from fetal liver and bone marrow of human IL-6-transgenic B6Ld46 mice produce and secrete human IL-6. When transplanted into severe-combined immunodeficient (SCID) or Rag2 knockout (Rag2-T) mice, these pre-B-cell lines establish a part of the B cell compartment but yield no T cells, as do pre-B cell lines from genetically matched non-transgenic mice. Within 2 to 3 months after transplantation, the serum of mice transplanted with pre-B cells from normal mice contains normal levels of IgM (200-600 micrograms/ml) but 10-100-fold lower levels of the IgG subclasses and of IgA. In contrast, the sera of mice transplanted with IL-6 transgenic pre-B cells contain not only IgM, but also IgG and IgA at nearly normal levels. The results indicate that at least a part of the plasmacytosis and elevated IgG production observed previously in the IL-6-transgenic mice appears to be due to a T cell-independent activation of IgG and IgA production by the IL-6-secreting pre-B cells and their differentiated progeny in the immunodeficient hosts.

Animals↗
PubMed1995

Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver.

Fas, a type I membrane protein that transduces an apoptotic signal, is expressed in lymphocytes as well as in various tissues such as the liver, lung and heart. The mouse lymphoproliferation (lpr) mutation is a leaky mutation in Fas. By means of gene targeting, we generated a mouse strain which is completely deficient in Fas. In addition to the massive production of lymphocytes, the Fas-null mice showed substantial liver hyperplasia, which was accompanied by the enlargement of nuclei in hepatocytes. The Fas system seems to play a role in the apoptotic process to maintain homeostasis of the liver as well as the peripheral lymphoid organs.

Animals↗
PubMed1994

The absence of IgE antibody-mediated augmentation of immune responses in CD23-deficient mice.

The CD23 antigen, a low-affinity receptor for IgE (Fc epsilon RII), is a type II membrane-bound glycoprotein expressed on various cells, particularly mature B cells. A number of functions have been ascribed to CD23, including specific regulation of IgE production, IgE-mediated cytotoxicity and release of mediators, IgE-dependent antigen focusing, promotion of B-cell growth, prevention of germinal center B cells from apoptosis, proliferation of myeloid precursors, and maturation of early thymocytes. It is not clear whether these activities represent in vivo functions. To explore in vivo functions of CD23, we have produced CD23-deficient mice. These mice displayed normal lymphocyte differentiation and could mount normal antibody responses, including IgE responses upon immunization with T-dependent antigens and infection with Nippostrongyrus brasiliensis. Germinal center formation after immunization and in vitro proliferative response of B cells were not affected in mutant mice. However, antigen-specific IgE-mediated enhancement of antibody responses was severely impaired.

Animals↗
PubMed1994

The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation.

An engagement of CD40 with CD40 ligand (CD40L) expressed on activated T cells is known to provide an essential costimulatory signal to B cells in vitro. To investigate the role of CD40 in in vivo immune responses, CD40-deficient mice were generated by gene targeting. The significant reduction of CD23 expression on mature B cells and relatively decreased number of IgM bright and IgD dull B cells were observed in the mutant mice. The mutant mice mounted IgM responses but no IgG, IgA, and IgE responses to thymus-dependent (TD) antigens. However, IgG as well as IgM responses to thymus-independent (TI) antigens were normal. Furthermore, the germinal center formation was defective in the mutant mice. These results suggest that CD40 is essential for T cell-dependent immunoglobulin class switching and germinal center formation, but not for in vivo T cell-dependent IgM responses and T cell-independent antibody responses.

Animals↗
PubMed1992

Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice.

The mechanisms through which pristane or mineral oil can induce plasmacytomas in BALB/c or NZB mice are not fully understood, but involvement of interleukin 6 (IL-6), a growth factor for plasmacytomas and myelomas, has been strongly suggested. To clarify the role of IL-6 in plasmacytomagenesis, a human IL-6 cDNA was introduced into mouse germ lines under the transcriptional control of the murine major histocompatibility complex class I (H-2Ld) promoter. IL-6 transgenic mice of C57BL/6 origin developed a massive plasmacytosis but not plasmacytomas. However, introduction of BALB/c genetic background into IL-6 transgenic mice could generate monoclonal transplantable plasmacytomas with the chromosomal translocation t(12;15). These results provide firm evidence of the critical role of IL-6 in the plasmacytoma development.

Animals↗