Biomedical subjects

M Utsuyama

Publications and source records attributed to M Utsuyama.

At least 19 recordsLinked to original sources

PubMed2002

Animal models and possible human application of immunological restoration in the elderly.

Autopsy reports by pathologists in geriatric hospitals reveal that the leading direct cause of death in the elderly over 65 years of age are infectious diseases such as pneumonia and urinary tract infection, neither cancer nor vascular diseases in the brain and heart. This indicates that severe impairment of immune functions is developing in the elderly people. The impairment of immune functions does not occur abruptly in the elderly people. The immune function starts to decline as early as at the 2nd decades, showing approximately 50 and 90% decline at the 5th and 8th decades, respectively. Thus, immunological restoration is acutely needed for the improvement of their general health condition of the elderly. This report communicates several methods of immunological restoration using animal models and suggests possibilities of human application. Methods presented are: (1) a low dose of cyclophosphamide; (2) vitamin E; (3) Japanese herbal medicines; (4) caloric restriction and exercise; (5) vaccine; (6) oral administration of antigens; (7) grafting of cells and tissues, including a future program. Discussion will be made on the possibilities of these methods for human application.

Aged↗

PubMed2001

Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia.

Susceptibility for Friend leukemia virus (FLV)-induced leukemogenesis was examined in the C3H/He (C3H)-->C57BL/6 (B6) radiation bone marrow chimeras of various age groups, and the effect of aging of host mice on the susceptibility was determined. The bone marrow chimera system provided the various age of FLV-resistant host mice (B6) possessing the same age of FLV-susceptible target cells from C3H mice. Using this system, we could determine the aging effect on the host resistancy against FLV without an influence of the aging effect on target cells. First, the young C3H-->young B6 chimeras and young C3H-->old B6 chimeras were compared. The young-->old chimeras were more susceptible to FLV-induced acute disease than the young-->young chimeras. The spleen CD4+ as well as CD8+ T cells were reduced in young-->old chimeras compared with young-->young chimeras. Similarly, the old C3H-->old B6 chimeras were more susceptible than old-->young chimeras and revealed the lower CD4+ T cell ratio in the spleen. Discussion was made on the possible implication of these findings on the role of T cells in age-related change of resistance to FLV-induced leukemogenesis.

Aging↗

PubMed2001

Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice.

We examined the effect of two Japanese herbal medicines (Kampo-Hozai) on immunological functions and anti-tumor activity in old mice. Hochu-ekki-to (TJ-41) was remarkably effective in the restoration of impaired immune functions of old mice, in terms of number of T cells and NK cells, and anti-SRBC antibody response, while it was not effective in enhancing immune functions of young mice. Juzen-taiho-to was also effective in increasing the number of T cells, remarkably, and NK cells, slightly, in the aged mice. While a significant increase was not observed in young mice. NK activity increased both in young and old mice with the treatment of TJ-48. A significant decrease was observed in metastatic pulmonary colonies of B16 melanoma cells both in young and old mice treated with Juzen-taiho-to for 16 weeks. These results suggested that some of Japanese herbal medicines were useful in restoration of impaired immune functions of old mice and could be recommended for human elderly.

Administration, Oral↗

PubMed2001

Immunohistological analysis of thymoma by molecules differentially expressed in the thymic cortex and medulla, and its application in the differential diagnosis of thymoma from esophageal and lung cancer.

The purpose of this study was to verify the WHO classification of thymic tumors using immunohistological methods, and to discover whether these methods can be applied to differentiate thymoma from squamous cell carcinoma (SCC) of the esophagus and the lung. Twenty-nine thymoma cases were classified according to WHO and were then immunohistologically examined for the positivity of these molecules. All thymoma cases investigated in this study were positive for IL-1R, and most of them were also positive for bek. In contrast, UH-1 was highly positive in B1 and B2 type thymomas, but negative or weakly positive in A, AB and B3 type thymomas. Twelve esophageal cancers and 21 lung cancers were also examined for the positivity of the same molecules. All esophageal cancers were negative for UH-1. Three of 12 cases were weakly positive for IL-1R, and four of these 12 cases were also weakly positive for bek. Twelve of 21 lung cancer cases were adenocarcinomas, all of them negative for IL-1R, bek and UH-1. Nine of 21 lung cancer cases were SCCs, all of them negative for UH-1. Eight of nine SCC cases were strongly positive for IL-1R, while seven of these were weakly positive for bek. We conclude that the WHO classification of thymic tumors is still valid as demonstrated by immunohistological analysis and that the positivity of UH-1, IL- 1R and bek might be helpful in differentiating thymoma from SCC of the esophagus and the lung.

Adenocarcinoma↗

PubMed2001

Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus.

The receptor activator of nuclear factor (NF)-kappaB ligand [RANKL; also known as tumor necrosis factor-related activation-induced cytokine, osteoprotegerin ligand, and osteoclast differentiation factor] is known to bind with the receptor activator of NF-kappaB (RANK) and act not only as a key factor for osteoclastogenesis but also as a regulator of lymphocyte development. In this study, we found two additional isoforms of RANKL. RANKL 2 has a shorter intracellular domain than the original RANKL (RANKL 1), and RANKL 3 lacks a transmembrane domain and was thought to act as a soluble form. In the bone marrow stromal cell line ST2 and preosteoblastic cell line MC3T3-E1, all three RANKL isoforms were detected, but the expression of RANKL 2 was preferentially suppressed by treatment with 1alpha,25-dihydroxyvitamin D(3) and dexamethasone. In young adult thymus, CD4(-)CD8(-) double-negative cells were positive for all three isoforms, CD4(+)CD8(+) double-positive cells were positive for RANKL 1 and RANKL 3 but negative for RANKL 2, and CD4(+)CD8(-) and CD4(-)CD8(+) single-positive cells were positive for all three isoforms. Immunofluorescence analyses of NIH3T3 cells transfected with each RANKL isoform indicated that the three RANKL isoforms were translated, and RANKL 2 protein predominantly stayed in the endoplasmic reticulum and Golgi networks. These results indicate that there are three kinds of RANKL-RANK pathways. The presence of multiple RANKL-RANK pathways suggests a more complicated RANKL-RANK system for osteoclastogenesis or T cell differentiation than previously thought.

Amino Acid Sequence↗

PubMed2001

Expression profiles of receptor activator of nuclear factor kappaB ligand, receptor activator of nuclear factor kappaB, and osteoprotegerin messenger RNA in aged and ovariectomized rat bones.

The receptor activator of nuclear factor-kappaB ligand (RANKL; also known as tumor necrosis factor-related activation-induced cytokine [TRANCE], osteoprotegerin ligand [OPGL], and osteoclast differentiation factor [ODF]) is a transmembrane ligand expressed in osteoblasts and bone marrow stromal cells. It binds to RANK, which is expressed in osteoclast progenitor cells, and induces osteoclastogenesis. OPG, a decoy receptor for RANKL, also binds to RANKL, and competitive binding of RANKL with RANK or OPG is thought to regulate bone metabolism. To investigate roles of the RANKL/RANK/OPG system in pathophysiological conditions, the expression of RANKL, RANK, and OPG messenger RNA (mRNA) was analyzed in bones of aged and ovariectomized rats by means of in situ hybridization. In the control 8-week-old male and sham-operated female rat bones, the expression of RANKL mRNA was detected in hypertrophic chondrocytes of the growth plate and some periosteal and endosteal mesenchymal cells. The expression of RANK mRNA was detected in osteoclast-like cells and mononuclear cells in contact with the cortical and trabecular bones. The expression of OPG mRNA was detected in proliferating chondrocytes and osteocytes. In the 2.5-year-old rat bones, the expression of RANKL, RANK, and OPG mRNA tended to decrease except for the endosteal region. In the ovariectomized rat bones, the expression of RANKL, RANK, and OPG mRNA increased, and high expression of OPG mRNA was induced in resting chondrocytes and osteocytes. These results suggest that estrogen deficiency stimulates the RANKL/RANK/OPG system and induces OPG in cells that have been thought to be less important for bone metabolism.

Aging↗

PubMed2001

Hypothalamic control of thymic function.

Removal of the pituitary gland results in atrophy of the thymus. As the former is under the control of hypothalamus, destruction of anterior portion of the hypothalamus (AHTL) would be expected to negatively influence the thymic function. Contrary to our expectation, however, the thymus became hypertrophic and serum level of growth hormone (GH) markedly increased, when the anterior portion of the hypothalamus was destroyed in rats at 1 month of age and older. The results suggested that AHTL removed the cells secreting GHRIH (growth hormone release inhibitory hormone), but not GHRH (growth hormone releasing hormone), leading to increased pituitary secretion of GH. This high serum level of GH appeared to be responsible for the thymic hyperplasia occurring after AHTL. In other words, the development and aging of the thymus appear to be dependent on the serum level of GH which is under the balance of positive (GHRH) and negative (GHRIH) signals from the hypothalamus. In rats and mice, the serum level of GH is very high just after birth, quickly declines in young adults and does not change greatly thereafter. Thus, it is likely that the initial positive signal is high just after birth and decreasing thereafter with a concomitant increase of negative signal, leading to the onset ofthymic atrophy at around puberty, in association with sex steroid release.

Adrenal Glands↗

PubMed2000

Molecular mechanism of the impairment in activation signal transduction in CD4(+) T cells from old mice.

It is well known that IL-2 production of CD4(+) T cells from old mice (old T cells) is impaired. In this study, we have examined TCR complex zeta chain expression of old T cells and their TCR downstream signal transduction pathways stimulated with anti-CD3. Activation of protein tyrosine kinases, Fyn and ZAP-70, and turnover of inositol phosphates stimulated with anti-CD3 were severely impaired in old T cells, although levels of these proteins were comparable to those in young T cells. Increase in intracellular Ca2+ concentration in old T cells was also impaired. Old T cells starting the Ca(2+) oscillation by the anti-CD3 stimulation were severely decreased in number and the oscillation waves were broader in shape. T cells with zeta-FcvarepsilonRgamma heterodimer in the TCR-CD3 complex were increased in proportion in old T cells with a concomitant decrease in the T cells with zeta-zeta homodimer. The density of the TCR-CD3 complex on old T cells was confirmed to be comparable to that on young T cells. The impairment in TCR downstream signal transduction pathways and the increase in zeta-FcvarepsilonRgamma heterodimer in the TCR-CD3 complex were confirmed to be the situation in Th1 clones established from old mice. These results indicate that old T cells are impaired in response to TCR stimulation, because T cells with the TCR-CD3 complex containing the zeta-FcvarepsilonRgamma heterodimer are increased in proportion in old T cells.

Aging↗

PubMed2000

Measurement of anti-thyroglobulin and anti-thyroid peroxidase antibodies using highly sensitive radioimmunoassay: an effective method for detecting asymptomatic focal lymphocytic thyroiditis in the elderly.

Subclinical thyroiditis or thyroid dysfunction is relatively common in the elderly. To estimate the effectiveness of measurement of serum levels of anti-thyroglobulin and anti-microsomal or thyroid peroxidase antibodies for detecting focal lymphocytic thyroiditis (FLT) in the elderly, we examined the relationships between antibody titer and postmortem histological finding of the thyroid gland in 180 consecutive autopsies (69 women and 111 men) over 60 years of age without any overt clinical thyroid or collagen diseases. FLT was found in 25 cases (13.9%) with female predominance (21.7% in female vs. 9.0% in male). Measurements of serum levels of anti-thyroglobulin and anti-thyroid peroxidase antibodies by radioimmunoassay (TgAb and TPOAb, respectively) were compared with the measurements of anti-thyroglobulin and anti-microsomal antibodies by a hemagglutination technique (TGHA and MCHA, respectively), using sera from 25 patients with FLT and age- and sex-matched 51 patients without FLT. Among 25 cases with FLT, TgAb and TPOAb were positive in 17 (68%) and 12 (48%), respectively. There was a close relationship between degree of FLT and serum level of TgAb or TPOAb (P<0.0001). On the other hand, TGHA and MCHA were positive only in 8 (32%) and 10 (40%), respectively. TgAb and TPOAb were more sensitive than TGHA (68% vs. 32%, P<0.05) and MCHA (48% vs. 40%) to detect FLT. Positive findings in either TgAb or TPOAb significantly improved sensitivity (76%) compared with that of TGHA or MCHA (44%) (P<0.05). Specificities of combined measurements of TgAb and TPOAb (90%) were not significantly different from those of TGHA and MCHA (100%). These findings indicate that TgAb is a more sensitive method for detecting FLT and that its diagnostic sensitivity for FLT increases by using it in combination with TPOAb. Therefore, in the elderly without clinically or biochemically overt thyroid dysfunction, positive TgAb and/or TPOAb could imply presence of FLT, and their titers might reflect degree of inflammation.

Aged↗

PubMed2000

[Interrelationship between disease activity and nutrient intake or serum cytokine in patients with rheumatoid arthritis].

OBJECTIVE: This study was designed to investigate the possibility of nutrition guidance for patients with rheumatoid arthritis (RA). We studied interrelationship between disease activity and nutrient intake or serum cytokine concentration in patients with RA. METHODS: Dietary survey was performed to assess nutrient intake of RA patients. Disease activity parameters, such as weariness index, arthritically index and QOL index were evaluated by self-questionnaire. CRP and serum cytokine concentrations were measured. Interactions between these parameters and nutrient intake were analyzed. RESULTS: In comparison of nutrient intake between patients with RA and healthy controls, RA patients indicated lower ratio of polyunsaturated to saturated fatty acid (P/S) than controls. Preceding with the analysis between disease activity parameter and nutrient intake, RA patients were divided into two groups according to their activities. High weariness group indicated higher lipid intake and energy supplies from fat than low group, suggesting the relationship between disease activity and lipid intake in RA patients. From the comparative study of serum cytokine concentration between patients with RA and healthy controls, RA patients indicated higher concentration of IL-1 beta, IL-6 and IL-8. Serum concentrations of these proinflammatory cytokines correlated significantly with some nutrient intakes. CONCLUSION: These results imply the relationship between nutrient intake and disease activity in patients with RA. It is important to develop nutrition guidance to improve symptoms for patients with RA.

Arthritis, Rheumatoid↗

PubMed1999

Immunological enhancement with a low dose of cyclophosphamide in aged mice.

Aged mice treated with a low dose of cyclophosphamide (CY) showed significantly enhanced immune capacity in cellular proliferation and antibody response. In these mice, total cell numbers were increased both in the thymus and spleen, compared to those in non-treated mice. Treatment with a low dose of CY induced apoptosis of thymocytes in the atrophic thymus of the aged mice, being followed by an increase of proliferation of thymocytes and leading to an increase of thymocytes and splenic T cells. Treatment with a high dose of CY also induced apoptosis in the thymus, but suppressed the proliferative capacity, therefore not leading to an enhancement of immune capacity. In young mice, however, CY suppressed immune capacity regardless of the dose. Thymocytes and splenic T cells of young mice were more susceptible to CY than those of old mice and were decreased in number after the treatment with even a low dose of CY.

Aging↗

PubMed1999

Differential age effect of oral administration of an antigen on antibody response: an induction of tolerance in young mice but enhancement of immune response in old mice.

Sheep red blood cells (SRBC) were orally administered to young (4 months old) and old (22 months old) mice, and its effect on the antibody production after systemic immunization was compared between young and old mice. The results showed that the dose-dependent suppression of antibody response (oral tolerance) was observed in young mice which had been previously treated with oral administration of SRBC. On the contrary, the enhancement of antibody production was observed in old mice which had been treated in the same way. The enhanced level of IgG antibody in old mice was higher than that of young mice. The critical age determining either suppression or enhancement of antibody response after the oral administration of the antigen was present between 6.5 and 10.5 months of age. When the oral administration of the antigen was performed in young (3 months old) and middle-aged mice (12 months old), the oral tolerance for young and the enhanced antibody response for middle-aged mice were observed even at 6 months after the treatment. The analysis by in vitro antibody response using T and B cells prepared from young and old mice showed that age-related alteration of T and B cells is responsible for the suppression and the enhancement of antibody response after oral administration of SRBC, respectively.

Administration, Oral↗

PubMed1999

Age-related alteration of cytokine production profile by T cell subsets in mice: a flow cytometric study.

Spleen cells from young and old C57BL/6 mice were stimulated with a combination of anti-CD3 and anti-CD28 antibodies, and the profile of cytokine production was examined by two different methods; the concentrations of cytokines as measured by ELISA, and identification of cytokine-positive cells by flow cytometry. The ELISA method revealed that IL-2 production by spleen cells after stimulation was significantly lower in the old mice compared to the young mice. while IFN-gamma production was the reverse. The flow cytometric analysis showed that the percentage of IL-2 positive cells in spleen cells after the stimulation was significantly lower in the older mice than in the young mice, and vice versa for the percentage of IFN-gamma-positive cells. Regarding the T cell subsets, CD4+ T cells were a major source of IL-2 in both the young and old mice. IL-2-positive cells in both CD4+ and CD8+ T cells showed a significant decrease with age. On the contrary, CDX T cells were the major source of IFN-gamma. An age-related increase of IFN-gamma positive cells was observed in both CD4+ and CD8+ T cells. CD4 T cells were the major source of IL-4, and the percentage of IL-4-positive CD4+ T cells also increased with age, although the level of IL-4 production was modest in C57BL/6 mice compared with IL-2 and IFN-gamma. Such age-related changes of cytokine production are presumed to play an important role in the alteration of immunological capacity with age.

Aging↗

PubMed1999

Vitamin E enhances the immune functions of young but not old mice under restraint stress.

Young and old C57BL/6 male mice were given a diet containing a high dose of vitamin E (VE treatment) and its effect on the immune system was examined before and after the exposure to restraint stress. The VE treatment per se gave rise to a slight increase of splenic T cells in percentage and a significant enhancement of Con A response of spleen cells in young, but not in old mice. The VE treatment also resulted in the enhancement of production of IL-2 and IFNgamma in young, but not in old mice. Restraint stress led to thymic involution in both young and old mice. This thymic involution was not ameliorated by the VE treatment. Percentage of splenic T cells and their mitogenic response decreased just after the stress, but soon rebounded over the control level. The VE treatment further enhanced the recovery after the stress in young mice, but on the contrary suppressed the recovery in old mice. The results in the present study suggested that the VE treatment was effective in the prevention of immunological decline of young mice before and after the exposure to the stress. On the other hand, such a preventive effect was not observed in old mice that were already in the depressed state of immunological functions.

Aging↗

PubMed1998

Hypothalamic control of development and aging of the thymus.

Removal of pituitary gland results in atrophy of the thymus. As the pituitary gland is under the control of the hypothalamus, destruction of the anterior portion of the hypothalamus (AHTL) is expected to negatively influence the thymic function. Contrary to our expectation, the thymus became hypertrophic and the serum level of the growth hormone (GH) markedly increased, when the anterior portion of the hypothalamus was widely destroyed in rats at 1 month and over. The results suggested that AHTL removed the cells secreting GHRIH (growth hormone release inhibitory hormone), but not GHRH (growth hormone releasing hormone), leading to increased secretion of GH from pituitary gland and thymic hyperplasia. In other words, the development and aging of thymus appears to be under the balance of the positive (GHRH) and negative (GHRIH) signals of the hypothalamus. It is most likely that the positive signal is high just after the birth and decreases thereafter with a concomitant increase of the negative signal, leading to the onset of thymic atrophy at around puberty.

Aging↗

PubMed1997

Effect of restraint stress on immune system and experimental B16 melanoma metastasis in aged mice.

An overnight restraint stress was given to young and old mice and its effect was examined in terms of the number and function of T cells and natural killer (NK) cells in spleen and patterns of lung metastasis of B16 melanoma cells. A great decrease was observed in the number and proliferative activity of splenic T cells in old mice after the stress. The decrease in young mice was rather temporary with a quick recovery. The number of NK cells in spleen was not different between young and old mice before giving the stress, but a significant decrease was observed in the old after the stress. NK activity was always much lower in old than in young throughout the experiment. The pattern of metastasis of B16 melanoma cells was different between young and old mice. Metastatic colonies in lungs were larger in number and bigger in size in young mice than in old mice. After the stress, the number increased and the size unchanged in old mice, while the size increased and the number remained unchanged in young mice. It was shown that the same restraint stress resulted in a more serious influence on the immune cells in old than in young mice and gave rise to a differential effect on the pattern of tumor metastasis between young and old mice.

Aging↗

PubMed1997

Impairment of signal transduction in T cells from old mice.

T cells from old mice showed impaired proliferative response to antigenic stimulation. To understand the mechanism underlying the age-related impairment of T cell functions, the signal transduction pathway was examined and compared between T cells from young and old mice, and between T cell clones established from a young and old mouse. The age-related changes in T cells were as follows: (1) reduction in the expression and the activation of protein tyrosine kinases associated with T cell receptor (TCR) after antigenic stimulation; (2) reduced phosphorylation of phospholipase C gamma 1 (PLC gamma 1); (3) reduced production of second messengers such as inositoltrisphosphate (IP3) and diacylglycerol (DAG); and (4) reduced influx of Ca2+ ion. Thus, a T cell clone established from an old mouse showed impaired proliferation by stimulation with anti-CD3 antibody, but was fully activated to the level of a T cell clone from a young mouse by stimulation with phorbol acetate myristate (PMA) plus ionomycin (INM). However, splenic T cells freshly prepared from old mice did not show full recovery by the same treatment. The results indicate that one major blockade in the signal transduction of T cells from old mice is present in the pathway just after TCR, but besides this, the blockade is also present in multiple sites down-stream, which can not be bypassed by stimulation with PMA plus INM.

Aging↗

PubMed1997

Aging of the recipients but not of the bone marrow donors enhances autoimmunity in syngeneic radiation chimeras.

Young and old mice have been lethally irradiated and injected with syngeneic bone marrow cells from young or old donors to investigate whether self reactivity in old mice results from age-related damage of the radioresistant stromal cells and/or of the bone marrow hematopoietic cells. Thymus and spleen cell repopulations and mitotic responses at 3 months after irradiation are lower in old than in young recipients, suggesting age-related accumulation of stromal cell damage in the thymus as well as in other central and peripheral lymphoid tissues. The same efficiency of bone marrow cells from young and old donors to repopulate the thymus and spleen in recipients of equal age rules out the detrimental effects of aging on stem cells as well as T and B cell precursors. The serum concentration of auto-antibody and glomerular lesions at 3 and 9 months after irradiation were more pronounced in old than in young recipients and displayed no difference in recipients of equal age, regardless of the age of the bone marrow cell donors. These findings support the possibility that age-related damage of stromal cells induces disregulation of the immune system leading to autoimmune phenomena.

Aging↗