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Biomedical subjects

T Makinodan

Publications and source records attributed to T Makinodan.

At least 37 records · Page 2Linked to original sources
PubMed1989

The effect of exercise on natural killer cell activity in young and old subjects.

Alterations in immune function have been commonly reported in elderly persons. We have examined the effect of age on the responsiveness of natural killer (NK) cells to in vitro stimulation with recombinant interleukin-2 (rIL-2) and in vivo stimulation with exercise in 17 healthy subjects (8 young and 9 old). The old subjects were found to have NK cell numbers and function that were not significantly different from the young subjects at baseline. They also responded as well as the young subjects to rIL-2 stimulation of NK cells in vitro. In response to maximal bicycle ergometry exercise, there was a marked rise in NK activity in the old (7.52 +/- 1.71 LU/10(6) pre-exercise vs 15.20 +/- 3.27 LU/10(6) post-exercise, p less than .03) and the young (6.29 +/- .48 LU 10(6) vs 14.56 +/- 1.86 LU 10(6), p less than .005) subjects. Lymphocytes bearing the NK marker Leu 11a also rose significantly post-exercise in both old and young subjects. We conclude that healthy elderly subjects increase their NK activity in response to the acute stressor, exercise, at least as effectively as do young subjects.

Adult↗
PubMed1988

Decline in the production of interleukin-3 with age in mice.

Previously, we and others have found that the ability to produce interleukin-1 (IL-1) and interleukin-2 (IL-2) declines with age in mice. The purpose of this study was to determine the influence of age on the capacity of mice to produce interleukin-3 (IL-3). Splenic cells (5 X 10(6)/ml) from young (3-4 months) and old (24-32 months) C57BL/6 mice were first assessed for their IL-3-producing capacities in response to varying doses of concanavalin A (Con A; 2-20 micrograms/ml) in a time-dependent manner. The results showed that the production of IL-3 by both young and old C57BL/6 mice was maximal on Days 3 and 4 in response to 20 micrograms/ml of Con A, and that of IL-2 was minimal (activity was less than 0.1 unit) on Day 4. Consequently, Day 4, was selected to assess the effect of age on IL-3 production by splenic cells. The results showed a twofold reduction in IL-3 production with age (P less than 0.05). Young-old splenic cell mixture experiments at ratios of 1:0, 3:1, 1:1, 1:3, and 0:1 indicated that the decrease in IL-3 production with age was not due to an increase in suppressor cell activity. Experiments based on mixtures of nylon wool-enriched splenic T-cell and adherent cells and on anti-MAC-1 plus complement-treated spleen cells indicated that (a) adherent cells are not required for T-cell production of IL-3, unlike IL-2 production, and (b) the decrease in IL-3 production with age is due solely to alteration in IL-3-producing T cells. Finally, a strong correlation was demonstrated between the production of IL-2 and IL-3 by spleen cells of individual young and old mice (r = 0.92, P less than 0.01). That production of both IL-2 and IL-3 is affected in a similar manner by age would suggest that a single class of helper T cells may be responsible for production of both lymphokines.

Aging↗
PubMed1988

Decreased in vitro polymerase II activity of whole-cell extracts from late passage human diploid fibroblasts.

Age-associated decreases in gene expression have been observed in several different species, but the mechanisms of the decrease have not yet been adequately studied at molecular level. Using an in vitro transcription assay, we have obtained data suggesting that there is an age-associated decrease in polymerase II-specific transcriptional activity in fibroblasts aged in vitro.

Aging↗
PubMed1988

T cell potentiation in normal and autoimmune-prone mice after extended exposure to low doses of ionizing radiation and/or caloric restriction.

In order to better understand the apparent physiologic up-regulation in response to low levels of potentially lethal insults, murine T lymphocytes were analysed for functional and phenotypic alterations after exposure to 0.005 Gy/day, 0.01 Gy/day and 0.04 Gy/day in groups of ad-libitum-fed and calorie-restricted mice. These studies were conducted in two strains of mice: the long-lived and immunologically normal C57Bl/6 +/+ and the congenic short-lived immunologically depressed C57Bl/6 lpr/lpr. Whole-body exposure to 0.01 Gy/day and 0.04 Gy/day for an extended period of 20 days was associated with an increase in splenic proliferative response and with shifts in the proportions of T cell subpopulations in the thymus and spleen of both strains. Caloric restriction independently altered functional activity and T cell subpopulations in the same direction as low dose rates of ionizing radiation. Although the dose-response augmentation in proliferative activity was similar in the two strains, observed alterations in thymic and splenic T cell subpopulations were clearly different, suggesting that different mechanisms were responsible for immune enhancement in each strain.

Animals↗
PubMed1988

Age-related alteration in the composition of immunocompetent blood cells in atomic bomb survivors.

A total of 1328 atomic bomb survivors in Hiroshima were studied to determine alterations in the number of blood lymphocytes belonging to T-cell subpopulations, the number of CD19 antigen-positive B cells and the number of Leu 7 and CD16 antigen-positive lymphocytes. Overall, with increasing age, significant decreasing trends in the numbers of some lymphocytes in T-cell subpopulations and of B cells were observed. Furthermore, the number of blood lymphocytes positive for CD5 antigen was significantly lower in the people exposed to radiation (greater than 1 Gy) in the older age group (more than 30 years old at the time of the bombing). A similar tendency for decreases in the numbers of CD4, CD8, and CD19 antigen-positive cells was observed in these older survivors, although the differences were not statistically significant. These results suggest that aging of the T-cell related immune system is accelerated in the irradiated people of advanced age. This may be explained by the age-related decrease in thymic function in those subjects who were older at the time of the bombing resulting in a decreased functional ability of the immune system after radiation injury. On the contrary, the number of Leu 7 or CD16 antigen-positive cells was found to be increased significantly in the older age group compared to the younger group, although there was little dependence on dose.

Age Factors↗
PubMed1988

Immunological responses of aging Japanese A-bomb survivors.

Immune response parameters were studied on 1341 A-bomb survivors residing in Hiroshima, Japan. Mononuclear cells were isolated from venous blood and tested for interleukin-2 production; lymphocytes were purified and tested for natural killer (NK) cell activity and interferon (IFN) production; and serum was tested for IFN and circulating immune complex (CIC) levels. Statistical analyses were performed for each type of assay using a linear models procedure including sex, age at the time of the bomb, radiation exposure, all the interaction variables, and the categorical variable day-of-assay in the model. The findings showed that (1) none of the immunologic variables were significantly affected by radiation exposure; (2) NK activity and CIC levels were positively associated with age; and (3) NK activity was on average higher for males than females. The data exemplify the difficulty in reaching firm conclusions concerning associations with radiation exposure when the dependent variable exhibits a large degree of interindividual and day-of-assay variability.

Aging↗
PubMed1988

Endogenous opioids and the exercise-induced augmentation of natural killer cell activity.

Based on prior observations that both beta-endorphin and exercise stimulate natural killer (NK) cell activity, we have examined the hypothesis that the release of endogenous opioids during the stress of acute exercise may mediate this NK cell augmentation. Eight healthy young women underwent a maximal bicycle ergometer exercise test with prior in vivo administration of a placebo and an opioid antagonist, naloxone (100 micrograms/kg), in a randomized, blind protocol. Exercise after the placebo injection was accompanied by a dramatic rise in NK activity, as well as an increase in the percentage of lymphocytes bearing the NK cell surface markers Leu 11a and Leu 19. Significant stimulation of NK activity was observed with beta-endorphin in vitro before exercise, but after exercise, beta-endorphin had a nonsignificant inhibitory effect. When these experiments were carried out in the presence of naloxone in vivo, the rise in NK activity after exercise was no longer significant. Naloxone did not significantly alter the rise in Leu 11a+ or Leu 19+ cell after exercise, as compared with the placebo. Finally, when naloxone was given to the subjects beforehand, exercise no longer completely blocked the in vitro beta-endorphin stimulation of NK cells. In conclusion, our observations that the exercise-induced augmentation of NK activity and the lack of effect of beta-endorphin in vitro on NK activity after exercise are both significantly attenuated by prior administration of naloxone suggest that the opioid system may play a major role in the modulation of NK cells during physiologic stress.

Adult↗
PubMed1987

Macrophage-mediated depression of T-cell proliferation in zinc-deficient mice.

Splenic T-cells and macrophages (adherent cells) from zinc-deficient (ZD) mice and pair-fed (PF) control mice were isolated, purified and recombined in defined proportions to evaluate the contribution of each cell type to impaired mitogenesis. The results of cell crossover experiments revealed that the observed depression in T-cell proliferation in the ZD mice was indirect and due to a primary defect in the macrophage population that could be overcome by increasing the proportion of macrophages in culture. In contrast, the proliferative capacity of purified T-cells from ZD mice was not different from control levels when the cells were combined with macrophages from PF control mice. Similar results were obtained in neonatally thymectomized ZD and PF mice, suggesting that long-lived T-cells may have been processed normally through the thymus before the 6 wk of dietary zinc deprivation. After 12 wk of zinc depletion, however, the proliferative capacity of T-cells from ZD mice was significantly depressed, suggesting a direct effect on the maintenance or maturational state of T-cell subpopulations when the period of deficiency approached the half-life of these cells. These results emphasize the continuum of immunologic alteration with progressive nutritional intervention, which may vary depending on the age of induction and the duration of depletion.

Animals↗
PubMed1987

Delayed effects of low-dose radiation on cellular immunity in atomic bomb survivors residing in the United States.

Several parameters of cellular immune function were assessed among persons who survived the 1945 atomic bombs in Hiroshima and Nagasaki but who now reside in the United States. The subjects in this study were exposed to various low doses (T65D) of radiation at the time of the bomb. More than half received an estimated 0 Gy (S0 group). Of those exposed to more radiation (S+ group), nearly 90% received less than 0.50 Gy (50 rad). Lymphocytes were isolated from the peripheral blood of these individuals and were assessed for the following parameters of cellular immunity: mitogenic response to phytohemagglutinin, mitogenic response to allogeneic lymphocytes, natural cell-mediated cytotoxicity (NCMC), and interferon production. In every case, the response of the S+ group was greater than that of the S0 group, although only the difference for NCMC was statistically significant. Results of studies presently being performed on A-bomb survivors residing in Hiroshima do not confirm this difference. Therefore, it is difficult to say whether the increase in natural cytotoxicity observed among the American and not the Japanese A-bomb survivors exposed to very low doses of radiation is a hormetic effect which was modulated by post-radiation environmental conditions or a result of selective migration.

Cytotoxicity, Immunologic↗
PubMed1987

Cellular, biochemical, and molecular basis of T-cell senescence.

The elucidation of age-related changes in immune functions is of great importance in light of the rising susceptibility of elderly individuals to infections, the likelihood that immunosenescence might also contribute to the age-related rise in cancer, and the role autoantibodies and immune complexes might play in general physical deterioration of aging individuals through their participation in subclinical chronic tissue damage. An attempt has been made to summarize our present knowledge on immune functions that are vulnerable to aging. It revealed that at the cellular level, all four antigen-responsive immune cells (T cells, B cells, monocytes, and killer cells) are vulnerable to aging, but T cells are perhaps the most vulnerable. Therefore, this article specifically examines the cellular and biochemical T cell-dependent concomitants of age-altered immune functions. One picture that is emerging suggests that at the molecular level, several control points exist along the path of gene expression that could be vulnerable to aging.

Aging↗
PubMed1987

Thymic stromal cells produce inhibitors of proliferation of thymic, but not splenic T cells.

Thymic stromal cells from newborn, 2 wk, 2 and 5 mo old BALB/c mice, which are adherent to plastic surface, were cultured in vitro for 3 weeks. The supernatants collected twice weekly were pooled and assessed for their ability to inhibit the proliferation of indicator cells stimulated with crude interleukin(IL)-2. The indicator cells were peanut agglutinin (PNA)+ and PNA- thymic T cells, splenic T cells, splenic T blast cells and cytolytic T lymphocytes line 2 (CTLL-2) cells, and they were all stimulated with crude IL-2 to proliferate. Supernatants from splenic and bone marrow stromal cells from 2 mo old BALB/c mice were cultured and were tested in a similar manner. The following results were obtained: (1) Supernatants of thymic stromal cells inhibited the proliferation of PNA+ and PNA- thymic T cells but not that of splenic T cells, splenic T blast cells and CTLL-2 cells; (2) The supernatants of splenic and bone marrow stromal cells had no inhibitory activity against PNA- thymic T cells stimulated with crude IL-2; (3) The gel elution patterns of nondialyzable inhibitory factors produced by thymic stromal cells of 2 and 5 mo old mice were polydispersed, in contrast to those produced by thymic stromal cells of newborn and 2 wk old mice; (4) Diethylaminoethyl (DEAE)-Sephadex ion exchange chromatography resolved the inhibitory factors produced by thymic stromal cells of 5 mo old mice into 3 peaks, and the major peak was estimated to be molecular weight (Mr) 68,000 based on Sephacryl S-300 gel filtration analysis; (5) This fraction was relatively heat stable; it inhibited the proliferation of crude IL-2 stimulated PNA- thymic T cells in apparently a nonstoichiometric manner; and bovine serum albulmin (BSA), which is present in the fraction, and interferon, which could be present in the fraction, had no inhibitory activity.

Aging↗
PubMed1986

Age-related RNA polymerase I activity in isolated nuclei of PHA stimulated human lymphocytes.

In order to extend to the immune system previous findings that there is an age-related loss of hybridizability of the genes for ribosomal RNA (rRNA) in several tissues of mice, dogs and humans, we have investigated the function of the genes for rRNA in human T lymphocytes. These cells were chosen because they show a substantial decline in function with age, greater than that of other components of the immune system. rRNA synthesis was determined by measuring tritiated-UTP incorporation into acid precipitable counts as a result of the action of RNA polymerase I in nuclei isolated from phytohemagglutinin (PHA) stimulated peripheral-blood lymphocytes from 24 young adult and old human donors. The number of PHA-responsive cells from each donor was determined by counting grains in autoradiographs after a pulse of tritiated-uridine had been administered to them. The aggregate PHA induced synthesis of rRNA in the cultures decreased as a function of the age of the donor. However, the number of PHA-responsive cells also dropped with age. When the data are normalized for the number of PHA-responsive cells in each culture, it appears that rRNA synthesis per PHA-responding cell does not significantly decline with age, even though there is a suggestion of a decrease after corrections are made. On the average, differences between individuals of the same age group were as great or greater than age-related differences.

Adult↗
PubMed1986

Frequency of 6-thioguanine-resistant T cells is inversely related to the declining T-cell activities in aging mice.

The frequency of clonable 6-thioguanine-resistant (6-TGr) splenic T cells increased moderately with age in female BALB/c mice ranging in age from 3 to 32 months; however, the correlation between the frequency of clonable 6-TGr cells and age was weak. Those clonable 6-TGr T cells were deficient in hypoxanthine/guanine phosphoribosyltransferase (HGPRT) activity and sensitive to hypoxanthine/aminopterin/thymidine medium, as in the case of HGPRT-deficient L5178Y mouse lymphoma cells. When splenic T cells of individual aging mice were assessed simultaneously for the frequency of clonable 6-TGr T cells and for their ability to produce interleukin 2 or to proliferate in response to mitogenic stimulation, an inverse correlation was observed. These results indicate that the frequency of 6-TGr T cells is more closely related to physiologic age than chronologic age. This would mean that the frequency could be used as an index of physiologic age and that the T cells could serve as a cellular model relating gene alterations to physiologic age.

Aging↗
PubMed1986

Increased susceptibility of old mice to plasmacytoma induction.

Because multiple myeloma is a malignancy that appears in aging humans, the murine plasmacytoma model was selected to investigate the association between tumor formation, age, and immunity. Plasmacytomas were induced in young, middle-aged, and old BALB/c mice by intraperitoneal injections of pristane. Old mice were more vulnerable than middle-aged mice who were more vulnerable than young mice to histopathologically documented plasmacytoma formation. The difference between old and young mice was significant (p less than .05). The increased frequency of plasmacytomas was associated with decreased in vitro immune parameters in pristane-treated mice compared with age-matched saline-treated controls. The decrease was especially marked with T cell responses (mitogenic responses to concanavalin A, phytohemagglutinin, or allogeneic spleen cells) and natural killer (NK) cell activity. It was less striking with the predominantly B-cell parameters of mitogenic response to lipopolysaccharide (LPS) and LPS-induced plaque-forming cells. These findings support the hypothesis that old mice have increased vulnerability to plasmacytoma formation because of diminished NK and T cell activities.

Age Factors↗