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T Makinodan

Publications and source records attributed to T Makinodan.

At least 19 recordsLinked to original sources
PubMed1991

DNA strand breaks and DNA repair response in lymphocytes after chronic in vivo exposure to very low doses of ionizing radiation in mice.

In contrast to the well-documented negative effects of high-dose oxidant exposure, accumulating evidence supports a positive, perhaps essential physiologic role for very low-level oxidant stress. For example, low-level oxidant exposure, within or below the physiologic range, has been reported to stimulate membrane signal transduction, proliferation, antioxidant defense and DNA repair. In the present study, we have examined whether whole-body exposure to low-dose radiation (LDR) results in an alteration in constitutive (steady state) levels of DNA-strand breaks and whether an adaptive increase in DNA-repair response is induced. C57B1/6J mice were exposed to 0.04 Gy (4 cGy) of gamma-radiation as a model of low level oxidant stress. End points measured after chronic in vivo LDR included: (1) constitutive expression of DNA-strand breaks in quiescent spleen cells; (2) sensitivity to DNA damage after high-dose radiation exposure in vitro; (3) repair of constitutive and radiation-induced DNA strand breaks after mitogen stimulation: (4) activity of the DNA-repair associated enzyme, poly(ADP-ribose)transferase (ADPRT) and its substrate, NAD. The results indicated that the constitutive expression of DNA-strand breaks is significantly decreased after chronic LDR; however, DNA-repair capacity after high-dose radiation exposure is not increased above that observed in sham-irradiated mice. Associated with the reduction in constitutive DNA-strand break accumulation was a decrease in resting levels of the DNA-repair-associated enzyme poly(ADP-ribose) transferase (ADPRT). These results are consistent with the interpretation that cumulative DNA damage and associated DNA-repair activity in unstimulated cells are both reduced after chronic LDR exposure.

Adenine Phosphoribosyltransferase↗
PubMed1991

Cellular immunosenescence: an overview.

Recent studies on space flights suggest that certain T cell immunologic activities are vulnerable to microgravitation. It would be desirable to know the extent to which these changes can be prevented or reversed. Since the changes observed are analogous to the effects of aging on immunity, a brief overview is presented of our current knowledge of age-related changes in immune cells and of the various interventional methods which have been used successfully in preventing the decline with age and in elevating the levels of immune functions of old individuals.

Aging↗
PubMed1990

The aging process.

The intricate cause of the aging process in humans and animals, at present a matter of intense speculation, has given rise to many theories. Despite its uncertain cause, aging constitutes the most significant and universal problem confronting physicians today. Age-related physiologic deterioration and age-associated diseases are of immense concern to physicians because of the "old-age boom" anticipated in the first part of the twenty-first century. Biomedical research achievements in the twentieth century have permitted more persons to approach the fixed upper limit of the human lifespan. We discuss the functional decline of the aging heart and the underlying mechanisms of that decline; quantitative and qualitative changes in the immune system; and normal aging of the human brain contrasted to the brain changes seen in Alzheimer disease. With our growing geriatric population, we greatly need to increase our understanding of both the causes of human aging and the goals of gerontology and geriatrics and to expand research into the significant problem of Alzheimer disease.

Aging↗
PubMed1990

Immune potentiation after fractionated exposure to very low doses of ionizing radiation and/or caloric restriction in autoimmune-prone and normal C57Bl/6 mice.

Very low doses of ionizing radiation can enhance immune responsiveness and extend life span in normal mice. Total lymphoid irradiation at relatively high doses of radiation can retard autoimmune disease in genetically susceptible mice, but may impair immune function. In order to determine whether fractionated low dose exposure would enhance immune response and retard lymphadenopathy in autoimmune-prone mice, groups of C57B1/6 lpr/lpr mice were sham irradiated, exposed 5 days/week for 4 weeks to 0.04 Gy/day (0.8 Gy cumulative dose), or to 0.1 Gy/day (2.0 Gy cumulative dose). After the radiation protocol, the mice were evaluated for splenic T cell proliferative capacity, T cell subset distribution, and total spleen cell numbers. The independent and additive effect of caloric restriction was additionally assessed since this intervention has been shown to increase immune responsiveness and retard disease progression in autoimmune-prone mice. The congenic C57B1/6 +/+ immunologically normal strain was evaluated in parallel as congenic control. The results indicated that mitogen-stimulated proliferation was up-regulated in both strains of mice after exposure to 0.04 Gy/day. The proliferative capacity was additively enhanced when radiation at this dose level was combined with caloric restriction. Exposure to 0.1 Gy/day resulted in further augmentation of proliferative response in the lpr/lpr mice, but was depressive in the +/+ mice. Although the proportions of the various T cell subpopulations were altered in both strains after exposure to LDR, the specific subset alterations were different within each strain. Additional experiments were subsequently performed to assess whether the thymus is required for LDR-induced immune potentiation. Thymectomy completely abrogated the LDR effect in the +/+ mice, suggesting that thymic processing and/or trafficking is adaptively altered with LDR in this strain. In contrast, augmentation in proliferative activity after LDR in the lpr/lpr mice was maintained, although attenuated, in thymectomized mice. Taken together, these results indicate that fractionated exposure to LDR augments the proliferative response of spleen cells in both autoimmune-prone and immunologically normal mice; however, within each strain, the mechanisms appear to be different.

Animals↗
PubMed1990

T cell potentiation by low dose ionizing radiation: possible mechanisms.

The phenomenon of a stimulatory response induced by an exposure to a low dose of an otherwise toxic agent has been observed in a wide variety of organisms, ranging from the simplest prokaryotes to higher eukaryotes and with a spectrum of stimuli. This would suggest that the phenomenon is evolutionarily conserved and biologically important. However, we do not understand the mechanism responsible for the phenomenon, although it has been known for over 100 y. A reasonable assumption would be that adequate models and challenging paradigms are lacking to resolve this fundamental problem. Evidence is presented to show that the potentiation of T cell response by exposing them to single or multiple low doses of ionizing radiation is a feasible cellular model to understand the phenomenon. In addition, several possible mechanisms are discussed, including the participation of stress proteins and prostaglandins in stabilizing the signal transducing, transcriptional and translational machineries, and the possible role of a more efficient mechanism of DNA repair.

Animals↗
PubMed1990

Immunotoxicity of alcohol in young and old mice. I. In vitro suppressive effects of ethanol on the activities of T and B immune cells of aging mice.

A murine aging model was employed to assess effects of ethanol exposure on the T-cell proliferative response to mitogenic stimulation and on the T cell-dependent primary antibody response to sheep red blood cells (RBC) in vitro. Splenic cells from young (3-5 months) and old (28-32 months) BALB/c mice were first assessed for their ability to produce interleukin (IL) 2 and proliferate in response to mitogenic stimulation in the presence of various doses of ethanol. Then, splenic T blast cells from young and old mice, generated by Con A-activation, were assessed for their IL2-dependent proliferative capacity in the presence of various doses of ethanol. Finally, splenic cells of young and old mice were assessed for their ability to generate plaque-forming cells (PFC) in response to sheep RBC in the presence of various doses of ethanol. The results revealed that ethanol has a much greater suppressive effect on old than young splenic T cells (10-15 times), as judged by their ability to proliferate in response to mitogenic stimulation. However, the magnitude of the difference in the suppressive effect is less when the cells are cycling (2 times). Furthermore, ethanol had only a minimal suppressive effect on IL2 production by T cells of both young and old mice, even at the concentration of 100 mM. These findings would suggest that the ethanol-mediated suppression of T cell proliferation of both young and old mice is more likely due to an impairment of metabolic event(s) associated with or subsequent to the interaction of IL2 and IL2 receptor leading to cellular replication.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1990

Analysis of cutaneous delayed-type hypersensitivity reaction and T cell proliferative response in elderly nursing home patients: an approach to identifying immunodeficient patients.

Clinical experience suggests the delayed-type hypersensitivity (DTH) skin test lacks sensitivity in assessing the integrity of systemic cell-mediated immunity (CMI) or the status of recent or remote mycobacterial infections in elderly nursing home residents. In an attempt to clarify this issue, DTH reaction to purified protein derivative (PPD), tetanus toxoid and Candida albicans was compared with circulating thymus-derived lymphocyte (T cell) proliferation (TCP) to stimulation with PPD and anti-CD3 antibody in 24 randomly selected nursing home residents. The DTH reaction and the TCP response correlated reasonably well among the DTH reactors but poorly among DTH nonreactors, suggesting there may be age-related immunologic changes in the skin itself. Also, the DTH skin test to PPD alone was found to be a poor index of the integrity of systemic CMI.

Aged↗
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↗
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↗
PubMed1979

Restoration of impaired immune functions in aging animals. II. Effect of mercaptoethanol in enhancing the reduced primary antibody responsiveness in vitro.

The enhancing effect of 2-ME on the in vitro primary antibody forming capacity of young and old spleen cells from 5 different strains and hybrids was investigated by assessing the number of antibody-forming cells in response to sheep RBC stimulation. The following results were obtained: (1) the optimum concentration of 2-ME is 5 x 10(-5) M; (2) the best time to expose cultures to 2-ME is on day 0 together with the antigen, although days 3 and 4 were equally as effective with young but not old spleen cells; (3) 2-ME can enhance slightly the time of peak antibody response, but this appears to be strain dependent; (4) in response to antigenic stimulation over a 10,000-fold range in antidgen dose, antibody response by cultures exposed to it; (5) 2-ME is comparable to, or better than, those which had been exposed to it; (5) 2-ME is effective in enhancing antibody response because it probably promotes proliferation and transformation, as well as protects dividing cells which otherwise could not survive the culture conditions; (6) the relative number of viable cells detected on the third day of culture after antigen stimulation can be used in predicting with a reasonable accuracy (pie 2, 0.94) the magnitude of peak antibody response, which is detected normally about 2 days later; (7) 2-ME enhances antibody response of young spleen cells by about 30%, but is quite variable depending upon the genetic strain, varying from a low of --20% with random bred CV1 cells to a high of 100% with inbred C57B1 cells; (8) the enhancing effect of 2-ME on old spleen cells is much more impressive, being more that 10 times greater than on young spleen cells (i.e., 500 vs. 30%), although it too is quite variable, ranging from a low of 85% with C3H cells to a high of about 1100% with C57BL cells; (9) the enhancing effect of 2-ME on limiting numbers of spleen cells is most impressive, as judged by the relative magnitude of response by limiting (3 x 10(6)) and optimum numbers (10 x 10(6)) of young and old spleen cells and by the frequency of antibody response of cultures with limiting and optimum numbers of cells exposed to 2-ME was 23 and 3 times greater than that not exposed to 2-ME, respectively; and with old spleen cells, it was 30 and 12 times greater. In terms of the frequency of antibody responding cultures with limiting numbers of young spleen cells (3 x 10(6)), 77% responded in absence of 2-ME, whereas 100% of the cultures responded in the presence of 2-ME. The effect of 2-ME on cultures containing limiting numbers of old spleen cells was much more striking, for, in contrast to only 9% of the cultures responding in the absence of 2-ME, 78% responded in the presence of 2-ME.

Age Factors↗
PubMed1979

Restoration of impaired immune functions in aging animals. III. Effect of mercaptoethanol in enhancing the reduced primary antibody responsiveness in vivo.

The enhancing effect of 2-ME on the primary antibody forming capacity of young and old mice from 5 strains and hybrids was investigated by assessing the number of hemolytic antibody-forming spleen cells in response to sheep RBC stimulation. The following results were obtained: (1) the optimum dose of 2-ME is 4 micrograms per mouse; (2) the best time to administer 2-ME is just prior to, or at the same time as, antigen is given; (3) 2-ME can enhance response to suboptimum and optimum, but not supra-optimum doses of antigen; (4) 2-ME is effective in enhancing the primary antibody forming capacity of both young and old mice, with one exception, but the enhancement of old mice was greater than that of young mice (80% vs. 20%). The exception was old C57Bl mice, in which 2-ME was ineffective; (5) the level of primary antibody forming capacity of old mice can be restored to that of young mice by treating them with 3--4 weekly injections of 2-ME at a dose of 4 micrograms per injection.

Aging↗
PubMed1979

Control of immunologic abnormalities associated with aging.

In an attempt to encourage more intensive studies on the control of immunologic abnormalities associated with aging, the six different approaches which have been attempted are reviewed briefly. They are as follows: (a) internal body temperature control, (b) tissue ablation, (c) dietary manipulation, (d) genetic manipulation, (d) genetic manipulation (e) cell therapy and (f) chemical therapy. The first four are preventive and the latter two are restorative in approach. Many of these studies are very preliminary, but overall, the findings are most encouraging. These studies should resolve the extent to which decline in immunologic vigor with age influences the disease pattern of aging individuals and on their life expectancy.

Aging↗
PubMed1976

Decline in the growth potential of spleen-colonizing bone marrow stem cells of long-lived aging mice.

The growth capacity of femoral bone marrow stem cells from young and old long-lived mice was assessed in the spleen of X-irradiated young and old syngeneic recpients by determining: (a) the number of stem cells colonizing the spleen, (b) the rate of incorporation of 125I-labeled iododeoxyuridine by proliferating colony cells, and (c) the number of cells present in the largest colonies at the end of the growth phase.We found that the growth capacity of stem cells declined with age. We further found that the spleen-seeking and spleen colony growth capacities of old stem cells remained characteristically old even after they were allowed to self-replicate in the bone marrow of young recipients for an extended period of time. On the other hand, the spleen colony growth capacity of young stem cells could be reduced by allowing them to self-replicate in old recipients. These results suggest that the growth capacity of old stem cells is an intrinsic characteristic which cannot be readily altered, but that of young stem cells can be aged in an accelerated manner by allowing them to self-replicate in old recipients. An additional reduction was noted in the frequency of both young and old stem cells colonizing the spleen of old recipients and in the cell density of the largest colonies produced. These results indicate that factors extrinsic to the stem cells are also responsible for the decline with age in their spleen colony growth capacity.Thus, the growth capacity of old stem cells in old recipients could be as low as 10% that of young stem cells in young recipients.

Aging↗
PubMed1976

Immunobiology of aging.

Normal immune functions can begin to decline shortly after an individual reaches sexual maturity. Although changes in cellular environment are partially responsible, the decline is due primarily to changes within the cells, especially the T cells and to some extent the stem cells. This is reflected in their inability to proliferate and differentiate efficiently. What needs to be resolved is whether the altered properties of T cells and stem cells are permanent or reversible and, if permanent, whether they are due to a stochastic or genetically programmed event. The decline with age in certain normal immune functions is associated with an increase in the frequency of autoimmune and immune complex diseases, certain types of cancer, and viral and fungal infections. These diseases, compromise normal immune functions in short-lived strains of mice. In long-lived mice and in humans, however, the decline in immune functions to threshold levels seems to predispose in individuals to illness.

Aging↗