Hiroshi Sogawa

The restraint stress-induced reduction in lymphocyte cell number in lymphoid organs correlates with the suppression of in vivo antibody production

In this study, we examined the effects of restraint stress on some immune parameters such as the in vivo antibody levels, cytokine production, and lymphocyte cell number in the spleen or mesenteric lymph node (MLN). BALB/c mice were thus injected intraperitoneally 2-times with OVA absorbed into alum on days 0 and 21. Before the first injection, the animals were either restrained for 12 h (stress group) or returned to their home cage (control group). Exposure to stress resulted in a reduction in the serum levels of anti-OVA IgE, IgG1, and IgG2a. In addition, stress also caused a decrease in the IL-4 and IFN-gamma levels in the spleen or mesenteric lymph node cell culture supernatants. Furthermore, exposure to stress resulted in a decrease in the splenic and mesenteric lymphocyte cell number when examined immediately after the cessation of stress. This decrease persisted for at least 12 h after the termination of stress and thereafter disappeared 24 h after stress. The stress-induced reductions in antibody and cytokine production occurred only when antigen was given either immediately or 6 h after stress, but not when antigen was given 24 h post stress. These results thus suggest that the restraint stress-induced change in lymphocyte cell number in the spleen or MLN closely correlates with the altered antibody and cytokine levels.

Influence of short-term repeated fasting on the longevity of female (NZB×NZW)F1 mice

Abstract Caloric restriction in rodents is well known to retard the rate of aging, increase mean and maximum life-spans, and inhibit the occurrence of many age-associated diseases. However, little is known about the influence of short-term repeated fasting on longevity. In this study, female (NZB×NZW)F1 mice were used to test the physiological effect of short-term repeated fasting (4 consecutive days, every 2 weeks). The results showed that fasting mice survived significantly longer than the full-fed mice, in spite of the fasting group having a heavier body weight than the control group. Mean survival times for fasting and control mice were 64.0±15.3 and 47.9±9.4 weeks, respectively. Short-term repeated fasting manipulation was also effective on the prolongation of life-span in autoimmune-prone mice.

Electric foot shock stress‐induced exacerbation of α‐galactosylceramide–triggered apoptosis in mouse liver

Recently, liver natural killer T (NKT) cells, which are specifically stimulated by α‐galactosylceramide (α‐GalCer), were found to play a critical role in intrahepatic immunity to several infections and certain hepatic disorders. However, the role of psychophysical stress on NKT cell–dependent liver injury induced by α‐GalCer still remains to be elucidated. In this study, we employed inescapable electric foot shock as the mode of psychophysical stress and evaluated its effect on α‐GalCer–induced hepatitis. Pre‐exposure of 12 hours of foot shock stress before α‐GalCer administration significantly enhanced α‐GalCer–triggered increase in serum alanine aminotransferase levels, followed by increases in both liver caspase‐3 activity and terminal deoxynucleotidyl transferase–mediated dUTP nick‐end labeling (TUNEL)‐positive hepatocytes, thus indicating that the liver NKT cell–dependent apoptotic response was exacerbated by stress. Foot shock stress also significantly increased both the number of liver NKT cells and Fas expression levels on hepatocytes. Pretreatment with RU‐486, a glucocorticoid (GC) receptor antagonist, completely reversed such stress‐induced enhancement of the α‐GalCer–triggered serum alanine aminotransferase and hepatocyte Fas antigen responses. In contrast, such a reversal effect was not found in the mice pretreated with naloxone, a μ‐opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not β‐endorphin, as responsible for such stress‐induced aggravation in mouse hepatitis models. In conclusion, foot shock stress‐induced elevation of endogenous GCs exacerbates α‐GalCer–initiated hepatic apoptosis through the expansion of liver NKT cells and the up‐regulation of hepatocyte Fas antigen. (HEPATOLOGY 2004;39:1131–1140.)

Restraint stress causes tissue-specific changes in the immune cell distribution

In this study, the effect of restraint stress on alterations in the immune cell distribution was examined in bone marrow, liver, thymus, and spleen. In bone marrow, stress induced a striking increase in both the proportion and number of CD3+CD4+, CD3+CD8+, B220brightIgM+, CD3-IL-2R beta + and CD3intIL-2R beta + cells. Such an increase was partially reversed by pretreatment with RU-486, a steroid receptor antagonist, while it was profoundly enhanced by either sympathectomy with 6-hydroxydopamine hydrobromide or by a beta-adrenergic blockade with propranolol, a beta-adrenergic receptor antagonist; this suggests that corticosteroids and catecholamines may act in opposition with regard to such an immune-cell accumulation in bone marrow. In the liver, stress decreased the proportions of CD3intIL-2R beta +, CD3-IL-2R beta +, and B220brightIgM+ cells, while it increased the proportion of CD3brightIL-2R beta-cells, thus demonstrating that different subpopulations were differentially affected. In the thymus and spleen, stress only slightly affected the proportions of lymphocyte subpopulations, although both tissues showed a drastic reduction in the number of lymphocytes. Taken together, these results suggest that restraint stress induces tissue-specific changes in the immune-cell distribution.

Application of psychoimmunotherapy in patients with alopecia universalis.

Mental stress and immunological abnormality have recently been listed as causes of alopecia universalis. This disease is difficult to treat with only ordinary pharmacotherapy. Thus, from the standpoint of psychoneuroimmunology, stress was relieved by relaxation and image therapy, and administration of small doses of a strong immunosuppressant was effective, leading to clinically favorable results. In addition, changes were recognized in the subpopulation of peripheral lymphocytes and in beta-endorphin before and after relaxation and image therapy. The treatment of alopecia universalis favorably changed the subpopulations of T cells. A patient suffering from alopecia is always under stress. Alleviating this stress facilitates recovery of immunological competence. Our method was effective in 5 of 6 cases with refractory alopecia universalis.

Influence of stress on the maturity of T-cells.

Stress is known to influence the immune function via an effect on the central nervous system. We previously presented data showing that stress alters the population of T-cell subsets in mice. The variations of T-cell subsets in the thymus, peripheral blood, and spleen in mice similarly stressed by immobilization or by unavoidable and opioid-dependent stress were measured by flow cytometry using the monoclonal antibodies anti-L3T4, anti-Lyt 1, anti-Lyt 2 and anti-Thy 1, 2. Immobilization stress was applied for three days and T-cell subsets were measured on the days 1, 2 and 3, as well as on day 7 after release from immobilization. Lyt 2-positive cells in the thymus were the most sensitive to stress, showing significant variations. The proportion of immature T-cells increased in the thymus, blood and spleen of the stressed mice. When diazepam or naloxone were administered 30 min before the initiation of stress, these variations tended to decrease. Thus, the ratio of T-cell subsets varied with the duration of immobilization stress. This appeared to be partly mediated by the opioid system and the central nervous system.

Prevention of immunosuppression in stressed mice by neurotropin(NSP)

It is well known that the immune function can be compromised by stress. To investigate immune function in mice stressed by experimental restraint or unavoidable and opioid dependent stress, we evaluated the changes in total body weight and in organ weights (liver, spleen and thymus) of these animals, as well as the phagocytic activity of macrophages, the cytotoxicity of T cells and inhibitory effects on tumor growth and changes in T cell subset populations. At the same time we evaluated the effects of Neurotropin (NSP), a substance extracted from the inflamed skin of rabbits inoculated with the vaccinia virus and which appears to possess neuroimmunomodulating activity. The experimentally stressed group exhibited a reduction of phagocytic activity of macrophages, cytotoxicity of T cells and inhibitory effects on tumor growth. In addition there were changes in the population of T cell subsets. In those animals pretreated with NSP, the immunosuppression induced by stress was ameliorated. As compared with several agents which influence phagocytosis, neurotropin exhibited effects similar to that of agents that blocked the adrenaline receptor and an opioid antagonist rather than tranquilizer (diazepam) and a cholinergic receptor blocker. The pharmacologic effects of neurotropin support a relationship between the actions of the central nervous system and the immune system.