The relationsip between stress and immunity has gradually become the current topics in the recent immunological field, and the investigation of this field has been established as psychoneuro-endocrino-immunology.A series of investigations which were conducted in our department in regard to the immunological modulation by stress involvement is shown in this paper. The study of the healthy public by the Stress Check List showed a variety of stress-related symptoms which suggest disturbed immunity among the people exposed to the chronic physical or psychological stress. The serums which were drawn from the donors whose uncomfortable states were induced by hypnosis showed depressed anti-bacterial immunity against Ebelthera typhosa and Shigela sonnei Ohara. The production of IgE in the mice which loaded 8 hours of restriction in the wire net for 4 days prior to the primary antigen-sensitization was remarkably depressed, where-as it was not in the mice whose stress were loaded after primary sensitization. Stress-related substances such as prostagrandin E_2(PG-E_2), α-and, β-endorphin were examined as to how they made effects on lymphocyte function. PHA-and PWM-imduced proliferative response and IgM production of human peripheral mononuclear lymphocytes were suppressed by PG-E_2. The α-, and β-endorphin enhanced T cell function such as PHA-induced proliferative response and IL-2 production in a lower concentration but did not modulate PWM-induced IgM production. These neuropeptides showed no effect or rather suppression in higher concentration. Suppressed lympocyte function by PG-E_2 was restored by the existence of α-endorphin. Stress-induced immunological modulation appears to require several factors such as the mode, occasion, and strength of loading stress.We tried to explain some part of phenomenon of stress-related immunological enhancement and suppression through these data and several references.

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Rats which were housed in the activity-wheel cages and fed for 1hr daily, exerted high running activity and body weight loss. The rats which run more significantly during the 1hr feeding period die and reveal stomach lesions. Therefore, the ulcer was designated as "Activity-stress ulcer". They also revealed atrophy of the thymus and spleen, and hypertrophy of the adrenals. These phenomena resemble with "General adaptation syndrome of Selye". When rats were exposed to activity-stress, the plasma corticosterone increased and the antibody titer decreased in accordance with the length of activity-stress period. The appearance of dead rat was in accordance with decrease of antibody titer. When the ulcer development was prevented by psychotropic drugs, the corticosterone level was lower. These results suggest that the pathophy-siological changes of rats exposed to activity-stress relates with augmentation of plasma corticosterone closely. And, the role of the pituitary-adrenal hormones in stress-induced immunological changes was discussed.

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It has been postulated that various kinds of stresses can modulate immunological responses in experimental animals.In order to clarify the relationship between stress and so-called type-I allergic response, we investigated the effects of restraint stress on IgE antibody formation in mice and passive cutaneous anaphylaxis (PCA) reaction in rats and airway reactivity to histamine in guinea pigs.1. Mice were exposed to restraint stress, which was done by rapping the mice tightly with wire nets for 8 hours a day. IgE antibody formation was significantly suppressed in short term stress group which was exposed to the stress for 5 consecutive days prior to immunization, but not effected in the long term stress group which had been exposed to the stress from 5 weeks before immunization to 10 weeks after immunization.2. Rats were exposed to restraint stress which was done by almost the same procedure as that of mice. Two-fold dilutions of antiserum, which contained high titer mouse anti-ovalbumin (OA) IgE, were injected intracutaneously for passive sensitization, and the PCA titer was determined by measuring the maximal dilution giving a positive reaction after injecting OA and evans blue. The PCA titer of stress group was not sinificantly different from control group.3. Guinea pigs were exposed to restraint stress, which was done by rapping the animals with wire nets for 1 hour a time, 2 times a day. Histamine threshold was determined by Mead's apparatus. The airway reactivity to histamine was not different significantly between stress group and control group.Long term restraint stress was not thought to affect the type-I allergic responses in the meaning of enhancing IgE antibody formation, skin reactivity, or air way reactivity.

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This study was constructed to elucidate bronchial hypersensitivity due to stress by means of animal model. Bronchial hyperresponsiveness was evaluated in artificially ventilated guinea pigs, which inhaled 4.9〜156μg/ml of histamine solution via a nebulizer. Stress to the guinea pigs was loaded by means of restriction in a wire net for 8 hours. PC_<200> (provocative concentration of histamine needed for double-time increase of pulmonary resistance from baseline) was tended to decrease in the restriction stress group compared with the control group. This increase of bronchial responsiveness due to restriction stress was not inhibited by pretreatment of atropine 5mg/kg(ip).Total cell counts in broncho-alveolar lavage fluid (BALF) were not significantly different between the control group and the restricion group. The percentage of alveolar macrophage in BALF was significantly decreased, and the percentage of lymphocytes and eosinophils were significantly increased in the restriction stress group compared with the control group. The ability to produce active oxygens of BALF cells, which was evaluated by luminol-dependent chemiluminescence stimulated by A23187,was significantly increased in the restriction stress group as compared with the control group. Although the mechanism of these alterations of BALF cells was not clear, it was suggested the participation of active oxygens in increased bronchial responsiveness due to restriction stress.

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In order to clarify the influence of emotional stress on T cells, we examined changes in the ratios of T cell subsets in the stressed mice, the patients with alopecia areata, and the student nurses before taking examinations for the national license. T cell subsets were measured using by flowcytometry and fluorescent monoclonal antibodies. The results are as follows. (1) In the restriction stressed mice, the ratio of T cell subsets are changed in the peripheral blood and the thymic gland. Percentage of suppressor T cells was decreased in the stressed mice and the changes are removed by administration of diazepam before restriction. (2) After administration of the autonomic drugs, adrenalin, acetylcholine, yohinbin and hydrocortisone, the ratios of T cell subsets are changed in the peripheral blood of mice. (3) In the peripheral blood of patients with alopecia areata, the ratio of the helper T cells to suppressor T cells is changed to be high during existance of uncontroled aloperia. But in the improved patients after psychotherapy, the ratio is decreased to the normal level. (4) After the examination stress, the ratio of OKT 8 positive cells is found to be elevated in the peripheral blood significantly. Other somatic parameters responsed to the examination stress.

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It has been proposed that immune and allergic responses are probably regulated by the central nervous system (CNS). In order to elucidate the relationship between the CNS function and immune and allergic responses, the influence of non-physical emotional stress on the number of plaque forming cells (PFC), IgE antibody formation and passive systemic anaphylaxis was investigated in mice employing the communication box in which shocked mice communicated their distress to unshocked mice in neighboring boxes.Besides, the effects of hypothalamic lesions on IgE antibody formation and passive cutaneous anaphylaxis (PCA) were investigated in rats. First, in order to determine the most effective timing of stress loading, mice were subjected to conditioned emotional stimulus (CES) for 8 hours per day before or after the immunization with sheep red blood cells (SRBC) according to various schedules, and 5 days after the immunization, the number of PFC was measured. When the CES was loaded immediately before the immunization for 1 day, the number of PFC showed a tendency to decrease, but was not affected in other conditions. This decrease in the number of PFC was alleviated by antianxiety drugs such as diazepam and zopiclone, but not by an antidepressant, desipramine. It is therefore clear that immune respomses are suppressed by nonphysical emotional stress, such as anxiety or fear. IgE antibody formation was nor affected by CES, but anaphylactic mortality was obviously reduced when CES was loaded immediately before the challenge for 1 day. These results suggest that non-physical emotional stress affects the efector phase of type I allergic reaction rather than the induction phase.Next, the influence of lesioning of the ventromedial hypothalamus (VMH) or lateral hypothalamus (LH) on IgE antibody formation and PCA was investigated. In results, neither VMH nor LH lesion affected IgE antibody formation, but both VMH and LH lesions apparently suppressed PCA. These results suggest that VMH and LH play a certain role in the regulation of the effector phase of type I allergic reaction.

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The excellent effect of fasting therapy for psychosomatic disease is already well known. Its effectiveness to allergic disease such as bronchial asthma gives us a suggestion that fasting therapy may have a certain influence in immunoactivity. On the other hand, starvation itself gives strong stress to human body, not only physically but also psychologically. For this reason, we may be able to regard "effect of fasting thrapy" as "effect of stress".In order to study the effect of fasting as therapy and as stress on immuoactivity, immunological factors were investigated in 29 cases with psychosomatic diseases and neuroses. All subjects were deprived of all food for 10 days and in an attempt to avoid dehydration the daily intake of normal drinking water was allowed without any limitation and were injected 500 ml of amino acid solution every day to protect the liver function during fasting period. Immunoglobulin, the number of total leucocytes, neutrophiles, lymphocytes and the ratio of T cell subsets in peripheral blood and serum cortisol were measured on the first and tenth day of the fasting period.By exposure of subjects to fasting, significant increases were obtained in the concentration of immunoglobulin (p<0.01) and serum cortisol (p<0.001). While there were sugnificant reductions in number of circulating total leucocytes (P<0.001), neutrophyles (p<0.001) and lymphocytes (p<0.01) at 10th day of fasting. The percentage of helper inducer T cells also fell significantly (p<0.01), but that of suppressor-cytotoxic T cells did not change, it seemed rather stable. It was found that there are significant negative correlations between the change of helper T cells and the changes of other immunological factors [total leucocytes count (p<0.01), cortisol (p<0.05)].These results indicate that the response of cortisol to the fasting play an important role in depression of immunoactivity. Fasting reduces the percentage of helper T cells and number of leucocytes in peripheral blood. But when helper T cells were reduced excessively, the number of leucocytes seems to be prevented from decreasing.It might be concluded that there is an autoregulatory mechanism in immune system, not to be depressed excessively by starvation stress.

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It is frequently stated that high fat diets are harmful with respect to nutrition and disease development. Herein, (NZB×NZW) F_1 autoimmune-prone mice were compared under the influence of, different calorie intakes and different calorie sources. When the energy intake of (NZB×NZW) F_1 female mice was reduced to 60% of the intake of simultaneously ad libitum-fed mice, the early death associated with autoimmune-based renal disease in this strain was greatly delayed. This influence of restriction of energy intake was greater thatn any influences of dietary energy source. In the group of mice with 60% intake of a carbohydrate-free (i.e. high fat) diet, the mean longevity was doubled as compared to that of ad libitum-fed mice. However, the nonprotein energy was supplied by carbohydrate (sourose and glycerol) the mean longivity was three times that of the ad libitum-fed group. With ad libitum feeding the nonprotein energy source did not significantly affect longevity. Clearly, although energy intake restriction provides significant influence on logevity, very high fat diets do not give the same protection as do high carbohydrate diets. Next experiments analyze the influence of protein intake on the development of autoimmune disease in (NZB×NZW) F_1 mice. Ad libitum feeding of diets with protein composition ranging from 15 to 50% did not alter longevity or onset and manifestations of renal disease. In mice consuming a restricted energy intake of a diet providing identical amounts of protein to those condumed by ad libitum-fed mice, whether the protein intake was very high or normal, longevity was equally prolonged. In summary, total calorie intake is the most important factor for the development of autoimmune disease in (NZB×NZW) F_1 mice. Fat intake is also a crucial factor in mice restricted energy intake. However, protein intake does not affect the development of autoimmune disease in these mice.

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We studied the immunological consequences of patients with psychosomatic disorders. Eating Disorder (ED) patients who are under malnutrition and psychological stress, have clinically shown a low incidence of infection.Ten patients with ED were compared with normal weight control, regarding their natural killer cell activity (NK activity) in blood samples. The ED patients did not show a statistically significant decrease in NK activity, and there were no correlations between the NK activity and weight loss, visceral protein indicator (S-Albumin).Fifteen patients with ED were studied for cell mediated immunity in terms of lymphocyte transformation responses (LTR) to T cell mitogen (PHA, ConA), B cell mitogen (PWN). The mitogen responsiveness was preserved untill weight loss and physical sevevity were far advanced.The LT responsibilities to T cell mitogen (PHA, Con A) in 8 depressive patients and 9 somatoform disorder patients shoswed a low tendency, although clinical data were conflicting.In the depressive patients who have high cortisol secretions, the LT responsibilities to mitogen were not correlated with hypercortisolnemia.

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