Marion U. Goebel

Behavioral conditioning of immunosuppression is possible in humans

Behavioral conditioned immunosuppression has been described in rodents as the most impressive demonstration of brain‐to‐immune system interaction. To analyze whether behavioral conditioned immunosuppression is possible in humans, healthy subjects in this double‐blind, placebo‐controlled study were conditioned in four sessions over 3 consecutive days, receiving the immunosuppressive drug cyclosporin A as an unconditioned stimulus paired with a distinctively flavored drink (conditioned stimulus) each 12 h. In the next week, re‐exposure to the conditioned stimulus (drink), but now paired with placebo capsules, induced a suppression of immune functions as analyzed by the IL‐2 and IFN‐γ mRNA expression, intracellular production, and in vitro release of IL‐2 and IFN‐γ, as well as lymphocyte proliferation. These data demonstrate for the first time that immunosuppression can be behaviorally conditioned in humans.—Goebel, M. U., Trebst, A. E., Steiner, J., Xie, Y. F., Exton, M. S., Frede, S., Canbay, A., Michel, M. C., Heemann, U., Schedlowski, M. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 16, 1869–1873 (2002)

G protein-coupled receptor kinase 2 in multiple sclerosis and experimental autoimmune encephalomyelitis

Many modulators of inflammation, including chemokines, neuropeptides, and neurotransmitters signal via G protein-coupled receptors (GPCR). GPCR kinases (GRK) can phosphorylate agonist-activated GPCR thereby promoting receptor desensitization. Here we describe that in leukocytes from patients with active relapsing-remitting multiple sclerosis (MS) or with secondary progressive MS, GRK2 levels are significantly reduced. Unexpectedly, cells from patients during remission express even lower levels of GRK2. The level of GRK2 in leukocytes of patients after stroke, a neurological disorder with paralysis but without an autoimmune component, was similar to GRK2 levels in cells from healthy individuals. In addition, we demonstrate that the course of recombinant myelin oligodendrocyte glycoprotein (1–125)-induced experimental autoimmune encephalomyelitis (EAE), an animal model for MS, is markedly different in GRK2+/− mice that express 50% of the GRK2 protein in comparison with wild-type mice. Onset of EAE was significantly advanced by 5 days in GRK2+/− mice. The earlier onset of EAE was associated with increased early infiltration of the CNS by T cells and macrophages. Although disease scores in the first phase of EAE were similar in both groups, GRK2+/− animals did not develop relapses, whereas wild-type animals did. The absence of relapses in GRK2+/− mice was associated with a marked reduction in inflammatory infiltrates in the CNS. Recombinant myelin oligodendrocyte glycoprotein-induced T cell proliferation and cytokine production were normal in GRK2+/− animals. We conclude that down-regulation of GRK2 expression may have important consequences for the onset and progression of MS.

Behavioral Conditioning of Antihistamine Effects in Patients with Allergic Rhinitis

Background: Allergic symptoms can be induced by behavioral conditioning. However, the conditionability of antiallergic effects has not yet been studied. Thus, we investigated whether the effects of a histamine 1 (H1) receptor antagonist are inducible in patients suffering from house-dust mite allergy using a behavioral conditioning procedure. Methods: During the association phase, 30 patients with allergic house-dust mite rhinitis received a novel-tasting drink once daily, followed by a standard dose of the H1 receptor antagonist, desloratadine, on 5 consecutive days. After 9 days of drug washout, the evocation trial commenced: 10 patients received water together with an identically looking placebo pill (water group), 11 patients were re-exposed to the novel-tasting drink and received a placebo pill [conditioned stimulus (CS); CS group] and 9 patients received water and desloratadine (drug group). Results: During the association phase, desloratadine treatment decreased the subjective total symptom scores, attenuated the effects of the skin prick test for histamine and reduced basophil activation ex vivo in all groups. During the evocation trial, the water group, in which subjects were not re-exposed to the gustatory stimulus, showed a reduction in subjective total symptom scores and skin prick test results, but no inhibition of basophil activation. In contrast, re-exposure to the novel-tasting drink decreased basophil activation, the skin prick test result and the subjective symptom score in the CS group to a degree that was similar to the effects of desloratadine in the drug group. Conclusions: These data show that behaviorally conditioned effects are not only able to relieve subjective rhinitis symptoms and allergic skin reactions, but also to induce changes in effector immune functions.

Flares in Patients with Systemic Lupus erythematosus Are Associated with Daily Psychological Stress

Background: The aetiology of systemic lupus erythematosus (SLE) remains unclear. Clinical observations and a small number of studies performed so far suggest an association between psychological stress and self-reported symptoms of SLE patients. This longitudinal study was designed to investigate whether daily psychological stress is associated with flares in SLE patients, measured by clinical and laboratory parameters. Methods: Female SLE patients (n = 41) were followed over a period of six months. Daily stress was monitored by a hand-held PC diary programmed with 44 items based on standardized measures and clinical experience. Once every four weeks patients visited the outpatient clinic for medical evaluation. Disease activity was evaluated using the European Consensus Lupus Activity Measurement (ECLAM), laboratory parameters, and intake of steroids. Results: Classification and regression tree (CART) patient-wise analyses revealed that SLE patients with vs. without flares using complement and ECLAM as activity measures show greater negative self-ratings in mood, and social duties (p < 0.01). In addition, mixed model analysis of variance showed that daily hassles with social relationships were significantly associated with flares in SLE measured by an increase in steroid medication >5mg/d (p < 0.01). Conclusions: These results suggest that psychological stress is associated with flares in SLE. Particularly daily stress with social relationships and social duties may be factors to be related to the course of disease activity in SLE.

Are There Alterations of Neuroendocrine and Cellular Immune Responses to Nutrients in Women with Irritable Bowel Syndrome

OBJECTIVES:The goal was to investigate the neuroimmune axis in irritable bowel syndrome (IBS) by analyzing the neuroendocrine and cellular immune responses to nutrient load.METHODS:In the fasting state and 20, 40, 70, and 100 min following nutrient load, blood samples were collected and cardiovascular recordings were accomplished in 15 female IBS patients and 15 healthy women. Plasma norepinephrine, prolactin, cortisol, and growth hormone were analyzed, and blood pressure and heart rate responses were measured. The distribution of peripheral leukocytes and lymphocyte subpopulations and the in vitro production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) after whole blood stimulation with in lipopolysaccharide (LPS) were analyzed.RESULTS:IBS patients demonstrated significantly greater postprandial increases in plasma norepinephrine and systolic blood pressure (p < 0.05), but no cortisol response. A postprandial redistribution of circulating leukocytes and lymphocyte subpopulations was observed in both groups, including significant increases in the numbers of leukocytes and granulocytes and significant decreases in the numbers of monocytes, T-cells, and natural killer (NK) cells (all p < 0.05). However, IBS patients demonstrated significantly greater postprandial increases in leukocytes and granulocytes, while changes in the numbers of monocytes and NK cells were significantly diminished (all p < 0.05). Patients also failed to show the postprandial decrease in the in vitro TNF-α production observed in controls. Postprandial norepinephrine concentrations were negatively correlated with NK cell numbers in IBS patients (r= 0.58, p < 0.05) but not controls.CONCLUSIONS:IBS may involve an autonomic hyper-responsiveness to visceral stimuli, which occurs throughout the entire gut, is independent of acutely perceived GI symptoms, and does not necessarily involve HPA axis activation. Women with IBS show altered cellular immune responses to food intake, which may at least in part be mediated by adrenergic mechanisms. Thus, autonomic disturbances may have implications for cellular immune function along the neuroendocrine-immune axis in patients with IBS.

Behaviorally conditioned immunosuppression in the rat is regulated via noradrenaline and β-adrenoceptors.

Using Cyclosporin A (CsA) as an unconditioned stimulus has previously demonstrated that behaviorally conditioned inhibition of splenocyte proliferation and cytokine production is mediated via the splenic nerve. Therefore, we currently examined the adrenergic modulation of conditioned suppression of splenocyte function. Chemical sympathectomy via 6-OHDA completely blocked the conditioned suppression of splenocyte proliferation to mitogens and cytokine (IL-2, IFN-gamma) production. Furthermore, administration of beta-adrenoceptor antagonist propranolol abrogated the conditioned effect on splenocyte proliferation. Supporting the position that conditioning is beta-adrenergic-dependent, addition of beta-adrenoceptor agonist, but not alpha-adrenoceptor agonists, to splenocytes in vitro mimicked the conditioned suppression of splenocyte functions, with these effects blocked by propranolol. Therefore, these data indicate that behavioral conditioning of splenocyte function in the rat is regulated by the sympathetic nervous system, predominantly via beta-adrenergic mechanisms.

Central catecholamine depletion inhibits peripheral lymphocyte responsiveness in spleen and blood

Experimental and clinical evidence has demonstrated extensive communication between the CNS and the immune system. To analyse the role of central catecholamines in modulating peripheral immune functions, we injected the neurotoxin 6‐hydroxydopamine (6‐OHDA) i.c.v. in rats. This treatment significantly reduced brain catecholamine content 2, 4 and 7 days after injection, and in the periphery splenic catecholamine levels were reduced 4 days after treatment. Central catecholamine depletion induced an inhibition of splenic and blood lymphocyte proliferation and splenic cytokine production and expression (interleukin‐2 and interferon‐γ) 7 days after injection. In addition, central treatment with 6‐OHDA reduced the percentage of spleen and peripheral blood natural killer (CD161 +) cells, and T‐cytotoxic (CD8 +) cells in peripheral blood. The reduction in splenocyte proliferation was not associated with a glucocorticoid alteration but was completely abolished by prior peripheral sympathectomy. These data demonstrate a crucial role of central and peripheral catecholamines in modulating immune function.

Quantification of DeQi Sensation by Visual Analog Scales in Healthy Humans after Immunostimulating Acupuncture Treatment

Acupuncture is the most popular component of traditional Chinese medicine in Western countries. However, the mechanisms of its effects remain unclear. The therapeutic effect of acupuncture appears when a sensation of DeQi is achieved. We previously reported that repeated, but not single acupuncture treatment affected leukocyte circulation and blood pressure in healthy young humans. The objective of this study was to quantify DeQi sensation by using visual analog scales (VASs) and, to test whether DeQi induction is an important factor for the therapeutic effects of acupuncture in the same cohort. After either acupuncture or sham-acupuncture (placebo) treatment, a questionnaire containing five individual VASs was given to subjects to evaluate their DeQi sensation, including numbness, pressure, heaviness, warmth, and radiating paraesthesia, respectively. A separate VAS to measure their levels of anxiety during the treatment was also included. Our results showed that acupuncture significantly induced higher VAS values for numbness, pressure, warmth, and radiating paraesthesia, but not for heaviness than the placebo across three treatment sessions. Additionally, acupuncture did not induce higher anxiety levels than the placebo. These data confirm that VAS is an objective and reliable way to quantify DeQi sensation and, indicate that DeQi is unique to verum acupuncture treatment. Furthermore, either acupuncture-induced therapeutic effects or DeQi sensation should not be attributed to the stress-mediated effects. In summary, the induction of DeQi in each treatment session is an important factor for the physiological outcomes of repeated acupuncture treatment, and VASs offer objective, an easy and reliable way to assess it.

Behavioral conditioning with interferon beta-1a in humans.

Behavioral conditioning is one of the most impressive demonstrations of brain-immune system interaction. Numerous animal studies have demonstrated behavioral conditioned effects on immune functions, however, human studies are rare. We investigated whether it is possible to behaviorally condition the acute response to interferon (IFN)beta-1a. In a double-blind placebo-controlled study, 30 healthy subjects received a single injection of IFN(beta)-1a (6MIU of REBIF, Serono International) (unconditioned stimulus, UCS) together with a novel drink (conditioned stimulus, CS). Blood was drawn at baseline, 4, 8, and 24 h after drug administration. Within the first 8 h peripheral granulocytes significantly increased, while monocytes, lymphocytes, T-, B- and natural killer (NK) cell numbers were significantly reduced. In parallel, body temperature, heart rate, norepinephrine and interleukin (IL)-6 plasma levels were heightened within 8 h after injection. 8 days later, all previously IFN(beta)-treated subjects received a subcutaneous placebo (NaCl) injection, but only 15 subjects were re-exposed to the CS (experimental group), while a control group (N=15) drank water and an additional group of subjects (n=8) remained untreated (untreated group). Blood sampling was performed at baseline and at 4, 8, and 24 h. Re-exposition to the CS did not elicit conditioned responses in the experimental group. Moreover, no differences were observed between groups. These data provide negative findings regarding behavioral conditioning of cytokine effects in humans employing a one-trial learning paradigm.

Repeated acupuncture treatment affects leukocyte circulation in healthy young male subjects : A randomized single-blind two-period crossover study

Acupuncture is the most popular component of traditional Chinese medicine in western countries, which has been widely used in the treatment of numerous medical conditions, e.g., pain, emesis or asthma. However, the effects of acupuncture on neuroendocrine and immune functions in humans remain unclear. Therefore, the present study was performed to analyse whether acupuncture treatment affects leukocyte circulation as well as plasma levels of cortisol and norepinephrine in humans. Ten healthy young male subjects were enrolled in a randomized single-blind two-period crossover study. Each period contained three sessions of either acupuncture or sham acupuncture (placebo) treatment. After randomisation, the group 1 (n=5) received acupuncture treatment at acu-points ST36, LI11, SP10, and GV14, while sham acupuncture was performed for group 2 (n=5). Two weeks later, each group received the alternative treatment. Blood samples were taken before needling, 10 min after, and 30 min after removing the needles in the first and the third session. In addition, blood pressure and heart rate were determined simultaneously. Although acupuncture treatment did not affect leukocyte circulation in peripheral blood after the first session, we observed a significant decrease in leukocyte and lymphocyte values after the third session. In contrast, cortisol and norepinephrine plasma levels remained unchanged by acupuncture. These data indicate that repeated acupuncture treatment can affect leukocyte circulation in healthy humans by still unknown mechanisms.