Egarding the kinetics of learned immunosuppression, the present study analyzed whether a learned immunosuppression can be detected not only after four reexpositions to the CS [19] but also already after a single CS reexposure. Our data MedChemExpress 113-79-1 clearly demonstrate that a single re-exposition to the CS is not sufficient to induce an immunosuppressive response. This finding confirms previous data of animal studies revealing that once consolidated, the extinction of the taste-CsA engram is prolonged and the more this engram is activated at evocation, the more pronounced is the behaviorally conditioned immunosuppression [20]. We could recently demonstrate in both rodents and humans that the learned immunosuppression is not restricted to a single event but is retrievable and can be repeatedly recalled [19]. In addition, plasma noradrenaline and state anxiety seem to predict this learned immunosuppression in placebo responders [24]. Regarding these findings it is important to consider that repeated unreinforced re-expositions to the CS will finally lead to an extinction of the conditioned response [37]. However, the processes modulating extinction learning in conditioned immunosuppression such as context changes, retention intervals and reconsolidation are for the most part unknown [38]. Thus, regarding the potential feasibility of the conditioning procedure in clinical situations, further research focusing on the question how to overcome the extinction process is of essential significance. Furthermore, a better understanding of the neurobiological mechanisms steering learned immune responses is of great importance. So far, 1480666 experimental evidence reveals that the learned immune response employing CsA as an US is mediated centrally via the insular cortex, the amygdala and the ventromedial nucleusPlacebo Effects on the Immune ResponseFigure 3. Expectation induced cytokine response. (A) Expectation did not induce a significant reduction in IL-2 production in any of the four expectation groups differing in the probability of receiving CsA. IL-2 (pg/ml) concentration in supernatants of anti-CD3 stimulated PBMC was analyzed before and after placebo pill intake (25 n = 9, 50 n = 8, 75 n = 8, 100 n = 8). Data are shown as mean 6 SEM. (B) Expectation did not reduce the percentage of IL-2 producing CD4+T cells. IL-2 producing CD4+T cells were analyzed as percent of total CD4+T cells before and after placebo pill intake. Data are shown as mean 6 SEM. doi:10.1371/journal.pone.0049477.gof the hypothalamus [39] and steered via sympathetic innervation of the spleen, noradrenaline 1407003 and b-adrenoreceptor-dependent mechanisms [40]. However, more detailed knowledge about the kinetics of the learned immune response and the mechanisms behind the CNS-immune system interaction is urgently needed. Only with this 166518-60-1 cost information it will be possible to design conditioning protocols which can be employed in clinical settings to reduce the required drug dose while maximizing the therapeutic outcome for the patients benefit [8].Supporting InformationTable S1 Sociodemographic and psychological characteristics (experiment A and B). No significant differences between experimental and respective control groups were observed in experiments A and B (results of unpaired samples ttests or chi2-test, all p.0.05) (DOCX) Table S2 Sociodemographic and psychological characteristics and cardiovascular parameters (experiment C).Placebo Effects on the Immune ResponseAge, body mass index, Beck Depre.Egarding the kinetics of learned immunosuppression, the present study analyzed whether a learned immunosuppression can be detected not only after four reexpositions to the CS [19] but also already after a single CS reexposure. Our data clearly demonstrate that a single re-exposition to the CS is not sufficient to induce an immunosuppressive response. This finding confirms previous data of animal studies revealing that once consolidated, the extinction of the taste-CsA engram is prolonged and the more this engram is activated at evocation, the more pronounced is the behaviorally conditioned immunosuppression [20]. We could recently demonstrate in both rodents and humans that the learned immunosuppression is not restricted to a single event but is retrievable and can be repeatedly recalled [19]. In addition, plasma noradrenaline and state anxiety seem to predict this learned immunosuppression in placebo responders [24]. Regarding these findings it is important to consider that repeated unreinforced re-expositions to the CS will finally lead to an extinction of the conditioned response [37]. However, the processes modulating extinction learning in conditioned immunosuppression such as context changes, retention intervals and reconsolidation are for the most part unknown [38]. Thus, regarding the potential feasibility of the conditioning procedure in clinical situations, further research focusing on the question how to overcome the extinction process is of essential significance. Furthermore, a better understanding of the neurobiological mechanisms steering learned immune responses is of great importance. So far, 1480666 experimental evidence reveals that the learned immune response employing CsA as an US is mediated centrally via the insular cortex, the amygdala and the ventromedial nucleusPlacebo Effects on the Immune ResponseFigure 3. Expectation induced cytokine response. (A) Expectation did not induce a significant reduction in IL-2 production in any of the four expectation groups differing in the probability of receiving CsA. IL-2 (pg/ml) concentration in supernatants of anti-CD3 stimulated PBMC was analyzed before and after placebo pill intake (25 n = 9, 50 n = 8, 75 n = 8, 100 n = 8). Data are shown as mean 6 SEM. (B) Expectation did not reduce the percentage of IL-2 producing CD4+T cells. IL-2 producing CD4+T cells were analyzed as percent of total CD4+T cells before and after placebo pill intake. Data are shown as mean 6 SEM. doi:10.1371/journal.pone.0049477.gof the hypothalamus [39] and steered via sympathetic innervation of the spleen, noradrenaline 1407003 and b-adrenoreceptor-dependent mechanisms [40]. However, more detailed knowledge about the kinetics of the learned immune response and the mechanisms behind the CNS-immune system interaction is urgently needed. Only with this information it will be possible to design conditioning protocols which can be employed in clinical settings to reduce the required drug dose while maximizing the therapeutic outcome for the patients benefit [8].Supporting InformationTable S1 Sociodemographic and psychological characteristics (experiment A and B). No significant differences between experimental and respective control groups were observed in experiments A and B (results of unpaired samples ttests or chi2-test, all p.0.05) (DOCX) Table S2 Sociodemographic and psychological characteristics and cardiovascular parameters (experiment C).Placebo Effects on the Immune ResponseAge, body mass index, Beck Depre.
