Zentrale Mechanismen bei der klassisch konditionierten Immunsuppression

Die Klassische Konditionierung von Funktionen des Immunsystems konnte mittlerweile überzeugend in tier- als auch humanexperimentellen Studien belegt werden. Dabei konnten bisher adrenerge Mechanismen identifiziert werden, die diese konditionierten Effekte vom ZNS in die Peripherie auf dem efferenten Weg vermitteln. Im Gegensatz dazu liegen bisher keine Daten zu den zentralnervösen Mechanismen der konditionierten Immunsuppression vor. Daher wurde in einer Reihe von Experimenten männlichen Dark Agouti Ratten bilaterale exzitotoxische Läsionen in den Inselkortex bzw. in den ventromedialen Kern des Hypothalamus sowohl vor dem Konditionierungsprozess (Erwerb/afferenter Weg) als auch nach der stattgefundenen Konditionierung (Abruf/efferenter Weg) appliziert. Mit Hilfe des Modells der Klassisch konditionierten Immunsuppression mit Cyclosporin A als unkonditioniertem Stimulus und Saccharin als konditioniertem Stimulus wurden die operierten Tiere konditioniert. Die Effekte der Läsionen auf den Konditionierungsprozess wurden im Vergleich zu Ratten gesetzt, die einerseits konditioniert wurden aber Scheinläsionen erhielten, sowie drei weiteren Kontrollgruppen, die keinen chirurgischen Eingriff erhielten. Die Hauptergebnisse zeigen, dass die Läsionen des Inselkortex sowohl den Erwerb als auch den Abruf der konditionierten Geschmacksaversion vollständig blockierten. Die Läsionen des ventromedialen Kern des Hypothalamus dagegen ließen die konditionierte Geschmacksaversion unbeeinflusst stattfinden. Der Erwerb und der Abruf der Klassisch konditionierten Immunsuppression gemessen in der Milzlymphozytenproliferation und in der Produktion der Zytokine IL-2 und IFN-? wurde vollständig durch die Läsionen des Inselkortex blockiert. Im Gegensatz dazu blieb der Erwerb der konditionierten Effekte auf das Immunsystem durch die VMH-Läsionen unbeeinflusst. Der Abruf der konditionierten Immunsuppression wurde jedoch durch diese Läsionen blockiert. Zusammengefasst zeigen diese experimentellen Befunde erstmalig, dass die Klassische Konditionierung zellulärer Immunfunktionen sowohl über den Inselkortex (afferent und efferent) als auch über den ventromedialen Kern des Hypothalamus (efferent) gesteuert werden

Behavioural conditioning of immune functions: how the central nervous system controls peripheral immune responses by evoking associative learning processes

During the last 30 years of psychoneuroimmunology research the intense bi-directional communication between the central nervous system (CNS) and the immune system has been demonstrated in studies on the interaction between the nervous-endocrine-immune systems. One of the most intriguing examples of such interaction is the capability of the CNS to associate an immune status with specific environmental stimuli. In this review, we systematically summarize experimental evidence demonstrating the behavioural conditioning of peripheral immune functions. In particular, we focus on the mechanisms underlying the behavioural conditioning process and provide a theoretical framework that indicates the potential feasibility of behaviourally conditioned immune changes in clinical situations

Acute amygdaloid response to systemic inflammation

The amygdala, a group of nuclei located in the medial temporal lobe, is a key limbic structure involved in mood regulation, associative learning, and modulation of cognitive functions. Functional neuroanatomical studies suggest that this brain region plays also an important role in the central integration of afferent signals from the peripheral immune system. In the present study, intracerebral electroencephalography and microdialysis were employed to investigate the electrophysiological and neurochemical consequences of systemic immune activation in the amygdala of freely moving rats. Intraperitoneal administration of bacterial lipopolysaccharide (100 μg/kg) induced with a latency of about 2 h a significant increase in amygdaloid neuronal activity and a substantial rise in extracellular noradrenaline levels. Activated neurons in the amygdaloid complex, identified by c-Fos immunohistochemistry, were mainly located in the central nucleus and, to a lesser extent, in the basolateral nucleus of the amygdala. Gene expression analysis in micropunches of the amygdala revealed that endotoxin administration induced a strong time-dependent increase in IL-1β, IL-6, and TNF-α mRNA levels indicating that these cytokines are de novo synthesized in the amygdala in response to peripheral immune activation. The changes in amygdaloid activity were timely related to an increase in anxiety-like behavior and decreased locomotor activity and exploration in the open-field. Taken together, these data give novel insights into different features of the acute amygdaloid response during experimental inflammation and provides further evidence that the amygdala integrates immune-derived information to coordinate behavioral and autonomic responses

Calcineurin inhibition in splenocytes induced by pavlovian conditioning

Pavlovian conditioning is one of the major neurobiological mechanisms of placebo effects, potentially influencing the course of specific diseases and the response to a pharmacological therapy, such as immunosuppression. In our study with behaviorally conditioned rats, a relevant taste (0.2% saccharin) preceded the application of the immunosuppressive drug cyclosporin A (CsA), a specific calcineurin (CaN) inhibitor. Our results demonstrate that through pavlovian conditioning the particular pharmacological properties of CsA can be transferred to a neutral taste, i.e., CaN activity was inhibited in splenocytes from conditioned rats after reexposure to the gustatory stimulus. Concomitant immune consequences were observed on ex vivo mitogenic challenge (anti-CD3). Particularly, Th1-cytokine, but not Th2-cytokine, production and cell proliferation were impeded. Appropriate pharmacological and behavioral controls certify that all these changes in T-lymphocyte reactivity are attributable to mere taste reexposure. Furthermore, the underlying sympathetic-lymphocyte interaction was revealed modeling the conditioned response in vitro. CaN activity in CD4(+) T lymphocytes is reduced by beta-adrenergic stimulation (terbutaline), with these effects antagonized by the beta-adrenoreceptor antagonist nadolol. In summary, CaN was identified as the intracellular target for inducing conditioned immunosuppression by CsA, contributing to our understanding of the intracellular mechanisms behind "learned placebo effects.

Neurobehavioural activation during peripheral immunosuppression

Like other physiological responses, immune functions are the subject of behavioural conditioning. Conditioned immunosuppression can be induced by contingently pairing a novel taste with an injection of the immunosuppressant cyclosporine A (CsA) in an associative learning paradigm. This learned immunosuppression is centrally mediated by the insular cortex and the amygdala. However, the afferent mechanisms by which the brain detects CsA are not understood. In this study we analysed whether CsA is sensed via the chemosensitive vagus nerve or whether CsA directly acts on the brain. Our experiments revealed that a single peripheral administration of CsA increases neuronal activity in the insular cortex and the amygdala as evident from increased electric activity, c-Fos expression and amygdaloid noradrenaline release. However, this increased neuronal activity was not affected by prior vagal deafferentation but rather seems to partially be induced by direct action of CsA on cortico-amygdaloid structures and the chemosensitive brainstem regions area postrema and nucleus of the solitary tract. Together, these data indicate that CsA as an unconditioned stimulus may directly act on the brain by a still unknown transduction mechanism

Time-dependent alterations of peripheral immune parameters after nigrostriatal dopamine depletion in a rat model of Parkinson's disease

Dysfunction of the central dopaminergic system is associated with neurodegenerative disorders and mental illnesses such as Parkinson's disease and schizophrenia. Patients suffering from these diseases were reported to exhibit altered immune functions compared to healthy subjects and imbalance of the central dopaminergic system has been suggested as one causative factor for the immune disturbances. However, it is unclear whether the observed immune changes are primary or secondary to the disease. Here we demonstrate that central dopamine (DA) depletion in a rat model of Parkinson's disease induced transient changes in blood leukocyte distribution and cytokine production that were apparent until four weeks after bilateral intrastriatal administration of the neurotoxin 6-hydroxydopamine (6-OHDA). Eight weeks after treatment, no differences in blood immune parameters were anymore evident between neurotoxin-treated and control animals. Nevertheless, animals with a widespread damage of dopaminergic neurons in the nigrostriatal system showed an exacerbated pro-inflammatory response following in vivo challenge with bacterial lipopolysaccharide. Our data indicate that peripheral immune perturbations in the early phase after intrastriatal 6-OHDA administration might have been related to the neurodegenerative process itself whereas the increased sensitivity to the inflammatory stimulus seems to have resulted from an impaired dopaminergic control of prolactin (PRL) and corticosterone (CORT) secretion. The findings demonstrate that the brain dopaminergic system is involved in peripheral immune regulation and suggest that central dopaminergic hypoactivity bears the risk of excessive inflammation, e.g., during infection or tissue injury