Klassische Konditionierung von Immunfunktionen: Mechanismen und klinische Relevanz

Zusammenfassung

Die klassische Konditionierung immunologischer Reaktionen ist ein beeindruckendes Beispiel für die bi-direktionale Kommunikation zwischen dem Zentralen Nervensystem und dem Immunsystem. Der vorliegende Artikel gibt einen Überblick über aktuelle experimentelle Forschungsansätze im Arbeitsfeld der klassischen Konditionierung immunologischer Reaktionen. Neben einer Zusammenfassung efferenter sowie afferenter Signalwege zwischen Gehirn und peripherem Immunsystem, werden sowohl bisher bekannte neurobiologische Mechanismen des Konditionierungsprozesses, als auch die potentielle klinische Relevanz der „gelernten Immunreaktion“ beschrieben. Abschließend werden neuropsychologische Mechanismen der klassischen Konditionierung wie Prozesse der Extinktion oder der Rekonsolidierung und ihre Bedeutung für die Konditionierung immunologischer Reaktionen näher erläutert und kritisch diskutiert.

Abstract

Behavioural conditioning of immune responses is one of the most impressive examples for the bidirectional communication between the nervous and immune systems. The present article provides an outline on the current approaches in the field of behaviourally conditioned immunomodulation. Efferent and afferent communication pathways between the brain and the peripheral immune system mediating learned immunosuppression, as well as the potential clinical relevance of behaviourally conditioned immunosuppression are discussed. Furthermore, neuropsychological processes that affect learning, and possible consequences for behaviourally conditioned immunosuppression will be highlighted.

Schlüsselwörter

klassische Konditionierung - Geschmacksaversion - Cyclosporin A - Immunsuppression - Extinktion

Key words

classical conditioning - conditioned taste aversion - cyclosporine A - immunosuppression - extinction

• Literatur

• 1 Exton MS, Herklotz J, Westermann J et al. Conditioning in the rat: an in vivo model to investigate the molecular mechanisms and clinical implications of brain-immune communication. Immunol Rev 2001; 184: 226-235
• 2 Dantzer R, O’Connor JC, Freund GG et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56
• 3 Tracey KJ. Understanding immunity requires more than immunology. Nat Immunol 2010; 11: 561-564
• 4 Ader R. Conditioned immunomodulation: research needs and directions. Brain, behavior, and immunity 2003; 17 (Suppl. 01) S51-S57
• 5 Riether C, Doenlen R, Pacheco-Lopez G et al. Behavioural conditioning of immune functions: how the central nervous system controls peripheral immune responses by evoking associative learning processes. Reviews in the neurosciences 2008; 19: 1-17
• 6 Schedlowski M, Pacheco-Lopez G. The learned immune response: Pavlov and beyond. Brain Behav Immun 2010; 24: 176-185
• 7 Exton MS, von Horsten S, Schult M et al. Behaviorally conditioned immunosuppression using cyclosporine A: central nervous system reduces IL-2 production via splenic innervation. J Neuroimmunol 1998; 88: 182-191
• 8 Pacheco-Lopez G, Engler H, Niemi MB et al. Expectations and associations that heal: Immunomodulatory placebo effects and its neurobiology. Brain, behavior, and immunity 2006; 20: 430-446
• 9 Sewards TV. Dual separate pathways for sensory and hedonic aspects of taste. Brain Res Bull 2004; 62: 271-283
• 10 Cubero I, Thiele TE, Bernstein IL. Insular cortex lesions and taste aversion learning: effects of conditioning method and timing of lesion. Brain research 1999; 839: 323-330
• 11 Sewards TV, Sewards MA. Cortical association areas in the gustatory system. Neurosci Biobehav Rev 2001; 25: 395-407
• 12 Pacheco-Lopez G, Niemi MB, Kou W et al. Neural substrates for behaviorally conditioned immunosuppression in the rat. The Journal of neuroscience: the official journal of the Society for Neuroscience 2005; 25: 2330-2337
• 13 Blalock JE, Smith EM. Conceptual development of the immune system as a sixth sense. Brain Behav Immun 2007; 21: 23-33
• 14 Banks WA. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Current pharmaceutical design 2005; 11: 973-984
• 15 Dantzer R, Konsman JP, Bluthe RM et al. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?. Autonomic neuroscience: basic & clinical 2000; 85: 60-65
• 16 Goehler LE, Gaykema RP, Hansen MK et al. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci 2000; 85: 49-59
• 17 Maier SF, Goehler LE, Fleshner M et al. The role of the vagus nerve in cytokine-to-brain communication. Annals of the New York Academy of Sciences 1998; 840: 289-300
• 18 Exton MS, Gierse C, Meier B et al. Behaviorally conditioned immunosuppression in the rat is regulated via noradrenaline and beta-adrenoceptors. Journal of neuroimmunology 2002; 131: 21-30
• 19 Exton MS, Schult M, Donath S et al. Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation. Am J Physiol 1999; 276: R1710-R1717
• 20 Pacheco-Lopez G, Riether C, Doenlen R et al. Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2009; 23: 1161-1167
• 21 Exton MS, von Horsten S, Strubel T et al. Conditioned alterations of specific blood leukocyte subsets are reconditionable. Neuroimmunomodulation 2000; 7: 106-114
• 22 Welzl H, D’Adamo P, Lipp HP. Conditioned taste aversion as a learning and memory paradigm. Behavioural brain research 2001; 125: 205-213
• 23 Bovbjerg DH. Conditioning, cancer, and immune regulation. Brain Behav Immun 2003; 17 (Suppl. 01) S58-S61
• 24 Schedlowski M, Hosch W, Oberbeck R et al. Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms. J Immunol 1996; 156: 93-99
• 25 Exton MS, Schult M, Donath S et al. Behavioral conditioning prolongs heart allograft survival in rats. Transplant Proc 1998; 30: 2033
• 26 Ader R, Mercurio MG, Walton J et al. Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med 2010; 72: 192-197
• 27 Ober K, Benson S, Vogelsang M et al. Plasma noradrenaline and state anxiety levels predict placebo response in learned immunosuppression. Clinical pharmacology and therapeutics 2012; 91: 220-226
• 28 Wirth T, Ober K, Prager G et al. Repeated recall of learned immunosuppression: evidence from rats and men. Brain, behavior, and immunity 2011; 25: 1444-1451
• 29 Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron 2008; 59: 195-206
• 30 Enck P, Bingel U, Schedlowski M et al. The placebo response in medicine: minimize, maximize or personalize?. Nature reviews Drug discovery 2013; 12: 191-204
• 31 Hadamitzky M, Engler H, Schedlowski M. Learned immunosuppression: extinction, renewal, and the challenge of reconsolidation. Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology 2013; 8: 180-188
• 32 Pacheco-Lopez G, Bermudez-Rattoni F. Brain-immune interactions and the neural basis of disease-avoidant ingestive behaviour. Philosophical transactions of the Royal Society of London Series B, Biological sciences 2011; 366: 3389-3405
• 33 Myers KM, Carlezon Jr WA. Extinction of drug- and withdrawal-paired cues in animal models: relevance to the treatment of addiction. Neuroscience and biobehavioral reviews 2010; 35: 285-302
• 34 Bouton ME, Westbrook RF, Corcoran KA et al. Contextual and temporal modulation of extinction: behavioral and biological mechanisms. Biol Psychiatry 2006; 60: 352-360
• 35 Dudai Y, Eisenberg M. Rites of passage of the engram: reconsolidation and the lingering consolidation hypothesis. Neuron 2004; 44: 93-100
• 36 Monfils MH, Cowansage KK, Klann E et al. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 2009; 324: 951-955
• 37 Nader K, Hardt O. A single standard for memory: the case for reconsolidation. Nat Rev Neurosci 2009; 10: 224-234
• 38 Schiller D, Monfils MH, Raio CM et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463: 49-53
• 39 Tronson NC, Taylor JR. Molecular mechanisms of memory reconsolidation. Nature reviews Neuroscience 2007; 8: 262-275
• 40 Bahar A, Dorfman N, Dudai Y. Amygdalar circuits required for either consolidation or extinction of taste aversion memory are not required for reconsolidation. Eur J Neurosci 2004; 19: 1115-1118
• 41 Berman DE, Dudai Y. Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 2001; 291: 2417-2419
• 42 Eisenberg M, Kobilo T, Berman DE et al. Stability of retrieved memory: inverse correlation with trace dominance. Science 2003; 301: 1102-1104
• 43 Garcia-DeLaTorre P, Rodriguez-Ortiz CJ, Arreguin-Martinez JL et al. Simultaneous but not independent anisomycin infusions in insular cortex and amygdala hinder stabilization of taste memory when updated. Learn Mem 2009; 16: 514-519
• 44 Berman DE, Hazvi S, Stehberg J et al. Conflicting processes in the extinction of conditioned taste aversion: behavioral and molecular aspects of latency, apparent stagnation, and spontaneous recovery. Learn Mem 2003; 10: 16-25
• 45 Rief W, Bingel U, Schedlowski M et al. Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clinical Pharmacology & Therapeutics 2011; 90: 722-726
• 46 Doering B, Rief W. Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends in Pharmacological Science 2012; 33: 165-172
• 47 Acosta JI, Thiel KJ, Sanabria F et al. Effect of schedule of reinforcement on cue-elicited reinstatement of cocaine-seeking behavior. Behavioural pharmacology 2008; 19: 129-136
• 48 Doering BK, Rief W. Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends in pharmacological sciences 2012; 33: 165-172
• 49 Sandler AD, Glesne CE, Bodfish JW. Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder?. Journal of developmental and behavioral pediatrics: JDBP 2010; 31: 369-375
• 50 Leech J, Mazzone SB, Farrell MJ. The effect of placebo conditioning on capsaicin-evoked urge to cough. Chest 2012; 142: 951-957