Norman Cousins LectureThe learned immune response: Pavlov and beyond
Introduction
The behavioral conditioning of immune functions is a fascinating example illustrating the bidirectional interactions between the central nervous system (CNS) and the peripheral immune system (Ader and Cohen, 2001). While expressions such as learning and memory are fixed components in the immunological terminology, when referring to the processes to improve recognition of antigens by B or T lymphocytes, for a long time it remained enigmatic why peripheral immune responses should be affected by classical, or Pavlovian, conditioning. In recent years, it is becoming increasingly acknowledged and accepted that this “learned immune response” indeed developed during evolution as an adaptive strategy.
Ambulatory organisms evolved to face rapidly changing internal and external environments by acquiring the ability to learn and to modify instinctive behaviors. Classical conditioning can thus be understood as the process of learning about the temporal and/or causal relationships between external and internal stimuli. This process enables the organism to use the appropriate preparatory set of responses before biologically significant events occur (Rescorla, 1988, Rescorla, 2003). From this perspective, the capacity to associate a specific environmental context or a particular flavor (conditioned stimuli: CS) with specific immune challenges e.g. allergens, toxins or antigens (unconditioned stimuli: US) is certainly of highly adaptive value. Thus, it can be hypothesized that this capacity was acquired during evolution as an adaptive strategy in order to protect the organism and prepare it for danger. For example, the exposure to a specific antigen and its categorization as an allergen might be centrally associated (i.e., a learning process) with a specific environment or food. An adaptive response is then elicited (i.e., a memory process), consisting first of behavioral modifications to avoid the place or food associated with the antigen (Costa-Pinto et al., 2005, Markovic et al., 1992). If avoidance is not possible, the organism will try to reduce the contact with the allergen, for instance by coughing or sneezing (Pinto et al., 1995). At the same time, the immune system may prepare the body for interaction with the antigen, e.g. by mast cell degranulation (Irie et al., 2001, MacQueen et al., 1989, Palermo-Neto and Guimarães, 2000, Russell et al., 1984) or antibody production (Ader et al., 1993, Alvarez-Borda et al., 1995, Chen et al., 2004, Husband et al., 1993). Although under experimental conditions such associative learning can be extinguished, it is likely that it will last for a long time, since the optimal adaptive strategy in a natural setting would be for the organisms to consistently avoid contact with the environmental cues that signal the CS. However, it should be emphasized that under artificial conditions, i.e. employing potent immunosuppressive drugs, the organism “learns” to mimic the pharmacologic effects, desirable under clinical settings, but to a certain extent contra-adaptive, if this would occurs under natural settings.
Two basic steps compose any classical conditioning protocol: an acquisition phase in which one or more CS–US contingent pairings occur in order to induce an associative learning process, and an evocation phase where the memory of the newly acquired association is retrieved after exposing the subject to the CS (Pavlov, 1927). The association of food or drink ingestion with its possible post-prandial toxic/immune consequences has been experimentally studied in rodents and humans employing the conditioned taste aversion model (Garcia et al., 1955). In this experimental paradigm, the individual learns to associate a particular taste with a delayed visceral malaise (Bermúdez-Rattoni, 2004). This learning capacity has been conserved across the animal kingdom (Kawai et al., 2004, Marella et al., 2006, Paradis and Cabanac, 2004, Schedlowski, 2006), including humans (Garb and Stunkard, 1974), reflecting its highly adaptive value, currently just attributed to food selection strategies but indeed involved in a more complex and diverse repertoire of physiological responses that the individual evokes in order to avoid, reject and/or initiate defense strategies against harmful unconditioned effects (Niemi et al., 2006). The majority of studies in rodents employ a sweet tasting solution (e.g. saccharin) as a CS and an injection of an immuno-modulating drug or agent as a US. After one or several pairings of CS and US during the acquisition (learning) phase, animals are re-exposed to the CS during the evocation phase (memory). The re-exposure to the CS is now inducing conditioned behavioral and immunological responses. At the behavioral level this response is characterized by avoidance and/or aversion to the CS reflected by a reduced consumption of the sweet tasting solution. More importantly, the re-exposure to the CS elicits an immune response, which is similar to the response induced by the drug or agent employed as the US (Ader, 2003, Ader and Cohen, 1991, Ader and Cohen, 2001, Brittain and Wiener, 1985, Hucklebridge, 2002, Markovic et al., 1993, Pacheco-López et al., 2006, Riether et al., 2008).
The uniqueness of the paradigm of behaviorally conditioned immune responses in analyzing CNS–immune system interaction is manifold (Fig. 1). From a systematic point of view, one advantage is certainly the chance to analyze the afferent and efferent communication pathways between the brain and the peripheral immune system in one model together with the stimuli processing by the CNS. In addition, by implementing diverse clinical readout systems, the potential therapeutic relevance of the behaviorally conditioned immune response can be investigated. In this review we summarize the neurobiological mechanisms mediating this kind of associative learning and subsequently address the pathways and mechanisms employed by the brain to harness the immune system. Finally, we discuss the therapeutic relevance of such learned immune responses, and their re-conceptualization within the framework of “learned placebo effects”.
To elucidate the peripheral and central mechanisms mediating conditioned immunosuppressive responses together with the potential clinical meaning of this phenomenon, our laboratory has established a paradigm in which the selective immunosuppressive drug cyclosporine A (CsA) as the US is contingently paired with a distinctive taste (saccharin) as the CS. CsA is a calcineurin (CaN) inhibitor reducing the synthesis of mainly Th1-cytokines, in particular IL-2 and is therefore relatively specifically suppressing the activity of T lymphocytes (Batiuk and Halloran, 1997, McCaffrey et al., 1993).
Section snippets
How the CNS receives the signals: Afferent pathways
In order to associate a CS (such as a taste or an odor) with a US (for example an immuno-modulating agent), the CNS must sense the signals induced by the CS and US. The neural mechanisms of olfactory or gustatory perception are reasonably well understood, including the transduction of taste signals by specific receptors on the taste buds, propagation of the gustatory signals via several peripheral nerves as well as brain stem and thalamic relays, and processing of gustatory perception by a
Conditioning takes place: Relevant brain structures and neurotransmitters
During the acquisition, both CS and US are associated in the CNS, and in the whole field of neurobiology, learning and memory will be essential to understand the mechanisms of association and long-term information storage (Berman and Dudai, 2001, Bermúdez-Rattoni, 2004, McGaugh et al., 2002). Studies involved in taste aversion learning demonstrated, that the insular cortex is particularly relevant for the acquisition and retention of the associative learning process (Bermudez-Rattoni and
The conditioned immune response: Efferent pathways
Based on the main findings on neural innervation of secondary lymphoid organs such as the spleen (Felten and Olschowka, 1987, Nance and Sanders, 2007) and the expression of receptors for neurotransmitters on lymphocytes (Sanders and Kohm, 2002, Sanders and Straub, 2002), the splenic nerve was identified as one major efferent pathway linking the brain and the immune system. Employing CsA as the US in a taste aversion paradigm, surgical denervation of the spleen completely blocked the conditioned
Animal models
A number of studies have addressed the possibility that conditioned changes in immune functions are able to affect disease outcome. Using experimental models of autoimmune or allergic diseases, tumor progression and organ transplantation, the vision to employ Pavlovian conditioning regimens as a complementary therapy supporting pharmacological treatment has been put to the test.
In New Zealand hybrid mice, which are prone to develop an autoimmune disease resembling human lupus erythematosus, a
The learned immune response: Summary, open questions and future perspectives
The brain’s capability to modulate peripheral immune reactivity has been demonstrated by paradigms of behavioral conditioning in animal experiments and human studies. Pavlovian conditioning can be considered adaptive mechanism by which an organism learns to anticipate the onset of a biologically important event, and initiates preparatory responses, including lymphoid- and myeloid cells based responses. Due to the physiological basis of the conditioned effects, the magnitude of the conditioned
Acknowledgments
This work was supported by a grant from the German Research Foundation (SCH 341/13-1). We greatly appreciate the contribution of all the colleagues how have been and who still are involved in our conditioning work: Federico Bermúdez-Rattoni, Hugo Besedovsky, Adriana del Rey, Raphael Doenlen, Andrea Engler, Harald Engler, Michael S. Exton, Joachim Fandrey, Marion Goebel, Uwe Heemann, Cobi Heijnen, Annemieke Kavelaars, Ute Krügel, Wolfgang Langhans, Volker Limmroth, Martin Michel, Maj-Britt
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