14.1. INTRODUCTION

Experimental evidence demonstrates intensive and extensive interactions between the nervous and immune systems.^1–4 The central capacity of associating a certain immune response or status (allergen, toxin, antigen) with a specific stimulus (environment or flavor) seems to be of high adaptive value; this special kind of associative learning may have been acquired as an adaptive strategy during evolution in order to protect an organism and/or prepare it for danger. Furthermore, it is possible that, depending on the different environmental challenges, the species formed species-specific associations during evolution.⁵

Classical conditioning or associative learning is often described as the transfer of the response-eliciting property of a biologically significant stimulus (unconditioned stimulus; US) to another stimulus (conditioned stimulus; CS) without that property.^6–10 This transfer is thought to occur only if the CS serves as a predictor of the US.^11–13 Thus, classical conditioning can be understood as learning about the temporal or causal relationships between external and internal stimuli, to allow for the appropriate preparatory set of responses before biologically significant events occur.

Regarding neuro-immune associative learning (NIAL), an immunomodulatory stimulus (antigen, immunomodulating drug) is employed as an US and paired with a neutral stimulus. After this associative phase, the neutral stimulus becomes a CS that can modify the immune response on demand (conditioned response; CR). The influence of NIAL on immune responses has been reviewed several times.^14–32 However, in this chapter we propose an innovative approach, pointing out the biological meaning and possible clinical implications of neuro-immune associative learning. Furthermore, after analyzing the available literature, we propose a general theoretical framework for this special kind of associative learning.

14.1.1. Historical Development

S. Metalnikov and V. Chorine are generally credited with having conducted the first studies on NIAL.³³ However, V.I. Luk’ianenko cites the 1911 dissertation of I.I. Makukhin at the University of St. Petersburg and a 1925 report by A. Voronov and I. Riskin as perhaps the first researchers to demonstrate the “conditioned leukocytic reaction.”¹⁷ Metalnikov and Chorine reported a series of experiments that clearly demonstrated the possibility of associating exteroceptive stimuli with alterations in immune parameters induced for the most part by injections of bacterial and viral preparations.^33,34 Guinea pigs were given daily association trials with contingent pairing of scratching or heating of the skin as a CS and an immune challenge (i.p. injection of a small dose of tapioca, Bacillus anthrax, or a Staphylococcus filtrate) as an US. The CR was an increase in peritoneal leukocyte numbers that was weaker and more transitory than the UR. Follow-up experiments indicated that after the recall phase, conditioned animals survived longer after lethal injections of Vibrio cholera bacteria.

These initial results were rapidly replicated,^35,37 and in the following years Soviet investigators paid considerable attention to this topic.^17,38 Many of these experiments were basically similar to those performed by Metalnikov and Chorine, and apparently a controversy arose over the reproducibility of certain experiments. In parallel to the Soviet experiments, but not as well-known, were investigations performed in Romania^39–41 and Switzerland^42–47 reporting modulation of phagocytic activity and anaphylactic reaction, respectively, by evoking specific NIAL. In 1975, R. Ader and N. Cohen reported an immunosuppressive status after recalling the specific association of a taste stimulus (CS) and an immunosuppressive drug (US).⁴⁸

Later, these researchers and other groups developed different NIAL protocols, most of them using taste and olfactory stimuli (CS) in rodents and humans. More than 30 years of clinical and experimental research have demonstrated that by evoking NIAL, the brain can suppress or enhance humoral as well as cellular immune responses (Table 14.1). These effects are biologically relevant for the organism, as they affect the course and outcome of disease and thus have possible applications in clinical settings.

TABLE 14.1

Immune Parameters Affected after Recalling Neuro-Immune Associative Learning Paradigms

14.2. PHENOMENON: ASSOCIATION BETWEEN EXTEROCEPTIVE AND IMMUNE STIMULI

Two basic steps compose any conditioning protocol: an association phase in which one or more CS-US contingent pairings occur, inducing an associative learning process, and a recall phase in which the memory of such an association is retrieved after exposing the subject to the CS. Pioneer NIAL reports were based on the association of somatosensory stimulation (CS) and peripheral immune challenges (US). See Figure 14.1C. However, most of the recent work reporting conditioned effects on immune function has followed two basic associative protocols (Figure 14.1). The principal difference between them is the nature of the CS: taste/olfactory (Figure 14.1A) or visual/auditory (Figure 14.1B).

FIGURE 14.1

Neuro-immune associative learning. A. After water regimen consumption is established, animals are exposed to a novel taste/olfactory conditioned stimulus (CS) paired with an immunomodulating unconditioned stimulus (US) generally administered intraperitoneally (more...)

Although conditioned stimuli may employ any of the exteroceptive sensory modalities (touch, vision, taste, olfaction, and audition), the naturalistic relation between the CS and the US may explain the feasibility and strength of a specific association.¹⁰

14.2.1. Taste- and Olfactory-Immune Associative Learning

Theoretically this protocol is based on the naturalistic relation of food and drink ingestion with possible immune consequences that may also induce behavioral modifications after the experience. On the experimental bench, the association step involves the pairing of a taste (e.g., saccharin), odor (e.g., camphor), or flavor (e.g., chocolate drink) as a CS with a stimulus that has immune consequences as a US (e.g., immunomodulating drug, or antigen), usually administered intraperitoneally. At recall time, subjects are normally exposed to the CS alone (Figure 14.1A) and some protocols employ a vehicle injection as an additional component of the CS.

Conditioned ingestive avoidance and aversion are often displayed after a single association trial; however, the conditioned effects on the immune system may not be evident until several association trials are applied.⁴⁹ It is important to indicate that the behaviorally conditioned response (i.e., aversion or avoidance) has been elicited by NIAL in which T-dependent antigens such as protein antigens,^50–52 T-independent antigens such as lipopolysaccharides,^53–55 superantigens such as staphylococcal enterotoxin,^56,57 immunosuppressive drugs such as cyclophosphamide,^48,58 and cyclosporine A^59,60 have been employed (Figure 14.2). Additionally, the magnitude of the behaviorally conditioned response seems to be modulated by the intensity of the immune stimulation at association time.

FIGURE 14.2

Neuro-immune associative learning differentially affects drinking behavior. Different immune stimuli were employed as unconditioned stimuli resulting in associative learning. klh = small dose of keyhole limpet hemocyanin. KLH = high dose of KLH (data (more...)

For instance, a dose–response relationship between the amount of antigen used (US) and the conditioned taste aversion has been demonstrated: the higher the antigen dose, the more pronounced the conditioned taste avoidance.^51,61 Using a mild dose of antigen after an immune sensitization procedure induces a strong behaviorally conditioned avoidance response.⁶² Regarding immunosuppressive drugs, it has been documented that the immunosuppressive effects of cyclosporine A (US) can be associated with the taste of saccharin (CS). After recalling such an association, experimental subjects displayed immunosuppressive status (CR).^30,60 However, different behaviorally conditioned responses result from such associative learning. In the case of mice, this specific taste-immune association does not result in conditioned taste avoidance behavior,⁵ whereas rats display reduced appetitive behavior,³⁰ and for humans the palatability of the conditioned taste is affected.⁶³

14.3. THEORETICAL FRAMEWORK FOR NEURO-IMMUNE ASSOCIATIVE LEARNING

After reviewing the existing data about NIAL, it is possible to summarize guidelines for the general mechanisms underlying these phenomena (summarized in Figure 14.3). Part of this conceptualization has already been elaborated.^28,71,72 According to this theory, in the terminology of behavioral conditioning, both the CS (changes in the external environment) and the US (changes in the internal environment) must be inputs to the CNS, which in turn processes and associates this information. Thus, at association time, only a change in the immune system sensed by the CNS can serve as a US. Furthermore, both the CR and the UR must be outputs of the CNS. Thus, only an immune parameter directed by the CNS can serve as a UR for conditioning and at recall time the CR will resemble such a UR.

FIGURE 14.3

Theoretical framework for neuro-immune associative learning. At association time two possible unconditioned stimuli (US) were associated with a conditioned stimulus (CS). The US directly detected by the CNS is defined as a directly perceived US. The one (more...)

14.4. NEUROBIOLOGY OF NEURO-IMMUNE ASSOCIATIVE LEARNING

The naturalistic associability of food and drink ingestion with its possible immune consequences has been experimentally appraised in rodents and humans employing the conditioned taste aversion paradigm.⁹⁰ Conditioned taste aversion or avoidance is a type of associative conditioning in which the subjects learn to associate a taste with delayed malaise.⁷⁰ This learning has been conserved across the animal kingdom^91–94 including humans⁹⁵ which reflects its high adaptive value in food selection strategies. However, reduced ingestive behavior may be only part of a complex and diverse repertory of physiological responses that the individual evokes to avoid, reject and/or prepare to counteract the unconditioned effects.⁵

One discrete neural network involved in taste-visceral associative learning has already been described, mainly including sensory and hedonic neural pathways.^96,97 Such a neural circuit consistently includes the nucleus tractus solitary, the parabrachial nucleus, medial thalamus, amygdala, and insular cortex.⁹⁸ In particular, the insular cortex is essential for the acquisition and retention of this associative learning^99,100 and it has been postulated that the insular cortex may integrate gustatory and visceral stimuli.¹⁰¹ More recently, using the neuronal activity marker c-Fos, it was possible to confirm the preponderant role of the insular cortex in conditioned antibody production¹⁰² in agreement with a previous report.¹⁰³

Regarding other forebrain structures, the amygdala seems to play an important role during the formation of aversive ingestive associations¹⁰⁴ and is also relevant for limbic–autonomic interactions.¹⁰⁵ A series of reports indicates that the insular cortex and amygdala are key structures in conditioned immunosuppression after evoking taste-cyclophosphamide association.^106,107

It has also been proposed that the ventromedial hypothalamic nucleus, widely recognized as a satiety center,¹⁰⁸ is intimately associated with sympathetic facilitation in peripheral tissues¹⁰⁹ including modulation of peripheral immune reactivity.¹¹⁰ In agreement with previous reports,^103,106,107 we have identified the neural substrates involved in behaviorally conditioned immunosuppression (CS: saccharin; US: cyclosporine A) in rats.¹¹¹ The conditioned effect on the immune system reducing splenocyte responsiveness and cytokine production (IL-2 and IFN-α) was affected by brain excitotoxic lesions; this shows that the insular cortex is essential to acquiring and evoking this conditioned response. In contrast, the amygdala seems to mediate the input of visceral information necessary at acquisition time, whereas the ventro-medial hypothalamic nucleus appears to participate in the output pathway to the immune system needed to evoke a behaviorally conditioned immune response.

Using a pharmacological approach, the neurochemical features of the conditioned effect enhancing NK cell activity in rodents have been described. Central catecholamines seem to be essential, and glutamate — but not GABA — is also required at the recall stage.^112,113 Furthermore, it has been demonstrated that cholinergic and serotonergic central systems are required at the association and recall stages.¹¹⁴

In addition to classical neurotransmitters, cytokines have been demonstrated to play an important role within the CNS, modulating neuronal and glial functions in non-pathological settings such as learning and memory processes.^2,115,116 Specifically, pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α have been shown to modulate spatial learning tasks and long-term potentiation phenomena.^117–124 In this sense, it is plausible that cytokines are significant factors in the associative processes occurring during behavioral conditioning of immune functions.

Apart from these neuromodulatory properties, pro-inflammatory cytokines seem to play an important part in the afferent pathway between the immune system and the CNS.^2,125,126 Therefore, it can be hypothesized that central cytokines act as mediators in the brain during “immune-sensing” in the association phases of behaviorally conditioned immunomodulating paradigms. These hypotheses are supported by observations that (1) receptors for these pro-inflammatory cytokines are expressed in the CNS,^127,128 (2) peripheral immune changes affect central cytokine production and cytokine receptor expression in the brain,^129,130 and (3) cytokines can act as unconditioned stimuli to induce conditioned taste aversion or avoidance.^131–134 Apart from these reports, we know of no systematic attempts to elucidate the neural substrates underlying immunomodulating effects based on neuro-immune associative learning.

14.5. BIOLOGICAL RELEVANCE OF NEURO-IMMUNE ASSOCIATIVE LEARNING

Neuro-immune interactions appear to bring several adaptive advantages to those organisms that acquired and further developed them during ontogeny and phylogeny.^94,135,136 This complex repertoire of physiological responses including immune, endocrine, neural, and behavioral responses may be orchestrated to achieve better adaptation of the organism to a constantly challenging environment. In vertebrates, the many intricate interactions in both directions between the immune and nervous systems are well established.^137–140 It was recently shown that invertebrate biology also evolved around acquiring and developing complex neuro-immune communications.

For example, interaction between neurons and immune cells has been demonstrated in the mollusk Aplysia californica.¹⁴¹ Furthermore, invertebrates also express neuropeptides (e.g., opioids) in the neural and immune tissues that play a key role as neuro-immune messengers during their evolution.¹³⁷ Neuro-immune complexity appears as well in the behavior of insects; for example, in the linkage between the immune and nervous systems of bees and humblebees.^142,143 Noninfected honey bees whose immune systems were challenged by a nonpathogenic immunogenic elicitor (lipopolysaccharide) displayed reduced abilities to associate an odor with sugar reward in a classical conditioning paradigm.

Classical conditioning can be understood as learning about the temporal or causal relationships between external and internal stimuli to allow for the appropriate preparatory set of responses before biologically significant events.^13,144 The capacity to associate a certain immune response or status (allergen, toxin, antigen) with a specific stimulus (environment or flavor) is of high adaptive value.

Thus, it can be hypothesized that this capacity was acquired during evolution as an adaptive strategy in order to protect organisms and/or prepare them to face danger. Furthermore, such associative learning is typically acquired under certain stressful conditions. For example, the exposure to a specific antigen (and its categorization as an allergen) may be associated (learning) with a specific environment or food. An adaptive response is then elicited (memory), consisting first of behavioral modification in order to avoid the place or food associated with the antigen.^66,69

If this is not possible, the organism will try to reduce contact with the allergen, i.e., by coughing or sneezing.¹⁴⁵ At the same time, its immune system may prepare the body for interaction with the antigen by mast cell degranulation^{64,65,146,147} or antibody production.^{50,102,148,149} Although under experimental conditions such associative learning can be extinguished, it is likely that it will last for a long time since an organism in a natural situation will try to avoid contact with the environmental cues that signal the CS.

14.6. CLINICAL RELEVANCE OF NEURO-IMMUNE ASSOCIATIVE LEARNING

Few attempts have been undertaken to specifically investigate conditioned effects that directly modulate peripheral immune functions in human subjects. Since the 19th century, anecdotic case studies have reported the occurrence of allergic symptoms in the absence of allergens provoked simply by different cues (i.e., conditioned stimuli) such as a picture of a hay field or an artificial rose.¹⁵⁰ Several decades later, researchers reported conditioned dermatitis responses in adolescent male subjects (n = 4) resulting from evocation of a specific association (CS: blue solution application; US: 2% raw extract R. Venicifera application).¹⁵¹

In another case report, two asthmatic patients suffering from skin sensitivities to house-dust extract and grass pollen were exposed to these allergens by inhalation.¹⁵² After a series of conditioning trials, they experienced allergic attacks after inhalation of the neutral solvent used to deliver the allergens. This work showed not only fast conditioning of the asthmatic attack (CR), but also tenacious retention, i.e., lack of extinction. This observation along with data from animal experiments resulted in the early hypothesis that asthma could be conceived of as a learned response.¹⁵³ This view was further supported by a conditioning protocol (CS: taste; US: dust mite allergen) in nine patients with allergic rhinitis.¹⁵⁴ After the association phase, elevated mast cell tryptase in mucosa was observed when an intranasal saline application was given simultaneously with the CS.

Another type of allergic reaction, the delayed-type hypersensitivity response, was tested in seven healthy volunteers who received five monthly tuberculin skin tests.¹⁵⁵ In this conditioning protocol both tuberculin (US) and saline were injected; while the latter was taken from a green vial (CS–), tuberculin was drawn from a red vial (CS+). On the test day, the color labeling of the substances was reversed. Although the saline injections did not induce skin reactions (erythema and induration), the severity of the symptoms was significantly blunted in all the subjects tested when the tuberculin was drawn from the green vial (conditioned effect). However, a similar protocol using various allergens (mite dust, fur) taken from colored vials did not result in conditioned modulation of skin reactions in the 15 subjects tested.¹⁵⁶

Associative learning has been consistently reported in the context of cancer treatment, particularly chemotherapy.²⁸ Chemotherapy agents (e.g., cyclophosphamide) generally have immunosuppressive effects. They are typically administered in cycles, with each outpatient treatment infusion followed by a period of recovery prior to the next infusion. From a conditioning perspective, clinic treatment visits can be viewed as association trials in which the distinctive salient features of the clinic environment (CS) are contingently paired with the infusion of agents (US: cyclophosphamide) that have effects on the immune system.

Immune function was assessed in 20 cancer patients in a hospital prior to chemotherapy and compared with assessments conducted at home. Proliferative responses to T cell mitogens were lower for cells isolated from blood samples taken in the hospital (after recall) than for home samples.¹⁵⁷ These results were replicated in 22 ovarian patients¹⁵⁸ and 19 pediatric patients receiving chemotherapy.¹⁵⁹ However, chemotherapy patients often develop conditioned nausea,^{157,160–162} anxiety,^163,164 and fatigue¹⁶⁵ responses to reminders of chemotherapy. These conditioned nausea and anxiety responses can also be elicited by thoughts and images of chemotherapy,^166,167 raising the possibility that conditioned effects may affect patients during the course of normal life for years after treatment.

Only a few human studies have tried to affect immune parameters on the cellular level by employing behavioral conditioning procedures. Based on the knowledge that adrenaline administration leads to the immediate mobilization of leukocytes in the periphery, especially of NK cell numbers with simultaneous augmentation of their lytic activity,^168,169 one research group assessed the conditionability of NK cell numbers and their lytic activity in healthy volunteers. Although positive results were reported after evoking a taste (CS)–adrenaline (US) association.^170,171 these effects could not be replicated by other research groups.¹⁷²

The efficacy of a conditioning protocol was also tested in multiple sclerosis patients, for whom four monthly cyclophosphamide infusions (US) were contingently paired with the taste of anise-flavored syrup (CS).¹⁷³ Long-term treatment with cyclophosphamide decreased blood leukocyte numbers, often leading to leukopenia. Interestingly, after 6 months of administering a placebo infusion paired with the drink, 8 of 10 patients showed conditioned reductions in peripheral leukocyte numbers. In addition, by pairing s.c. interferon-α injections (US) with a distinctively flavored drink (CS), it was possible to induce elevations of neopterin and quinolinic acid serum levels after evoking such an association in healthy volunteers (n = 10).¹⁷⁴

It has been hypothesized that more than a single associative learning trial pairing a distinctive taste (CS) with interferon-β injections (US) is necessary to produce immune conditioned effects.¹⁷⁵ This view is supported by experimental data for healthy male volunteers (n = 18). The immunosuppressive drug cyclosporine A (US) was paired four times with a distinctively flavored and colored solution (CS),⁶³ inducing taste-immune associative learning. The immunopharmacological mechanism of cyclosporine A involves its binding to cyclophilins, which leads to intracellular phosphatase calcineurin inhibition, then selectively reducing the expression of interleukin-2 (IL-2) and interferon- (IFN-α) cytokines, which finally resulted in specific suppression of T cell function.¹⁷⁶ After association, the mere re-exposure to the drink (CS) induced conditioned inhibition of ex vivo cytokine (IL-2 and IFN-α) mRNA expression and cytokine release along with the proliferative responsiveness of human peripheral blood lymphocytes similar to the drug effect.

14.7. SUMMARY AND FUTURE PERSPECTIVE

Conceptualizing Pavlovian conditioning as a mechanism by which an organism anticipates the onset of a biologically important event (US) and initiates preparatory responses (CR) to allow the organism to deal better with US effects invites the hypothesis that one reason for the neural control of immunity lies in accommodating the adaptive value of classical conditioning.¹⁸ In its natural environment, an animal with a cut or a scratch must build up immunological defenses against microorganisms. In the laboratory or a clinical setting, an antigen is reliably preceded by an injection. Therefore, conditioned immune effects may, in fact, be very common.

The difficulty for the investigator lies not so much in inducing such responses, but in employing the proper controls, both immunological and psychological, in order to demonstrate that these responses exist and to explore the underlying mechanisms. Due to the physiological basis of the conditioned effects, the magnitude of the conditioned immune response should not to be expected to override the homeostatic balance of the organism. However, this does not mean that conditioned effects on immune functions are not of biological and clinical significance, as reviewed here and in previous work.²⁷

A very small increase in the potential of the immune system may be of great value in the fight against pathogens when a system reaches an allostatic load,^177,178 but it may increase the occurrence and severity of allergies and autoimmune disorders in other conditions. It is important to emphasize that several immune responses may be affected by NIAL protocols, but this does not necessarily imply that such immune responses are conditioned. Because of the complexity of neuro-immune interaction, such differentiation is not easy to establish.

As we have seen, the use of a US with immune consequences, such as immunomodulating drugs or antigens, is not the only requirement for genuinely conditioning an immune response through behavioral protocol. Experimental data reflect a dichotomy that is possibly supported by different mechanisms that may follow different rules. In our own experience and after reviewing the available literature, we conclude that the direction of the CR is a key feature of conditioning; i.e., the direction of this response should be independent of the immune, endocrine, and circadian status of the subject at association and recall time.

Before NIAL can be implemented as supportive therapy together with traditional pharmacological regimens, it is essential to describe some of its features. For example, we do not yet know how long conditioned immune responses last and how immune-specific they are. Since it may be necessary to apply reinforcement at appropriate intervals, questions arise whether reconditioning is possible. Therapy will eventually stop. What is the forgetting pattern of conditioned immune responses? How predictable is the conditioned immune response in a human population with different immune and psychological histories? What are the impacts of age and gender on immunoconditioning? When using immunomodulating drugs as the unconditioned stimuli, are some side effects conditioned?

To date, experimental evidence indicates that behavioral conditioning may have practical implications in a clinical setting and be of use as supportive therapy, with the aim of reducing undesired side effects and maximizing the effects of pharmacological therapies.¹⁷⁹ In summary, we have reviewed and summarized the current data indicating that both innate and adaptive immune responses are affected by evoking neuro-immune associative learning. The effect of NIAL on immune functions is just about to be understood and the possible clinical applications seem to be enormous.

In future studies it will be essential to analyze the afferent and efferent pathways in brain-to-immune communications before NIAL paradigms can be employed as beneficial tools in clinical settings. Finally, research on behavioral immunoconditioning has revealed that organisms have important adaptive psychoneuroimmunological strategies acquired to deal with constantly changing and challenging environments in a better way.

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