Renal

Behavioral conditioning prolongs heart allograft survival in rats☆

Even though knowledge and systematic application of placebo responses in the immune system are sparse, this topic is of particular importance since it may aim at drug-dose reduction while maintaining therapeutic efficacy of treatment in clinical settings. Placebo responses in the immune system are inducible by associated learning paradigms, such as behaviorally conditioned immunosuppression. One established learning paradigm in both rats and humans is conditioned taste avoidance (CTA), where a novel taste as conditioned stimulus (CS) is paired with the administration of the immunosuppressive drug cyclosporine A (CsA) as unconditioned stimulus. By representing the CS alone at a later time point, the conditioned response is reflected by avoidance behavior toward the taste (CTA). Simultaneously, diminished cytokine production and proliferative capacity of T cells are observed, closely mimicking the pharmacological effects of CsA. This chapter provides an overview on placebo responses in the immune system and delineates actual approaches, translational aspects, and limitations of learning paradigms in clinical settings.

The importance of placebo responses for the treatment of various medical conditions has increasingly been recognized, whereas knowledge and systematic application in clinical settings are still sparse. One possible application for placebo responses in pharmacotherapy is given by learning paradigms, such as behaviorally conditioned immunosuppression, aiming at drug dose reduction while maintaining therapeutic efficacy of drug treatment. In an established learning paradigm of conditioned taste aversion/avoidance (CTA) in both, rats and humans, respectively, a novel-tasting drinking solution (conditioned stimulus, CS) is paired with an injection of the immunosuppressive drug cyclosporine A (CsA) as unconditioned stimulus (US). The conditioned response, evoked by re-presenting the CS alone at a later time, is reflected by avoidance behavior of consuming the solution (conditioned taste aversion; CTA) and a diminished interleukin (IL)-2 and interferon (IFN)-γ cytokine production as well as mRNA expression of rat splenic T cells or human peripheral T lymphocytes, closely mimicking the immunosuppressive effects of CsA. However, due to unreinforced CS-re-exposure conditioned responses progressively decreases over time (extinction), reflecting a considerable challenge for potential clinical applications of this learned immunosuppression. The present article discusses and critically reviews actual approaches, applications but also limitations of learning paradigms in immune pharmacotherapy.

Akin to other physiological responses, the immune system can be modified, via Pavlovian or behavioral conditioning. It is unknown, however, whether and to what extent learned immune responses can be repeatedly recalled over time. Here we demonstrate in both rats and humans that repeated contingent pairing of a novel taste (conditioned stimulus, CS) together with the immunosuppressive drug cyclosporine A as unconditioned stimulus (US) leads to the acquisition of a learned immunosuppression. Sole presentation of the CS caused a significant inhibition of interleukin (IL)-2 and interferon (IFN)-γ production by rat splenic T cells and human peripheral T lymphocytes, closely mimicking the effect of the drug. More importantly, a comparable suppression of cytokine production was also observed after a second, unreinforced exposure to the CS that was separated from the first evocation by an interval of 6 (rats) or 11 (humans) days, respectively. Together, our findings demonstrate that a learned immunosuppression can be repeatedly recalled in both animals and humans, which is an important prerequisite for the implementation of conditioning paradigms as supportive therapy.

The ability to associate physiological changes with a specific flavor was most likely acquired during evolution as an adaptive strategy aimed at protecting the organism while preparing it for danger. The behaviorally conditioned or learned immune response is an exquisite example of the bidirectional communication between the central nervous system (CNS) and the peripheral immune system. How is it possible that specific immuno-modulating properties of a drug or substance (unconditioned stimulus) can be re-enlisted just by the mere re-exposure to a particular taste, odor or environment (conditioned stimulus)? To answer this key question, we review the neurobiological mechanism mediating this type of associative learning, as well as the pathways and mechanisms employed by the brain to harness the immune system during the execution of the conditioned immune response. Finally, we focus on the potential therapeutic relevance of such learned immune responses, and their re-conceptualization within the framework of “learned placebo effects”.

Both animal and human studies reveal that immune-system activity can be modulated by behavioral conditioning. Unconditioned stimuli (US) are pharmacological regulators of immune system activity, which are variously stimulatory or inhibitory to aspects of immune function. This might properly be termed “behavioral immunopharmacological conditioning.” Antigen challenges to the immune system can also serve as the US such that on representation of a conditioned stimulus (CS), an enhanced immunological response is observed. In studies of the rat, a gustatory or odor CS can induce, in terms of specific antibody titer and isotype, the characteristics of a secondary response to a protein antigen challenge. The mechanism by which conditioning of the immune system occurs has only been partly explored although it is clear that no single mechanism could possibly be responsible for all of the observed effects. This merely reflects the complexity of both the nervous and the immune systems and their interrelatedness. A primary efferent pathway from the brain to the immune system is the neuroendocrine hypothalamic–pituitary–adrenal (HPA) axis, and it is clear that activation of the HPA axis and secretion of corticosterone can be conditioned and that some of the conditioning paradigms described in this chapter condition its activation in conjunction with conditioning of some aspect of immunity.