After organ transplantation or chronic inflammatory autoimmune diseases, patients depend on immunosuppressive medication for the rest of their lives, which can cause severe side effects. A recent study published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) suggests that learned immunosuppressive placebo responses increased efficacy of immunosuppressive medication in renal transplant patients who were already on immunosuppressive treatment.
These data provide evidence that behavioral conditioning of drug responses may be a promising tool that could be used as a placebo-based dose reduction strategy in ongoing immunopharmacological regimen, the aim being to limit unwanted drug side effects and to improve treatment efficacy.
Akin to other physiological responses, immune functions can be modified through associative conditioning procedures as part of a learned placebo response. The neurobiological and immunological mechanisms steering these behavioral conditioned effects in immune responses have been partially analyzed in a model of taste-immune learning in rats. When repeatedly pairing the calcineurin inhibitor and immunosuppressive drug cyclosporine A (CsA) (unconditioned stimulus/US) with a saccharine taste (conditioned stimulus/CS) during the learning phase (acquisition), the re-exposure to the conditioned stimulus (sweet saccharine taste) during evocation is inducing a learned immunosuppressive response reflected by an inhibition of T cell activity and cytokine production (IL-2, IFN-γ), and cytokine mRNA expression.
The conditioned immunosuppressive effects using CsA as an unconditioned stimulus are centrally mediated via the insular cortex and the amygdala. In the periphery, the learned inhibition of calcineurin activity in lymphocytes seemed to be mainly mediated via noradrenergic innervation of lymphatic organs such as the spleen and b-adrenoceptor-dependent mechanisms. In addition, the potential clinical applicability of learned immunosuppressive responses has been convincingly demonstrated in rodents, where conditioned immune responses significantly reduced the mortality in animals with inflammatory autoimmune disease, significantly reduced allergic responses or prolonged the survival time of transplanted vascularized organs.
In humans, the learned immunosuppressive response can be reproduced during a second, unreinforced re-exposition to the conditioned stimulus (CS) and induced by associative learning solely and not via patient expectations. In addition, extinction of the learned immunosuppressive response can be inhibited when “sub-therapeutic” dosages of the immunosuppressant drug are applied together with the CS during prolonged evocation.
Based on these data in experimental animals and healthy humans the question arose, whether and to what extend patients already on long term immunosuppressive therapy with calcineurin inhibitors such as CsA of Tac could still develop a learned immunosuppression. In this study with kidney transplant patients, long term treated with immunosuppressive drugs cyclosporine A or tacrolimus, the introduction of a taste-immune conditioning procedure induced a significant learned inhibition of T cell proliferative capacity. The conditioning paradigm increased the effectiveness of the medications without any increase in medication dose.
These data provide a “proof of concept” that learned placebo responses in immune functions can be employed as additional therapy during immunosuppressive treatment in order to maximize treatment efficacy.
Source: Kirchhof J, Petrakova L, Brinkhoff A, Benson S, Schmidt J, Unteroberdörster M, Wilde B, Kaptchuk TJ, Witzke O, Schedlowski M.; Learned immunosuppressive placebo responses in renal transplant patients; Proc Natl Acad Sci U S A. 2018 Apr 17; 115:4223-4227.