Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Apr 17;115(16):4223-4227.
doi: 10.1073/pnas.1720548115. Epub 2018 Apr 2.

Learned Immunosuppressive Placebo Responses in Renal Transplant Patients

Free PMC article

Learned Immunosuppressive Placebo Responses in Renal Transplant Patients

Julia Kirchhof et al. Proc Natl Acad Sci U S A. .
Free PMC article


Patients after organ transplantation or with chronic, inflammatory autoimmune diseases require lifelong treatment with immunosuppressive drugs, which have toxic adverse effects. Recent insight into the neurobiology of placebo responses shows that associative conditioning procedures can be employed as placebo-induced dose reduction strategies in an immunopharmacological regimen. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. Thus, 30 renal transplant patients underwent a taste-immune conditioning paradigm, in which immunosuppressive drugs (unconditioned stimulus) were paired with a gustatory stimulus [conditioned stimulus (CS)] during the learning phase. During evocation phase, after patients were reexposed to the CS, T cell proliferative capacity was significantly reduced in comparison with the baseline kinetics of T cell functions under routine drug intake (ƞp2 = 0.34). These data demonstrate, proof-of-concept, that learned immunosuppressive placebo responses can be used as a supportive, placebo-based, dose-reduction strategy to improve treatment efficacy in an ongoing immunopharmacological regimen.

Keywords: T cells; conditioning; immunosuppression; placebo; transplantation.

Conflict of interest statement

The authors declare no conflict of interest.


Fig. 1.
Fig. 1.
Proliferation of CD4+ T cells (A), IL-2 (B), and γ-IFN mRNA (C) expression in CD3+ cells 2, 6, and 10 h after morning drug intake at baseline and during the second evocation day (data are shown as means ± STE). ***P < 0.001; #P = 0.07.
Fig. 2.
Fig. 2.
Noradrenaline, adrenaline, and cortisol plasma levels (picograms per milliliter) 2, 6, and 10 h after morning drug intake at baseline and during the second evocation day (data are shown as means ± STE). *P = 0.06.
Fig. 3.
Fig. 3.
During baseline measures (day 1; without any drug-cue association), blood samples were taken at three different times: 2, 6, and 10 h after morning (9 AM) drug intake. During the acquisition days 2–4, the immunosuppressive drug intake (CsA or Tac) at 9 AM and 9 PM was combined with the CS (green-colored, new-tasting drink). During evocation days (study days 7 and 8), the morning and evening drug intake was again combined with the CS. In addition, patients received placebo pills 4 h (at 1 PM), as well as 8 h (at 5 PM), together with the CS. At the second evocation day, blood samples were taken at three times: 2, 6, and 10 h after morning drug intake (9 AM).

Comment in

Similar articles

See all similar articles

Cited by 8 articles

See all "Cited by" articles


    1. Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: Minimize, maximize or personalize? Nat Rev Drug Discov. 2013;12:191–204. - PubMed
    1. Benedetti F. Placebo effects: From the neurobiological paradigm to translational implications. Neuron. 2014;84:623–637. - PubMed
    1. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375:686–695. - PMC - PubMed
    1. Schedlowski M, Enck P, Rief W, Bingel U. Neuro-bio-behavioral mechanisms of placebo and nocebo responses: Implications for clinical trials and clinical practice. Pharmacol Rev. 2015;67:697–730. - PubMed
    1. Geuter S, Koban L, Wager TD. The cognitive neuroscience of placebo effects: Concepts, predictions, and physiology. Annu Rev Neurosci. 2017;40:167–188. - PubMed

Publication types

MeSH terms