Learned immunosuppressive placebo responses in renal transplant patients
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved March 7, 2018 (received for review November 30, 2017)
Significance
Akin to other physiological responses, immune functions can be modified in humans through associative conditioning procedures as part of a learned placebo response. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. In the present study, we demonstrate in renal transplant patients who were already receiving immunosuppressive treatment that learned immunosuppressive placebo responses increased efficacy of immunosuppressive medication. These data demonstrate that behavioral conditioning of drug responses may be a promising tool that could be used as a placebo-based dose-reduction strategy in an ongoing immunopharmacological regimen, the aim being to limit unwanted drug adverse effects and to improve treatment efficacy.
Abstract
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.
Acknowledgments
We thank Alexandra Kornowski, Christa Freundlieb, Chris Hemond, and Magdalene Vogelsang for their technical assistance and their skilled help; and Dr. Harald Engler for reading earlier versions of this manuscript. This work was supported by German Research Foundation Grant FOR 1328; SCHE 341/17-2 and the Foundation of the Science of the Therapeutic Encounter.
Supporting Information
Supporting Information (PDF)
- Download
- 361.58 KB
Table_S01 (DOCX)
- Download
- 42.07 KB
Table_S02 (DOCX)
- Download
- 62.49 KB
Table_S03 (DOCX)
- Download
- 38.75 KB
Table_S04 (DOCX)
- Download
- 39.76 KB
Table_S05 (DOCX)
- Download
- 44.31 KB
Table_S06 (DOCX)
- Download
- 142.57 KB
Table_S07 (DOCX)
- Download
- 18.68 KB
Table_S08 (DOCX)
- Download
- 99.29 KB
References
1
P Enck, U Bingel, M Schedlowski, W Rief, The placebo response in medicine: Minimize, maximize or personalize? Nat Rev Drug Discov 12, 191–204 (2013).
2
F Benedetti, Placebo effects: From the neurobiological paradigm to translational implications. Neuron 84, 623–637 (2014).
3
DG Finniss, TJ Kaptchuk, F Miller, F Benedetti, Biological, clinical, and ethical advances of placebo effects. Lancet 375, 686–695 (2010).
4
M Schedlowski, P Enck, W Rief, U Bingel, Neuro-bio-behavioral mechanisms of placebo and nocebo responses: Implications for clinical trials and clinical practice. Pharmacol Rev 67, 697–730 (2015).
5
S Geuter, L Koban, TD Wager, The cognitive neuroscience of placebo effects: Concepts, predictions, and physiology. Annu Rev Neurosci 40, 167–188 (2017).
6
L Colloca, P Petrovic, TD Wager, M Ingvar, F Benedetti, How the number of learning trials affects placebo and nocebo responses. Pain 151, 430–439 (2010).
7
K Jensen, I Kirsch, S Odmalm, TJ Kaptchuk, M Ingvar, Classical conditioning of analgesic and hyperalgesic pain responses without conscious awareness. Proc Natl Acad Sci USA 112, 7863–7867 (2015).
8
P Bąbel, et al., Classical conditioning without verbal suggestions elicits placebo analgesia and nocebo hyperalgesia. PLoS One 12, e0181856 (2017).
9
M Schedlowski, G Pacheco-López, The learned immune response: Pavlov and beyond. Brain Behav Immun 24, 176–185 (2010).
10
J Tekampe, et al., Conditioning immune and endocrine parameters in humans: A systematic review. Psychother Psychosom 86, 99–107 (2017).
11
R Ader, et al., Conditioned pharmacotherapeutic effects: A preliminary study. Psychosom Med 72, 192–197 (2010).
12
A Albring, et al., Preserving learned immunosuppressive placebo response: Perspectives for clinical application. Clin Pharmacol Ther 96, 247–255 (2014).
13
L Colloca, FG Miller, Harnessing the placebo effect: The need for translational research. Philos Trans R Soc Lond B Biol Sci 366, 1922–1930 (2011).
14
BK Doering, W Rief, Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends Pharmacol Sci 33, 165–172 (2012).
15
M Hadamitzky, et al., Memory-updating abrogates extinction of learned immunosuppression. Brain Behav Immun 52, 40–48 (2016).
16
M Perlis, et al., Durability of treatment response to zolpidem with three different maintenance regimens: A preliminary study. Sleep Med 16, 1160–1168 (2015).
17
AD Sandler, CE Glesne, JW Bodfish, Conditioned placebo dose reduction: A new treatment in attention-deficit hyperactivity disorder? J Dev Behav Pediatr 31, 369–375 (2010).
18
MU Goebel, et al., Behavioral conditioning of immunosuppression is possible in humans. FASEB J 16, 1869–1873 (2002).
19
T Wirth, et al., Repeated recall of learned immunosuppression: Evidence from rats and men. Brain Behav Immun 25, 1444–1451 (2011).
20
MR Irwin, SW Cole, Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 11, 625–632 (2011).
21
AM de Mattos, AJ Olyaei, WM Bennett, Nephrotoxicity of immunosuppressive drugs: Long-term consequences and challenges for the future. Am J Kidney Dis 35, 333–346 (2000).
22
M Naesens, DR Kuypers, M Sarwal, Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4, 481–508 (2009).
23
JM Gijtenbeek, MJ van den Bent, CJ Vecht, Cyclosporine neurotoxicity: A review. J Neurol 246, 339–346 (1999).
24
K Bosche, et al., Neurobehavioral consequences of small molecule-drug immunosuppression. Neuropharmacology 96, 83–93 (2015).
25
KJ Tracey, Understanding immunity requires more than immunology. Nat Immunol 11, 561–564 (2010).
26
R Ader, Conditioned immunomodulation: Research needs and directions. Brain Behav Immun 17, S51–S57 (2003).
27
G Pacheco-López, H Engler, MB Niemi, M Schedlowski, Expectations and associations that heal: Immunomodulatory placebo effects and its neurobiology. Brain Behav Immun 20, 430–446 (2006).
28
P Enck, F Benedetti, M Schedlowski, New insights into the placebo and nocebo responses. Neuron 59, 195–206 (2008).
29
A Albring, et al., Placebo effects on the immune response in humans: The role of learning and expectation. PLoS One 7, e49477 (2012).
30
L Lueckemann, et al., Pre-exposure to the unconditioned or conditioned stimulus does not affect learned immunosuppression in rats. Brain Behav Immun 51, 252–257 (2016).
31
R Ader, N Cohen, Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215, 1534–1536 (1982).
32
MS Exton, et al., Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation. Am J Physiol 276, R1710–R1717 (1999).
33
MS Exton, et al., Conditioned suppression of contact sensitivity is independent of sympathetic splenic innervation. Am J Physiol Regul Integr Comp Physiol 279, R1310–R1315 (2000).
34
MU Goebel, N Meykadeh, W Kou, M Schedlowski, UR Hengge, Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother Psychosom 77, 227–234 (2008).
35
G Pacheco-López, et al., Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB J 23, 1161–1167 (2009).
36
C Riether, et al., Stimulation of β2-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction. Brain Behav Immun 25, 59–66 (2011).
37
G Pacheco-López, et al., Neural substrates for behaviorally conditioned immunosuppression in the rat. J Neurosci 25, 2330–2337 (2005).
38
MS Exton, et al., Behaviorally conditioned immunosuppression using cyclosporine A: Central nervous system reduces IL-2 production via splenic innervation. J Neuroimmunol 88, 182–191 (1998).
39
K Ober, et al., Plasma noradrenaline and state anxiety levels predict placebo response in learned immunosuppression. Clin Pharmacol Ther 91, 220–226 (2012).
40
A Albring, et al., Short-term treatment with the calcineurin inhibitor cyclosporine A decreases HPA axis activity and plasma noradrenaline levels in healthy male volunteers. Pharmacol Biochem Behav 126, 73–76 (2014).
41
A Albring, et al., Relationship between pharmacokinetics and pharmacodynamics of calcineurin inhibitors in renal transplant patients. Clin Transplant 29, 294–300 (2015).
42
K Leineweber, et al., In patients chronically treated with metoprolol, the demand of inotropic catecholamine support after coronary artery bypass grafting is determined by the Arg389Gly-beta 1-adrenoceptor polymorphism. Naunyn Schmiedebergs Arch Pharmacol 375, 303–309 (2007).
43
C Herrmann-Lingen, U Buss, R Snaith Hospital Anxiety and Depression Scale - German Version (Huber-Verlag, Bern, Switzerland, 2005).
44
L Laux, et al. The State-Trait-Anxiety Depression Inventory (STADI) (Hogrefe, Göttingen, Germany, 2013).
45
F Faul, E Erdfelder, AG Lang, A Buchner, G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39, 175–191 (2007).
Information & Authors
Information
Published in
Classifications
Copyright
Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Submission history
Published online: April 2, 2018
Published in issue: April 17, 2018
Keywords
Acknowledgments
We thank Alexandra Kornowski, Christa Freundlieb, Chris Hemond, and Magdalene Vogelsang for their technical assistance and their skilled help; and Dr. Harald Engler for reading earlier versions of this manuscript. This work was supported by German Research Foundation Grant FOR 1328; SCHE 341/17-2 and the Foundation of the Science of the Therapeutic Encounter.
Notes
This article is a PNAS Direct Submission.
Authors
Competing Interests
The authors declare no conflict of interest.
Metrics & Citations
Metrics
Citation statements
Altmetrics
Citations
Cite this article
Learned immunosuppressive placebo responses in renal transplant patients, Proc. Natl. Acad. Sci. U.S.A.
115 (16) 4223-4227,
https://doi.org/10.1073/pnas.1720548115
(2018).
Copied!
Copying failed.
Export the article citation data by selecting a format from the list below and clicking Export.
Cited by
Loading...
View Options
View options
PDF format
Download this article as a PDF file
DOWNLOAD PDFLogin options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginRecommend to a librarian
Recommend PNAS to a LibrarianPurchase options
Purchase this article to access the full text.