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)
April 2, 2018
115 (16) 4223-4227

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.

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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)
Table_S01 (DOCX)
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Information & Authors

Information

Published in

The cover image for PNAS Vol.115; No.16
Proceedings of the National Academy of Sciences
Vol. 115 | No. 16
April 17, 2018
PubMed: 29610294

Classifications

Submission history

Published online: April 2, 2018
Published in issue: April 17, 2018

Keywords

  1. conditioning
  2. placebo
  3. immunosuppression
  4. T cells
  5. transplantation

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

Affiliations

Julia Kirchhof
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Liubov Petrakova
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Alexandra Brinkhoff
Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Sven Benson
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Justine Schmidt
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Maike Unteroberdörster
Clinic of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Benjamin Wilde
Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Ted J. Kaptchuk
Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215;
Oliver Witzke
Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Manfred Schedlowski1 [email protected]
Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden

Notes

1
To whom correspondence should be addressed. Email: [email protected].
Author contributions: O.W. and M.S. designed research; J.K., L.P., A.B., J.S., M.U., B.W., O.W., and M.S. performed research; J.K., L.P., S.B., J.S., M.U., B.W., T.J.K., and M.S. analyzed data; and S.B., T.J.K., O.W., and M.S. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Learned immunosuppressive placebo responses in renal transplant patients
    Proceedings of the National Academy of Sciences
    • Vol. 115
    • No. 16
    • pp. 3985-E3862

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