Learned Immunosuppressive Placebo Response Attenuates Disease Progression in a Rodent Model of Rheumatoid Arthritis.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
30
07
2019
accepted:
03
09
2019
pubmed:
12
9
2019
medline:
21
7
2020
entrez:
12
9
2019
Statut:
ppublish
Résumé
Patients with chronic inflammatory autoimmune diseases benefit from a broad spectrum of immunosuppressive and antiproliferative medication available today. However, nearly all of these therapeutic compounds have unwanted toxic side effects. Recent knowledge about the neurobiology of placebo responses indicates that associative learning procedures can be utilized for dose reduction in immunopharmacotherapy while simultaneously maintaining treatment efficacy. This study was undertaken to examine whether and to what extent a 75% reduction of pharmacologic medication in combination with learned immunosuppression affects the clinical outcome in a rodent model of type II collagen-induced arthritis. An established protocol of taste-immune conditioning was applied in a disease model of chronic inflammatory autoimmune disease (type II collagen-induced arthritis) in rats, where a novel taste (saccharin; conditioned stimulus [CS]) was paired with an injection of the immunosuppressive drug cyclosporin A (CSA) (unconditioned stimulus [US]). Following conditioning with 3 CS/US pairings (acquisition), the animals were immunized with type II collagen and Freund's incomplete adjuvant. Fourteen days later, at the first occurrence of clinical symptoms, retrieval was started by presenting the CS together with low-dose CSA as reminder cues to prevent the conditioned response from being extinguished. This "memory-updating" procedure stabilized the learned immune response and significantly suppressed disease progression in immunized rats. Clinical arthritis score and histologic inflammatory symptoms (both P < 0.05) were significantly diminished by learned immunosuppression in combination with low-dose CSA (25% of the full therapeutic dose) via β-adrenoceptor-dependent mechanisms, to the same extent as with full-dose (100%) pharmacologic treatment. These results indicate that learned immunosuppression appears to be mediated via β-adrenoceptors and might be beneficial as a supportive regimen in the treatment of chronic inflammatory autoimmune diseases by diminishing disease exacerbation.
Substances chimiques
Immunosuppressive Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
588-597Informations de copyright
© 2019, American College of Rheumatology.
Références
Chighizola CB, Ong VH, Meroni PL. The use of cyclosporine A in rheumatology: a 2016 comprehensive review. Clin Rev Allergy Immunol 2017;52:401-23.
Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50:485-9.
Bösche K, Weissenborn K, Christians U, Witzke O, Engler H, Schedlowski M, et al. Neurobehavioral consequences of small molecule-drug immunosuppression. Neuropharmacology 2015;96:83-93.
Doering BK, Rief W. Utilizing placebo mechanisms for dose reduction in pharmacotherapy. Trends Pharmacol Sci 2012;33:165-72.
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.
Pavlov VA, Chavan SS, Tracey KJ. Molecular and functional neuroscience in immunity. Annu Rev Immunol 2018;36:783-812.
Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 2011;11:625-32.
Kirchhof J, Petrakova L, Brinkhoff A, Benson S, Schmidt J, Unteroberdörster M, et al. Learned immunosuppressive placebo responses in renal transplant patients. Proc Natl Acad Sci U S A 2018;115:4223-7.
Lückemann L, Unteroberdörster M, Kirchhof J, Schedlowski M, Hadamitzky M. Applications and limitations of behaviorally conditioned immunopharmacological responses. Neurobiol Learn Mem 2017;142:91-8.
Hadamitzky M, Bösche K, Wirth T, Buck B, Beetz O, Christians U, et al. Memory-updating abrogates extinction of learned immunosuppression. Brain Behav Immun 2016;52:40-8.
Albring A, Wendt L, Benson S, Witzke O, Kribben A, Engler H, et al. Placebo effects on the immune response in humans: the role of learning and expectation. PloS One 2012;7:e49477.
Klosterhalfen W, Klosterhalfen S. Pavlovian conditioning of immunosuppression modifies adjuvant arthritis in rats. Behav Neurosci 1983;97:663-6.
Exton MS, Elfers A, Jeong WY, Bull DF, Westermann J, Schedlowski M. Conditioned suppression of contact sensitivity is independent of sympathetic splenic innervation. Am J Physiol Regul Integr Comp Physiol 2000;279:R1310-5.
Schedlowski M, Pacheco-López G. The learned immune response: Pavlov and beyond. Brain Behav Immun 2010;24:176-85.
Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 1982;215:1534-6.
Exton MS, Schult M, Donath S, Strubel T, Nagel E, Westermann J, et al. Behavioral conditioning prolongs heart allograft survival in rats. Transplant Proc 1998;30:2033.
Exton MS, Gierse C, Meier B, Mosen M, Xie Y, Frede S, et al. Behaviorally conditioned immunosuppression in the rat is regulated via noradrenaline and β-adrenoceptors. J Neuroimmunol 2002;131:21-30.
Pacheco-López G, Niemi MB, Kou W, Härting M, Fandrey J, Schedlowski M. Neural substrates for behaviorally conditioned immunosuppression in the rat. J Neurosci 2005;25:2330-7.
Exton MS, von Hörsten S, Schult M, Vöge J, Strubel T, Donath S, et al. Behaviorally conditioned immunosuppression using cyclosporine A: central nervous system reduces IL-2 production via splenic innervation. J Neuroimmunol 1998;88:182-91.
Lueckemann L, Bösche K, Engler H, Schwitalla JC, Hadamitzky M, Schedlowski M. Pre-exposure to the unconditioned or conditioned stimulus does not affect learned immunosuppression in rats. Brain Behav Immun 2016;51:252-7.
Hadamitzky M, Orlowski K, Schwitalla JC, Bösche K, Unteroberdörster M, Bendix I, et al. Transient inhibition of protein synthesis in the rat insular cortex delays extinction of conditioned taste aversion with cyclosporine A. Neurobiol Learn Mem 2016;133:129-35.
Berman DE, Hazvi S, Stehberg J, Bahar A, Dudai Y. Conflicting processes in the extinction of conditioned taste aversion: behavioral and molecular aspects of latency, apparent stagnation, and spontaneous recovery. Learn Mem 2003;10:16-25.
Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen: an experimental model of arthritis. J Exp Med 1977;146:857-68.
Choudhary N, Bhatt LK, Prabhavalkar KS. Experimental animal models for rheumatoid arthritis [review]. Immunopharmacol Immunotoxicol 2018;40:193-200.
Kehl LJ, Trempe TM, Hargreaves KM. A new animal model for assessing mechanisms and management of muscle hyperalgesia. Pain 2000;85:333-43.
Asquith DL, Miller AM, McInnes IB, Liew FY. Animal models of rheumatoid arthritis. Eur J Immunol 2009;39:2040-4.
Pacheco-López G, Riether C, Doenlen R, Engler H, Niemi MB, Engler A, et al. Calcineurin inhibition in splenocytes induced by pavlovian conditioning. FASEB J 2009;23:1161-7.
Riether C, Kavelaars A, Wirth T, Pacheco-López G, Doenlen R, Willemen H, et al. Stimulation of β2-adrenergic receptors inhibits calcineurin activity in CD4(+) T cells via PKA-AKAP interaction. Brain Behav Immun 2011;25:59-66.
Exton MS, Schult M, Donath S, Strubel T, Bode U, del Rey A, et al. Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation. Am J Physiol 1999;276:R1710-7.
Tracey KJ. Understanding immunity requires more than immunology. Nat Immunol 2010;11:561-4.
Klosterhalfen S, Klosterhalfen W. Conditioned cyclosporine effects but not conditioned taste aversion in immunized rats. Behav Neurosci 1990;104:716-24.
Lubahn CL, Schaller JA, Bellinger DL, Sweeney S, Lorton D. The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis. Brain Behav Immun 2004;18:563-71.
Pongratz G, Straub RH. Role of peripheral nerve fibres in acute and chronic inflammation in arthritis. Nat Rev Rheumatol 2013;9:117-26.
Levine JD, Coderre TJ, Helms C, Basbaum AI. β 2-adrenergic mechanisms in experimental arthritis. Proc Natl Acad Sci U S A 1988;85:4553-6.
Klatt S, Stangl H, Kunath J, Lowin T, Pongratz G, Straub RH. Peripheral elimination of the sympathetic nervous system stimulates immunocyte retention in lymph nodes and ameliorates collagen type II arthritis. Brain Behav Immun 2016;54:201-10.
Härle P, Pongratz G, Albrecht J, Tarner IH, Straub RH. An early sympathetic nervous system influence exacerbates collagen-induced arthritis via CD4+ CD25+ cells. Arthritis Rheum 2008;58:2347-55.
Schaible HG, Straub RH. Function of the sympathetic supply in acute and chronic experimental joint inflammation. Auton Neurosci 2014;182:55-64.
Berman DE, Dudai Y. Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 2001;291:2417-9.
Dudai Y. The restless engram: consolidations never end. Annu Rev Neurosci 2012;35:227-47.
Myers KM, Carlezon WA Jr. Extinction of drug- and withdrawal-paired cues in animal models: relevance to the treatment of addiction. Neurosci Biobehav Rev 2010;35:285-302.
Eisenberg M, Kobilo T, Berman DE, Dudai Y. Stability of retrieved memory: inverse correlation with trace dominance. Science 2003;301:1102-4.
Albring A, Wendt L, Benson S, Nissen S, Yavuz Z, Engler H, et al. Preserving learned immunosuppressive placebo response: perspectives for clinical application. Clin Pharmacol Ther 2014;96:247-55.
Hadamitzky M, Bösche K, Engler A, Schedlowski M, Engler H. Extinction of conditioned taste aversion is related to the aversion strength and associated with c-Fos expression in the insular cortex. Neuroscience 2015;303:34-41.
Nader K, Einarsson EÖ. Memory reconsolidation: an update. Ann N Y Acad Sci 2010;1191:27-41.
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.
Kahl AL, Kirchhof J, Petrakova L, Müller J, Laubrock J, Brinkhoff A, et al. Are adverse events induced by the acute administration of calcineurin inhibitor cyclosporine A behaviorally conditioned in healthy male volunteers? Clin Ther 2018;40:1868-77.
Lindenfeld J, Miller GG, Shakar SF, Zolty R, Lowes BD, Wolfel EE, et al. Drug therapy in the heart transplant recipient: part I-Cardiac rejection and immunosuppressive drugs. Circulation 2004;110:3734-40.
Kapturczak MH, Meier-Kriesche HU, Kaplan B. Pharmacology of calcineurin antagonists. Transplant Proc 2004;36:25-32.
Sizova L. Approaches to the treatment of early rheumatoid arthritis with disease modifying antirheumatic drugs. Br J Clin Pharmacol 2008;66:173-8.
Gerards AH, Landewé RB, Prins AP, Brujin GA, Goei Thé HS, Laan RF, et al. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis 2003;62:291-6.