Memory-updating abrogates extinction of learned immunosuppression

Hadamitzky, Martin; Bösche, Katharina; Wirth, Timo; Buck, Benjamin; Beetz, Oliver; Christians, Uwe; Schniedewind, Björn; Lückemann, Laura; Güntürkün, Onur; Engler, Harald; Schedlowski, Manfred

doi:10.1016/j.bbi.2015.09.009

Cited by 30 publications

(55 citation statements)

References 39 publications

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“…Conditioned placebo effects in pharmacotherapy provide sophisticated approaches that may reduce drug doses and detrimental side effects without losing therapeutic efficacy . In this regard, based on the bidirectional communication between the CNS and the immune system , behavioral conditioned immunosuppression with CSA has proven useful in animal disease models, healthy subjects, and patients . The present study was aimed at analyzing the potential impact of learned immunosuppression in a rat model of CIA .…”

Section: Discussionmentioning

confidence: 99%

“…Conditioned responses in general tend to decline progressively when subjects are reexposed to the CS in the absence of the US . However, evidence from animal and human studies has demonstrated that the extinction of learned immunosuppression could be abrogated when sub‐ or low‐therapeutic doses of the US (CSA) were administered as reminder cues in combination with the CS during the retrieval phase . Such modified conditioning protocols, using reminder cues, most likely induced a memory‐updating process of the learned immunosuppression during retrieval .…”

Section: Discussionmentioning

confidence: 99%

“…Such approaches are based on classic conditioning of physiologic responses and, alternatively, the bidirectional communication between the central nervous system (CNS) and the immune system . Classically conditioned or learned immunosuppressive responses have been proven effective in experimental animal disease models, healthy subjects, and patient populations . To sustain these conditioned effects, these learned immune responses are of clinical relevance, as in rodent studies they have been shown to prolong heart allograft survival and attenuate allergic responses, as well as disease progression and mortality in autoimmune diseases .…”

Section: Introductionmentioning

confidence: 99%

“…Reexposure to the CS results in reduced consumption of the saccharin (conditioned taste avoidance [CTA]) and, more importantly, a pronounced suppression of T cell functioning, as well as diminished interleukin‐2 (IL‐2) and interferon‐γ (IFNγ) protein production and messenger expression . However, taste‐associative learning extinguishes when animals are repeatedly exposed to the CS in the absence of the US . To prevent extinction of learned immunosuppression, low subtherapeutic dosages of the US were applied during the extinction process, which was ineffective in inducing CTA itself.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to controls that exhibited extinguished CTA at retrieval after the presentation of saccharin only, animals additionally treated with the “reminder cues” (low or subtherapeutic dosages of the US) had CTA that remained at a level similar to that acquired at acquisition . We recently adapted this “memory‐updating” procedure for our taste‐immune model, showing that the usage of CS saccharin together with subtherapeutic CSA as reminder cues prevented conditioned immunosuppression from being extinguished in rodents .…”

Section: Introductionmentioning

confidence: 99%

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Learned Immunosuppressive Placebo Response Attenuates Disease Progression in a Rodent Model of Rheumatoid Arthritis

Lückemann

Stangl

Straub

et al. 2020

Arthritis & Rheumatology

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Objective 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. Methods 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. Results 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. Conclusion 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Learned Immunosuppressive Placebo Response Attenuates Disease Progression in a Rodent Model of Rheumatoid Arthritis

Lückemann

Stangl

Straub

et al. 2020

Arthritis & Rheumatology

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View full text Add to dashboard Cite

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Taste‐Associative Learning in Rats: Conditioned Immunosuppression with Cyclosporine A to Study the Neuro‐Immune Network

et al. 2022

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The pharmacological effects of an immunosuppressive drug, such as cyclosporine A (CsA), can be learned and retrieved by humans and animals when applying associative learning paradigms. This principle is based on Pavlovian conditioning, in which repeated presentation of an "unconditioned stimulus" (US; here, the drug CsA) is paired with exposure to a "conditioned stimulus" (CS; here, the novel taste of saccharin). Re-exposure to the CS at a later time leads to an avoidance behavior. Concomitantly, using this paradigm, animals exposed to the CS (saccharin) display immunosuppression, reflected by reduced splenic T-cell proliferation and diminished interleukin-2 and interferonγ expression and release in ex vivo cultured splenocytes, mimicking the pharmacological effects of the US (CsA). Notably, this paradigm of taste-immune associative learning demonstrates the impressive abilities of the brain to detect and store information about an organism's immunological status and to retrieve this information, thereby modulating immunological functions via endogenous pathways. Moreover, conditioned pharmacological effects, obtained by means of associative learning, have been successfully implemented as controlled drugdose reduction strategies as a supportive treatment option to optimize pharmacological treatment effects for patients' benefit. However, our knowledge about the underlying neurobiological and immunological mechanisms mediating such learned immunomodulatory effects is still limited. A reliable animal model of taste-immune associative learning can provide novel insights into peripheral and central nervous processes. In this article, we describe protocols that focus on the basic taste-immune associative learning paradigm with CsA and saccharin in rats, where conditioned peripheral immunosuppression is determined in ex vivo cultured splenocytes. The behavioral protocol is reliable and adaptable and may pave the road for future studies using taste-immune associative learning paradigms to gain deeper insight into brain-to-immune-system communication.

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