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

Abstract

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.

Harnessing associative learning paradigms to optimize drug treatment

“…The underlying mechanisms steering learned immune responses are only partly understood. In a paradigm using the calcineurin inhibitor and immunosuppressant cyclosporine A, conditioned effects were centrally mediated via the insular cortex and the amygdala, peripherally via sympathetic innervation of lymphoid organs such as spleen and lymph nodes, and via noradrenaline and βadrenoceptors on immune competent cells [15]. The putatively important role of the insular cortex in learned immune responses is also supported by recent work showing that this brain structure is capable of detecting, storing, and retrieving specific peripheral immunological responses [16].…”

“…These findings indicate that the timing of presenting reminder cues during the labile phase of the memory trace (i.e., inside versus outside the reconsolidation window) is crucial for initiating a memory updating that prevents conditioned responses from being extinguished. The clinical relevance of this memory-updating procedure has already been proven in rodent models, as it prolonged the survival time of heterotopically transplanted hearts [6] and diminished disease progression of rheumatoid arthritis [15] (Figure 2A,B). Importantly, this approach seems to generalize across agents with distinct immunopharmacological mechanisms or pathways.…”

“…Additionally, the splenocyte production of cytokines, such as interleukin (IL)-2, was suppressed compared with controls [3]. Similarly, this procedure attenuated disease progression in experimentally induced rheumatoid arthritis (B), reflected by lower scores of symptomatology and histological inflammation [15]. In a recent, yet unpublished experimental glioblastoma approach, the extension of tumor growth was reduced in animals receiving low therapeutic doses of the mechanistic target of rapamycin (mTOR) inhibitor rapamycin (C).…”

Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats

“…Rats of the control groups received an equivolumed, weight-adapted dose of the stock solution diluted with sterile saline. The administered doses are based on previous studies, verifying this drugs' immunosuppressive properties and efficacy on progress and outcome in animal disease models (Hadamitzky et al 2016;Lückemann et al 2020).…”

Less Pain, More Gain: Should Placebo Be a Clinical Therapeutic?

“…In this issue of Arthritis & Rheumatology , Lückemann et al report that rats with collagen‐induced arthritis can be behaviorally conditioned to respond to placebo when the immunosuppressant cyclosporin A (CSA) is paired with saccharin solution . Clinical symptoms of arthritis, such as diminished grip strength, as well as objective measures of inflammation, such as interferon‐γ activation and histologic changes, were significantly improved in the conditioned group, achieving 75–100% of the therapeutic effect of high‐dose CSA treatment (unconditioned stimulus).…”