Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Abstract

Objective: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). Methods: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBP_p161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. Results: In naïve mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-γ/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen-specific splenocytes from animals behaviorally conditioned with CsA to naïve mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with β₂-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-γ but increased IL-17 immune responses. The β₂-adrenergic antagonist propranolol could restore IFN-γ production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. Conclusions: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases.

Cyclosporine A-Loaded Nanocarriers for Topical Treatment of Murine Experimental Autoimmune Uveoretinitis

“…As the inhibition of IL-2 secretion and proliferation is a central effector mechanism and is used as a pharmacodynamic measure of CsA, − we used the IL-2 secretion and proliferation to measure the response to CsA in our study. Thereby, we confirmed the findings of our manuscript . Herein, systemic CsA treatment in EAU was associated with reduced proliferation and IL-2 secretion.…”

“…Thereby, we confirmed the findings of our manuscript. 35 Herein, systemic CsA treatment in EAU was associated with reduced proliferation and IL-2 secretion.…”

“…B10.RIII mice are highly susceptible to developing EAU and possess a well characterized disease course. This model allows the analysis of new therapeutic strategies with a systemic, topical, or intraocular approach. ,− B10.RIII mice (8 weeks of age, female) were purchased from Jackson Laboratory (Bar Harbor, USA). Animals were housed in standard animal rooms under a 12 h light/dark cycle with food and water provided ad libitum.…”

Pavlovian Conditioning of Immunological and Neuroendocrine Functions

“…Even though results demonstrated that in comparison with rats taste-immune associative learning did not result in mice displayed reduced appetitive behavior(157). However, from the immunological perspective, learned immunosuppression was detectable reflected by a diminished production of IL-2(46,332).…”

Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats

“…16 For instance, in classic studies with humans and rodents, cyclosporine A endowed gustatory CSs with conditioned, immunosuppressive qualities. 17,18 As more connections are found between ethanol and the immune system, it is important to analyze the mutual influence between neuroimmune signaling and ethanol-induced learning. Yet, to our knowledge, very few studies have assessed if immunomodulation induced by drugs of abuse can also be subject to conditioning.…”