PDF(Pubmed)
Abstract：
Suppression of immune functions can be elicited by behavioural conditioning using drugs such as cyclosporin A or rapamycin. Nevertheless, little is known about the underlying mechanisms and generalisability of this phenomenon. Against this background, the present study investigated whether the pharmacological properties of fingolimod (FTY720), an immunosuppressive drug widely applied to treat multiple sclerosis, can be conditioned in rats by means of taste-immune associative learning. For this purpose, a conditioned taste avoidance paradigm was used, pairing the presentation of a novel sweet drinking solution (saccharin or sucrose) as conditioned stimulus (CS) with therapeutically effective doses of FTY720 as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time point revealed that conditioning with FTY720 induced a mild conditioned taste avoidance only when saccharin was employed as CS. However, on an immunological level, neither re-exposure with saccharin nor sucrose altered blood immune cell subsets or splenic cytokine production. Despite the fact that intraperitonally administered FTY720 could be detected in brain regions known to mediate neuro-immune interactions, the present findings show that the physiological action of FTY720 is not inducible by mere taste-immune associative learning. Whether conditioning generalises across all small-molecule drugs with immunosuppressive properties still needs to be investigated with modified paradigms probably using distinct sensory CS. Moreover, these findings emphasize the need to further investigate the underlying mechanisms of conditioned immunomodulation to assess the generalisability and usability of associative learning protocols as supportive therapies in clinical contexts.
摘要：
免疫功能的抑制可以通过使用药物如环孢菌素A或雷帕霉素的行为调节来引起。然而，对这种现象的潜在机制和普遍性知之甚少。在这种背景下,本研究调查了芬戈莫德（FTY720）的药理特性，一种广泛用于治疗多发性硬化症的免疫抑制药物，可以通过味觉免疫联想学习对大鼠进行调节。为此,使用了条件性的味道回避范式，将新型甜味饮用溶液（糖精或蔗糖）作为条件刺激（CS）与治疗有效剂量的FTY720作为非条件刺激（US）配对。随后在稍后的时间点再次暴露于CS表明，只有当糖精用作CS时，用FTY720调节才会引起温和的条件性味道回避。然而,在免疫学水平上，糖精和蔗糖的再次暴露均不会改变血液免疫细胞亚群或脾细胞因子的产生。尽管可以在已知介导神经免疫相互作用的大脑区域中检测到内给药的FTY720，目前的发现表明，FTY720的生理作用不能仅通过味觉免疫联想学习来诱导。调理是否适用于具有免疫抑制特性的所有小分子药物，仍需要使用可能使用不同的感觉CS进行修改的范例进行研究。此外，这些发现强调有必要进一步研究条件免疫调节的潜在机制,以评估联想学习方案作为临床支持疗法的普遍性和可用性.
