Immunomodulation by Classical Conditioning in NZB/W (Fi) Mice: Lifespan and Circadian Phase Modulation

*Corresponding author e-mail: mmiguel@usp.br Introduction: Systemic Lupus Eritematosus (SLE) is a systemic inflammatory disease, chronic, recurring and potentially fatal, being considered as an auto-immunological syndrome. The therapeutic basis for treating patients with SLE is the agent cyclophosphamide (CY), known to produce adverse reactions to the organism. Previously, Ader and Cohen have demonstrated an alternative way of administrating this immunossupressor agent, based on pavlovian classical conditioning, in order to reduce the aggression caused by CY. Considering that every organism on earth shows a temporal organization as well as the influence of this organization on learning and memory processes, the purpose of this study is to provide elements for the understanding of the temporal aspects involved in immunomodulation. The primary objective is the detection of a different pattern of response in a conditioned immunomodulation paradigm conducted in two different phases of the light-dark cycle. Methods: NZB/W (FI) mice were selected, a strain with high predisposition for the spontaneous development of SLE. Divided into two groups, the animals were submitted, in different phases of day, to a classical conditioning immunomodulation protocol, consisted in weekly parings of saccharin solution and CY injections. The success of the paradigm was evaluated by comparing the progression of proteinuria and the lifespan among the groups. Simultaneously, water intake behavior was recorded, in order to evaluate two rhythmic parameters, amplitude and spectral power density of the 24-hour rhythm, with the progression of SLE. Results: Comparing the development of proteinuria and lifespan of animals of the experimental to the control groups, it was possible to find significant differences. The comparison between the experimental groups revealed that the lifespan of the animals submitted to the CY during the light phase was greater than the dark phase animals. Concerning the rhythmic parameters, there was evidence of association between the stability of the signal from the timing systems and the evolution of SLE, demonstrated by the maintenance of higher levels of amplitude and spectral power density of the 24 hour rhythm in animals exposed to the conditioning paradigm. Conclusion: In this animal model of SLE, the classical conditioning of immunossupresion is sensitive to the phase of the light-dark cycle. Moreover, the lack of stability of the circadian system seems to be important to the progression of the disease. Support: Capes and Fapesp. Publication History Article published online: 16 June 2026 © 2009. Brazilian Sleep Academy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil