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Chronobiology of the Immune System

Implication for the Delivery of Therapeutic Agents

  • Immunological Basis Of Disease
  • Published:
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Summary

Activation, proliferation and circulation of immune cells vary predictably according to circadian (approximately 24-hour) rhythms. These biological rhythms are endogenous and genetically based. Rhythms in nocturnally active experimental animals such as mice or rats are 12 hours out of phase from those in diurnally active humans. In animal studies, the toxic and immunomodulatory effects of agents such as interferon, interleukin-2 and cyclosporin can vary by 50% or more according to time of administration, presumably as a result of circadian rhythms.

Immunological circadian rhythms appear to be maintained in liver transplant patients receiving continuous infused immunosuppressive therapy. However, rhythms were altered in patients with advanced stage malignancy or HIV infection, and in cancer patients receiving infusions of cytokines on a standard regimen.

Translation of these preclinical and clinical findings to drug delivery has just begun. A portable programmable-in-time pump was used to modulate delivery of interferon-α to patients with renal cell cancer. Maximal delivery was from 1800 to 2400h, with no delivery from 0600 to 1200h. Dosages of 15 to 20 MU/m2/day for 21 days were tolerated, 2 to 3 times higher than dosages administered using a standard regimen.

Further trials of chronobiologically modulated therapy are warranted to establish its effectiveness in treatment of immunological disorders.

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Acknowledgements

This work was supported in part by the Association pour la Recherche sur le Temps Biologique et la Chronothérapie, Hôpital Paul Brousse, 94800 Villejuif, France. The authors thank M. Lévi for the excellent editorial assistance.

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Authors and Affiliations

  1. Laboratoire ‘Rythmes Biologiques et Chronothérapeutique’, ICIG, Institut du Cancer et d’Immunogénétique, Hôpital Paul Brousse, 14 Avenue PV Couturier, 94800, Villejuif, France

    Francis Lévi, Philippe Bourin & Petra Deprés-Brummer

  2. Centre de Transfusion Sanguine des Armées, Clamart, France

    Philippe Bourin

  3. Centre de Chirurgie Hépatobiliaire, Hôpital Paul Brousse, Villejuif, France

    René Adam

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  1. Francis Lévi
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  2. Philippe Bourin
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  4. René Adam
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Lévi, F., Bourin, P., Deprés-Brummer, P. et al. Chronobiology of the Immune System. Clin Immunother 2, 53–64 (1994). https://doi.org/10.1007/BF03258522

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