Are we aiming to miss in translational autoimmunity treatments?
Gisela M Vaitaitis1,2, David H Wagner1,2
1Webb-Waring Center, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA.
Abstract:
Autoimmunity treatments, fruitfully pioneered in mouse models, can be disappointing or result in immunosuppression and opportunistic infections in translational trials. Many possible reasons exist, but one major, overlooked reason may be the treatment timing in relation to circadian oscillations of the immune system. Mice and humans both have immunological circadian clocks and experience the same circulatory oscillations of immune cells with regards to their sleep/wake phases, but have opposite sleep/wake phases with regard to the daylight cycle. Therefore, researchers mainly study mice and potential autoimmunity treatments during the murine sleep/rest phase, which is when pro-inflammatory mediators and more adaptive immune cells are prevalent in the circulation. In translational trials, however, treatment administration happens primarily during a patient's wake/activity phase, during the daytime, which is when more local and acute immune responses are active in the circulation. Therefore, we believe that the most opportune window for autoimmunity treatment may be missed in translational trials. Shifting the timing, and adjusting dosing to target only immune cells that are active at that time, may result in higher success with minimized immunosuppression or toxicities.
Insights
Timing of autoimmunity treatments may be critical. Optimizing drug administration based on the body's natural immune cell rhythms, rather than standard schedules, could improve treatment success and reduce side effects.
Area of Science:
- Immunology
- Chronobiology
- Pharmacology
Background:
- Autoimmunity treatments developed in mice often fail in human trials, leading to immunosuppression and infections.
- A key factor may be the timing of treatment relative to the body's internal biological clocks (circadian rhythms).
- Mice and humans have opposing sleep/wake cycles, impacting immune cell circulation patterns.
Purpose of the Study:
- To investigate the impact of circadian rhythms on the efficacy and safety of autoimmunity treatments.
- To identify optimal treatment timing windows for autoimmune diseases.
- To reduce immunosuppression and opportunistic infections associated with current treatment protocols.
Main Methods:
- Analysis of circadian oscillations of immune cells in mice and humans.
- Comparison of murine research conditions with human clinical trial administration schedules.
- Hypothesizing optimal treatment timing based on immune cell activity patterns.
Main Results:
- Murine studies often occur during the animals' rest phase, when pro-inflammatory immune cells are high.
- Human trials typically administer treatments during the day, when acute immune responses are active.
- This discrepancy suggests a potential mismatch in treatment timing, missing optimal therapeutic windows.
Conclusions:
- Treatment timing, synchronized with circadian immune rhythms, is a crucial, overlooked factor in autoimmunity therapy.
- Adjusting administration schedules and dosages to target specific immune cell activity phases may enhance treatment efficacy.
- This chronotherapeutic approach could lead to improved outcomes with reduced toxicity and immunosuppression.
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