Date Published: July 18, 2017
Publisher: Public Library of Science
Author(s): Cristina St. Pierre, Jane Guo, John D. Shin, Laura W. Engstrom, Hyun-Hee Lee, Alan Herbert, Laura Surdi, James Baker, Michael Salmon, Sanjiv Shah, J. Michael Ellis, Hani Houshyar, Michael A. Crackower, Melanie A. Kleinschek, Dallas C. Jones, Alexandra Hicks, Dennis M. Zaller, Stephen E. Alves, Ravisankar A. Ramadas, Giovanni Maga.
While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the ‘immune fingerprint’ of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.
A normally functioning immune system is key for the health and survival of humans, while aberrant immune responses lead to the development of a plethora of chronic inflammatory and autoimmune disorders [1, 2]. While the same cellular and molecular components of the immune system are responsible for both protective and detrimental outcomes, the nature of the outcome is defined by the context, quality, magnitude and duration of the immune response.
The compounds that antagonize the function of drug targets in the immune system straddle a thin line between efficacy and nonspecific immunosuppression, and the systematic evaluation of the qualitative and quantitative impact of these compounds on the immune system is rather limited. Since the immune system and its manifestations are multifaceted, contextual and pleiotropic in terms of impact, a high-dimensional, non-reductionist, systems immunology approach has been proposed to better understand the system-wide impact of key cellular and molecular mediators in the immune system [16–18]. Along similar lines, a systems pharmacology approach to better understand the impact of compounds and prediction of efficacy and safety have also been proposed, a theme that is also gaining interest with regulatory agencies [19–22]. Using a human tissue-based immune function assay platform, here we demonstrate that the evaluation of a comprehensive ‘immune function impact’ of pharmacological modulators may help better understand the benefit-risk profiles of compounds that target the immune system.