A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system

• Published in: PloS one Vol. 12; no. 7; p. e0180870
• Main Authors: St. Pierre, Cristina, Guo, Jane, Shin, John D., Engstrom, Laura W., Lee, Hyun-Hee, Herbert, Alan, Surdi, Laura, Baker, James, Salmon, Michael, Shah, Sanjiv, Ellis, J. Michael, Houshyar, Hani, Crackower, Michael A., Kleinschek, Melanie A., Jones, Dallas C., Hicks, Alexandra, Zaller, Dennis M., Alves, Stephen E., Ramadas, Ravisankar A.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.07.2017; Public Library of Science (PLoS)
• Subjects: Aberration; Analysis; Assaying; Autoimmune diseases; Biology and Life Sciences; Cancer; Chemokines - biosynthesis; Cytokines; Diagnosis; Disorders; Drug discovery; Drug Evaluation, Preclinical - methods; Health aspects; Health risks; Homeostasis; Humans; Immune response; Immune system; Immune System - cytology; Immune System - drug effects; Immune System - immunology; Immunology; Immunomodulation; Immunosuppression; Immunotherapy; Infections; Inhibitors; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Laboratories; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Medicine and Health Sciences; Metabolism; Modulation; Modulators; Oncology; Phagocytes - drug effects; Phagocytes - immunology; Phagocytes - metabolism; Pharmacology; Physical Sciences; Physiological aspects; Reactive Oxygen Species - metabolism; Risk; Small Molecule Libraries - pharmacology; Survival; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Toll-Like Receptors - metabolism; Transcriptome - drug effects; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0180870

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.