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

PLoS One. 2017 Jul 18;12(7):e0180870. doi: 10.1371/journal.pone.0180870. eCollection 2017.

Abstract

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.

MeSH terms

  • Chemokines / biosynthesis
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Immune System / cytology
  • Immune System / drug effects*
  • Immune System / immunology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology
  • Phagocytes / drug effects
  • Phagocytes / immunology
  • Phagocytes / metabolism
  • Reactive Oxygen Species / metabolism
  • Small Molecule Libraries / pharmacology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Toll-Like Receptors / metabolism
  • Transcriptome / drug effects

Substances

  • Chemokines
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Toll-Like Receptors

Grants and funding

All the co-authors in this manuscript are/were employees of Merck, Sharpe & Dohme Co., while this work was performed. Funding for this entire study was provided by Merck, Sharpe & Dohme Co. The funder provided support in the form of salaries for authors (CSP, JG, JDS, LWE, HHL, AH, LS, JB, MS, SS, JME, HH, MAC, MAK, DCJ, AH, DMZ, SEA, RAR), but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.