Dissertation

Lost in translation: The toll-like receptor 7 induced pharmacological challenge model of the skin

This thesis investigates a pharmacological challenge model induced by Toll-like receptor 7 (TLR7) activation, focusing on skin inflammation and its implications for early drug development.

Author: S. Assil
Date: 10 January 2025
Links: Thesis in Leiden Repository

It aims to bridge the translational gap between animal and human models by employing the synthetic compound imiquimod (IMQ). IMQ, a TLR7 agonist, is applied topically to induce inflammation in healthy human volunteers, mimicking characteristics of inflammation of the skin. The work involves comprehensive characterization of the model, assessing biophysical, cellular, and molecular responses to IMQ. Key studies explored the suppression of inflammation using oral prednisolone, a known anti-inflammatory, and tested the model's application with novel drugs, such as omiganan. The research integrates multimodal techniques, including imaging and molecular analyses, to deepen the understanding of inflammatory processes and drug mechanisms. This model addresses the shortcomings of murine studies, highlighting the significant interspecies differences in skin structure and immune response. By refining this human-compatible model, the thesis proposes an innovative framework for accelerating the development of therapeutics for inflammatory diseases, aiming to improve the efficiency and relevance of early-phase drug trials.