Abstract
The ability to regulate the recruitment of immune cells makes chemokines and their receptors attractive drug targets in many inflammatory diseases. Based on its preferential expression on T helper type 2 (Th2) cells, C-C chemokine receptor type 4 (CCR4) has been widely studied in the context of allergic diseases, but recent evidence on the expression of CCR4 in other cell types has considerably expanded the potential applications of CCR4 antagonism. However, the current number of approved indications, as well as the portfolio of CCR4-targeting drugs, are still limited. In the present study, we have assessed the potential therapeutic efficacy of a CCR4 small molecule antagonist, SP50, discovered via an in silico-based approach, against a variety of pre-clinical settings of infection with the fungus Aspergillus fumigatus. We show that SP50 efficiently worked as prophylactic vaccine adjuvant in immunocompetent mice, protected against invasive aspergillosis in immunosuppressed mice. Further, the CCR4 antagonist prevented allergic bronchopulmonary aspergillosis in susceptible mice, and in a murine model of cystic fibrosis, a genetic disorder characterized by chronic pulmonary inflammation and recurrent infections. In conclusion, our results extend the potential applications of CCR4 antagonism and prompt for the development of novel compounds with the potential to progress to clinical trials.
Highlights
Chemokines are cytokines endowed with chemotactic activity and play critical roles in the positioning and migration of immune cells in homeostasis and during immune responses [1]
Our results indicate that chemokine receptor type 4 (CCR4) antagonists can protect from aspergillosis and allergic bronchopulmonary aspergillosis (ABPA) in susceptible mice and in a murine model of cystic fibrosis (CF), extending the clinical indications for therapeutic development of CCR4 targeting drugs
Described the development of small molecule CCR4 antagonists that were able to target Treg cells and work as vaccine adjuvant by boosting immune responses when used in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis or recombinant hepatitis B virus surface antigen vaccines [20]
Summary
Chemokines are cytokines endowed with chemotactic activity and play critical roles in the positioning and migration of immune cells in homeostasis and during immune responses [1]. Since chemokines are dysregulated in many inflammatory diseases, pharmacological inhibition of the relevant chemokine receptors represents an active area of research. The knowledge of the chemokine/chemokine receptor system is a fundamental prerequisite for successful pharmacological targeting [4]. CCR4 has attracted considerable interest as a potential target in a variety of pathological conditions [5,6]. CCR4 is the chemokine receptor preferentially expressed on Th2 cells. Other T cell subsets can express CCR4, including cutaneous lymphocyte antigen (CLA)-positive skin-homing T cells, regulatory T cells (Treg cells), Th17, and Th22 cells [7]. CCR4 was found to be expressed by natural
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