The Mechanism of Regulation of Dendritic Cell Differentiation by Adenosine
Mikhail M. Dikov PhD
Vanderbilt University Medical Center – Nashville, Tennessee USA
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The optimal therapeutic strategies for multisystem Langerhans cell histiocytosis (LCH) remain to be defined. Advances in LCH immunology suggest that aberrant differentiation of dendritic cells (DCs) might underlie the defective interaction of immune cells, leading to a unique pathological picture within LCH lesions, which combines features of both carcinogenesis and chronic inflammation.
Recent works including ours have identified adenosine as an important factor responsible for altered differentiation of DCs and Langerhans cells (LCs). We have preliminary data demonstrating that these cells express a variety of proinflammatory and angiogenic cytokines and factors, the hallmarks of histiocytotic lesions, and thus can contribute to the development of the disease.
In the current project, we propose to determine the molecular mechanisms of adenosine effects on DC and LC differentiation and to provide rationale for therapeutic interventions aimed on disruption of adenosine signaling. We also intend to test in vitro the efficiency of adenosine receptor subtype-specific antagonist treatment in preventing accumulation of intermediate DCs and rescuing normal DC/LC differentiation. The goal of the study is to improve our understanding of the role of adenosine receptors in the differentiation of DC/LCs and pathophysiology of LCH and to validate the use of anti-adenosine receptor subtype-specific therapy in LCH. The generated data will lay basis for future clinical trials of adenosine receptor antagonists in treatment of LCH.