Local delivery of an adenosine receptor agonist reduces inflammation associated with contact hypersensitivity

Allergic contact dermatitis (ACD), a T-cell mediated inflammatory skin condition, is prompted by multiple, subsequent exposures to contact allergens (e.g., nickel). Current treatment approaches for ACD include repeated topical application or systemic delivery of immunosuppressants. These treatment strategies have many limitations, including non-specific mechanism of actions and the occurrence of side effects due to their delivery method. For this reason, we developed a novel therapeutic approach that is based upon adenosine (Ado) receptor signaling, a known anti-inflammatory pathway. Specifically, we developed a polymer microparticle-based controlled release system capable of presenting IBMECA (IBMECA-MPs), an Ado receptor agonist, to the local environment. In this study, we first sought to study the immunosuppressive effects of IBMECA on immune cells implicated in the pathogenesis of ACD (e.g., dendritic cells) in vitro. Subsequently, we examined the effects of enhancing adenosine signaling in contact hypersensitivity (CHS), an in vivo model of ACD, through local administration of IBMECA-MPs. We observed that IBMECA-MPs were capable of reducing the inflammatory response associated with CHS by reducing maturation markers of antigen-presenting cells, altering cytokine secretion, and reducing relative frequencies of effector T cell populations. To our knowledge, this is the first demonstration of therapeutic efficacy of IBMECA in CHS, as well as the first proof-of-principle demonstration of IBMECA application in the context of a local drug delivery system. Ultimately, this delivery system has the potential to be adapted for use in other T-cell mediated inflammatory conditions (e.g., transplant rejection), suggesting broader implications of this study.