Metabolite-Based Modulation of Dendritic Cells for Developing Effective Immunotherapy

INTRODUCTION – Aging and diabetes associated chronic / slow healing cutaneous wounds have hallmark immune signatures, including delayed T-cell and macrophage infiltration, and increased pro-inflammatory immune cell infiltration for extended periods (compared to non-aged control). If there were a method to modulate the local immune responses in a temporal manner then it would be possible to accelerate the wound healing of cutaneous wounds in aged and/or diabetic immune system. Notably, metabolic pathways control immune cell functions, and modulating these pathways can determine overall immune system response. Therefore, in this work, polymers were generated with metabolite monomers that can deliver metabolites and directly modulate the function of immune cells.

RESULTS – This work for the first time (to the best of our knowledge) demonstrates utilization of metabolites to modulate immune-metabolic responses in wound healing. NMR and FTIR studies were performed to characterize the polymers. Moreover, oil in water emulsions were utilized to generate microparticles of these metabolite-based polymers. These microparticles are capable of encapsulating drugs and release them in a sustained manner (shown via representative drug-molecule rhodamine). The release kinetics of metabolites from these polymers were determined using NMR. Moreover, degradation kinetics of the polymers was determined using weight loss experiments. Importantly, it was demonstrated that these polymers could modulate the function of mouse bone marrow derived dendritic cells and allogenic T-cells in a mixed lymphocyte reaction. Lastly, we demonstrate that these polymers when applied in the presence of tegaderm were able to modulate the wound healing rate in BALB/c mice.

CONCLUSION - In summary, metabolite-based polymers were generated that were capable of controlling the pro- or anti-inflammatory responses of immune cells in vitro and in vivo. Notably, these polymers were able to lead to healing of cutaneous wounds in mice.