Decoding vomocytosis for cell-medaited, intra-lymph nodal delivery of microparticle vaccines

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DECODING VOMOCYTOSIS FOR CELL-MEDIATED, INTRA-LYMPH NODAL DELIVERY OF MICROPARTICLE VACCINES ABSTRACT/ SUMMARY The Immuno-modulatory Biomaterials Laboratory at UC Davis focuses on the development of novel biomaterial systems that can manipulate the immune system. Our goal is to design the next generation of immunotherapeutics for applications in immune-related diseases. This multidisciplinary work incorporates aspects of biomaterials engineering, drug delivery, immunology, biochemistry, and cell physiology. One of the main research programs in our lab is understanding controlled vomocytosis (non-lytic exocytosis) of particulate matter from phagocytic cells. Our primary motivation for elucidation of this process is the development of a `smart' microparticle system that can accomplish phagocytic cell-mediated delivery of vaccines directly to the lymph node-residing cells. Phagocytic cells (particularly macrophages [MΦ] and dendritic cells [DCs])) have evolved to circulate through peripheral tissue, engulf foreign particulate matter and traffick to the lymph node following uptake to relay information about the peripheral environment to cellular agents of the adaptive immune system. Evidently, phagocytic cells can transport particulate materials from peripheral tissues to lymphatic organs. Typically, following phagocytosis, and as phagocytic cells traverse the lymphatic vessels, materials that have been engulfed are taken into the phagosome (vacuole in the cytoplasm of a cell containing a phagocytosed particles) where a degradative process occurs due to secretion of reactive oxygen species (ROS), acidic pH and digestive enzymes. This stage would be counterproductive to the integrity of a particulate, and our purpose of intra-lymph nodal delivery. Moreover, release of particles from the phagocytic cell is not an intrinsic quality. But, there is precedent for such behavior. The fungal cell, Cryptococcus neoformans, elicits vomocytosis or (non-lytic exocytosis) from macrophages. There is still little understanding about the mechanisms governing this phenomena. Some reports indicate that there is an increase in pH of the phagosome during this activity, others have suggested Ca2+ flux could be pivotal for vesicle exocytosis. We believe that elucidation of the intra- phagosomal physico-chemical conditions that propel this activity could be instructive for the design of a mimetic microparticle. Further, investigation of the transcriptomal signatures between the period of phagocytosis and exocytosis could give us clues as to what biophysical factors are altered in the phagosome. Ultimately, our long- term goal is develop universally-deployable, microparticle vaccine platform as an effective, long-lasting prophylactic against infectious agents. The research and development of this platform system has the potential to significantly transform the treatment of a plethora of immune pathologies. Therefore, the proposed program is highly relevant to the mission of the National Institute of General Medical Sciences (NIGMS), which pertains to supporting research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention.