Development of a particulate platform system for autoimmune disease therapy
Dendritic cells are the most potent APCs and activate T cells by displaying antigen-major histocompatibility complexes (MHC) and co-stimulatory molecules on their surface. Evidently, immuno-modulation of T cell-suppressing dendritic cells could provide an avenue for therapeutic intervention of autoimmune disease. The IMBL is currently developing a polymeric microparticle system composing of: i.) DC-targeting phagocytosable MPs delivering antigen and drug to intracellular targets and ii.) Non-phagocytosable MPs to extracellularly deliver at the injection site, DC recruitment and immuno-suppressive biological factors could be used to manipulate the phenotype of dendritic cells, particularly for tolerance induction and dampening of pro-inflammatory responses, which would be desirable for autoimmune disease immunotherapy.
Understanding controlled vomocytosis in phagocytic cells
Phagocytic cells have the innate ability to phagocytose particulate matter. Typically, this leads to degradation of the engulfed material in the phagolysosome of the phagocytic cell. However, Cryptococcus Neoformans cells when taken up by phagocytic cells induce swelling of the phagolysosome, followed by expulsion of live fungal cells via a process called vomocytosis. We’re interested in studying this phenomenon for potential applications in vaccine delivery.
Towards a Nanoparticle-based Prophylactic for Maternal Autoantibody-related Autism
Recently, ~23% of autism cases have been attributed to maternal immune dysfunction resulting in production of pathological autoantibodies in mothers of children with autism. During development, Maternal Autoantibody Related (MAR) autoantibodies cross the placenta and traverse the immature fetal blood brain barrier to target specific fetal brain proteins. The goal of the IMBL lab in collaboration with Prof. Judy Van De Water at the MIND Institute at UC Davis is to design an iron oxide-based nanoparticle system surface conjugated with the same epitopes to capture and clear the pathological MAR autoantibodies from the maternal circulation and result in normal development of the fetus. The prophylactic is called SNAREs as Systems for Nanoparticle-based Autoantibody Reception and Entrapment.
The effect of the lactate on the innate immune cells
In this study, the effect of PLGA microparticles (MPs) on the maturation status of murine bone marrow-derived dendritic cells (DCs), the primary initiators of adaptive immunity, is investigated to decipher the immunomodulatory properties of this biomaterial. Treatment of bone marrow-derived DCs from C57BL/6 mice with PLGA MPs led to a time dependent decrease in the maturation level of these cells, as quantified by decreased expression of the positive stimulatory molecules MHCII, CD80, and CD86 as well as the ability to resist maturation following challenge with lipopolysaccharide (LPS). These phenomena were correlated to an increase in lactic acid both intracellularly and extracellularly during DC/PLGA MP coculture, which is postulated to be the primary agent behind the observed immune inhibition. This hypothesis is supported by our results demonstrating that resistance to LPS stimulation may be due to the ability of PLGA MP-derived lactic acid to inhibit the phosphorylation of TAK1 and therefore prevent NF-κB activation.
Uncovering the role of dendritic cells in the foreign body response to materials
It has long been recognized that implantation of bulk biomaterials triggers a profound reaction of host immune responses, which in some instances culminates in the foreign body reaction. Tissue injury associated with biomaterial implantation results in the release of chemotactic agents that recruit immune cells to the site of implantation, including monocytes. Approximately, 25% of recruited monocytes differentiate into DCs. Dendritic cell potency to stimulate adaptive immune responses to pathogens has been well characterized, but an understanding of their role in the foreign body reaction to biomaterials is severely lacking. The goal of this project is to elucidate the role of dendritic cells in the foreign body response to implanted bulk biomaterials in mammalian systems.