Lewis Lab

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@2019 by IMBL

Amir Bolandparvaz

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.

Latent, Immunosuppressive Nature of Poly(lactic-co-glycolic acid) Microparticles

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. 

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.


 

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.

 

 

Towards a Nanoparticle-based Prophylactic for Maternal Autoantibody-related Autism

Autism Spectrum Disorder (ASD) comprises a range of developmental disorders diagnosed in early childhood, where their ability to communicate and interact are impaired. In the U.S., an estimated 1 in 59 children is born with ASD and the economic burden is a staggering $268 billion per year. Current therapies are post-symptomatic and include behavioral interventions or symptom-derived pharmacological treatments. Recently, the Van De Water group discovered that about a quarter of ASD cases are caused by maternal auto-antibodies that can hinder normal neurodevelopment in the fetus. Moreover, they elucidated the seven proteins targeted by these auto-antibodies in the fetal brain, including lactate dehydrogenase A and B (LDHA, LDHB) and stress-induced phosphoprotein 1 (STIP1). Herein, we aim to develop a System for Nanoparticle-based Autoantibody Retention and Entrapment (SNARE) prophylactic as a biomagnetic-trap for sequestration of disease-propagating Maternal Autoantibody-Related (MAR) autoantibodies. Our central hypothesis is that upon intravenous injection, the iron oxide NPs surface-conjugated with autoantigens will circulate throughout the maternal vasculature, and specifically ligate MAR auto-antibodies, thereby limiting antibody (Ab) transport across the placenta and preventing MAR autism.

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