Jamal Lewis, Ph.D., joined the Department of Biomedical Engineering at the University of California, Davis as an Assistant Professor in July 2015. Prior to his academic appointment, Lewis was a Senior Scientist at OneVax, LLC and a Post Doctoral Associate in the J. Crayon Pruitt Family Department of Biomedical Engineering at the University of Florida (UF). Lewis received his B.S. in Chemical Engineering from Florida A&M University in 2004, M.S. in Biomedical Engineering in 2007 from North Carolina State University and Ph.D. in Biomedical Engineering from the University of Florida in 2012. His Ph.D. and post doctoral work focused on the development and characterization of immuno-modulatory biomaterials. His research, educational and entrepreneurial efforts have been supported by NSF, NIH, and the Juvenile Diabetes Research Foundation. He is the recipient of numerous awards including the Biomedical Engineering Society Innovation, Career Development Award, the Society for Biomaterials STAR Award, and most recently received the NIH Maximizing Investigators’ Research Award (MIRA) for New and Early Stage Investigators. His current research interests include immuno-modulatory biomaterials, stimuli-responsive biomaterials and auto-immune disease therapy.
Title of Abstract
Current paradigms for the treatment of autoimmune diseases (e.g. rheumatoid arthritis [RA]) are woefully inadequate, often missing the mark on desired physiological responses and not targeting the root cause of the disease. Predictably, novel approaches to re-establish immune homeostasis in patients afflicted by autoimmune conditions are now under intense investigation. Notably, we are developing an array of multifunctional, biomaterial-based ‘anti-vaccines’ that can be easily administered to remediate some of the prevalent autoimmune diseases. Herein, we focus on two particulate systems currently under development in my lab, which attempt to control critical cellular and humoral mediators that engender conditions such as RA, and autoimmune autism. Additionally, the Lewis lab is currently investigating a novel method to enhance intra-lymph nodal delivery of particulates. Likened to the Trojan horse used by the Greeks to infiltrate Troy, this approach has the potential to tremendously boost the efficacy of modulatory agents (including vaccines) in the treatment of any immune condition.
RA Anti-vaccine: Safe, effective, antigen-specific therapy for rheumatoid arthritis (RA) remains an elusive clinical goal with few novel options on the horizon. Existing therapeutic interventions to halt RA progression are indiscriminately and inconsistently immunosuppressive, often leaving patient with a high risk of infection. We are currently investigating a dual-sized, microparticle “anti-vaccine” (Avac) that passively targets dendritic cells for antigen-specific immunotherapy of RA. This “anti-vaccine” employs poly(D,L-lactic-co-glycolic-acid) (PLGA) microparticles (MPs) encapsulating (i) a dendritic cell chemoattractant, (ii) potent immunosuppressive molecules, (iii) and RA-relevant autoantigen to provide a multifaceted approach for the treatment of collagen-induced arthritis (the primary mouse model of RA). Subcutaneous administrations of the Avac after mice had developed moderate clinical symptoms markedly diminished overt inflammation in the paws, halted cartilage degradation, and restored gait parameters within 56 days after initial treatment. Positron emission tomography imaging corroborated reduction of inflammation in the paws of Avac-treated mice. In-depth immunological assessments showed decreased expression of CD80, CD86, and MHCII on CD11c+ dendritic cells in joint-draining lymph nodes. Further, we observed significant increases in conventional regulatory CD25+FOXP3+ T cells, as well as, programmed cell death protein-1 (PD-1)-expressing CD4+ T cells in joint-proximal lymph nodes and spleen. Real time-PCR analysis of joint tissues from treated mice revealed significant decreases in inflammatory cytokine expression (IL-6), whilst IL-10 mRNA levels were significantly increased. These observations strongly hint towards the induction of multiple tolerogenic mechanisms by administration of this MP anti-vaccine. With regards to antigen specificity, ex vivo antigen recall assays revealed a lack of response to collagen by CD4+ T cells from the popliteal and inguinal lymph nodes of Avac-treated mice, contrasting with the proliferative response of CD4+ T cells from CIA+ mice. Taken altogether, our results strongly support the application of this MP “antivaccine” as a potent, biomaterial-based, antigen-specific therapy for RA.
Towards the first-ever prophylactic for autoimmune autism: Like RA, the incidence of autoimmune autism is approaching pandemic levels in the developed world. Recently, multiple research groups demonstrated that about a quarter of Autism Spectrum Disorder (ASD) cases are caused by maternal autoantibodies which cross the placenta and hinder fetal neurodevelopment. These pathological autoantibodies, at fault for Maternal Autoantibody-Related (MAR) autism, and their fetal protein targets (e.g. lactate dehydrogenase B [LDH B]) have been identified. Moreover, the dominant epitopic regions of these target proteins have been elucidated. These critical discoveries open the door for the development of a prophylactic measure for MAR autism. The use of nanoparticles as therapeutic platforms has been investigated due to their nano-sized structure and high surface to volume area. These features enable nanoparticles to potentially trap blood-resident proteins with great efficiency. In this vein, we are developing Systems for Nanoparticle-based Autoantibody Reception and Entrapment (SNAREs). This work represents a first-generational effort towards a MAR autism prophylactic which functions by scavenging disease-propagating MAR autoantibodies from the maternal blood. Specifically, we synthesized 15 nm dextran iron oxide nanoparticles surface-modified with citric acid, methoxy PEG(10 kDa) amine, and LDH B ASD peptide (SNARE). Through extensive physico-chemical characterization, including FTIR, XRD, and TGA, we confirmed presence of the desired surface moieties (e.g. PEG). PEGylation of NPs limited non-specific adsorption of Bovine Serum Albumin (BSA) protein on the surface of the PEG-coated NPs. Addition of LDH B peptide, via carbodiimide chemistry, resulted in a peptide surface density of 33.8 µg peptide/cm2. In vitro, we established an LC25 concentration of 500 µg/ml for SNAREs and demonstrated significantly lower macrophage uptake for SNAREs compared to unmodified NPs and citric acid-coated NPs. An in vitro capture assay demonstrated the efficacy of the SNAREs to remove 90% of LDH B autoantibody from prenatal, patient-derived serum. Furthermore, we showed SNARE exposure did not induce dendritic cell and macrophage maturation, nor elicit complement activation cascades. Whilst, histological analysis only exhibited nanoparticle deposition in liver and lungs at the highest NP dosage (150 mg NPs/kg). We believe this work provides credible evidence on the feasibility of SNAREs as the first-ever prophylactic against MAR autism.
Deciphering vomocytosis for intra-lymph nodal particulate delivery: The fungal species Cryptococcus neoformans, following engulfment by phagocytes, has been observed to stay alive within the acidic phagolysosome and escape through a process called vomocytosis. Using this phenomenon, C. neoformans is able to utilize the host body’s own immune cells to accumulate in critical immune organs. However, the underlying mechanisms of vomocytosis are poorly understood. In order to study vomocytosis, a method for quantifying phagocytosis and expulsion rates is required. Current studies rely on manual counting of vomocytosis events or flow cytometric staining, but with limited success. This work describes a novel, environmentally-responsive, dual fluorescent reporter system that would allow for precise monitoring of phagocytic entry and vomocytic expulsion. In this study, poly(lactic-co-glycolic acid) (PLGA) MPs are used to demonstrate proof-of-concept in order to eventually transfer the reporter system to C. neoformans and particulates.
In conclusion, we are developing multiple biomaterials-based approaches to either elucidate mechanisms behind immunological phenomena and create new therapeutics for autoimmune conditions. Our strong intent to translate our multifunctional platforms to the clinic should excite the regenerative medicine community at the Charleston meeting.
The Immuno-modulatory Biomaterials Laboratory 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 biology.
Currently, research efforts in the Lewis lab are centered on: Development of a particulate platform system for autoimmune disease therapy; Elucidating latent, Immunosuppressive Nature of Poly(lactic-co-glycolic acid) Microparticles; Understanding controlled non-lytic exocytosis in phagocytic cells; Uncovering the role of dendritic cells in the foreign body response to materials.