This work represents a biomaterials-based biomedical engineering research program integrated with immunology directed toward tolerance. Specifically, this project focuses on the engineering of technologies to provide personalized high-throughput screening of immune cell response to microparticle-based vaccines, using a limited number of cells. Microparticle-based vaccine systems can, in vivo, deliver antigen and relevant immuno- modulatory factors to targeted phagocytic cell population, specifically, dendritic cells, a key immune regulator. Typical assessment of a tolerance-inducing vaccine relies on testing one formulation at a time, hoping to uncover a single factor capable of generating long-lived immune tolerance. However, multiple critical signals are likely to combine to promote robust, enduring antigen-specific tolerance. A lack of understanding of the interactions between different immunomodulatory factors, and the lack of an efficient means to test large numbers of combinations of factors represents a significant blockade for the development of new vaccine technologies. In order to overcome this barrier, we are developing a high-throughput cell-based microarray approach for the testing of microparticles incorporating multiple components targeted to dendritic cells, a key antigen presenting cell type. Our preliminary data indicates that the unique high- throughput in vitro platform we are developing is feasible, and that in vitro screening of microparticle formulations can be useful for suggesting in vivo responses to injected microparticles. Our long-term test-bed application is the prevention of type-1 diabetes in a diabetic mouse model by injection of microparticles. We are optimizing multi- component particle formulations to direct DCs toward a tolerogenic phenotype and the induction of regulatory T-cells for antigen-specific immune suppression. Our miniaturized technology requires only small numbers of cells, taking steps toward the development of personalized vaccines.

Public Health Relevance

We are rapidly in vitro assessing and optimizing antigen-delivering, immuno-modulatory microparticles as an injectable microparticle-based vaccine, intended for targeted uptake in vivo by dendritic cells for future studies for the treatment of type 1 diabetes. Our in vitro system consists of fabricating cell-based microarrays of immune cells for high-throughput screening of microparticle formulations, and formulations will be assessed for their ability to generate immune cell phenotypes which have been linked to the induction of antigen-specific tolerance. This miniaturized approach uses only a small number of cells, and moves toward the development of personalized vaccines, which may be screened for a patient's specific immune cell response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI094360-02
Application #
8525337
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Lapham, Cheryl K
Project Start
2012-08-08
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$169,395
Indirect Cost
$51,895
Name
University of Florida
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Lewis, Jamal S; Roche, Chris; Zhang, Ying et al. (2014) Combinatorial delivery of immunosuppressive factors to dendritic cells using dual-sized microspheres. J Mater Chem B Mater Biol Med 2:2562-2574
Acharya, Abhinav P; Lewis, Jamal S; Keselowsky, Benjamin G (2013) Combinatorial co-encapsulation of hydrophobic molecules in poly(lactide-co-glycolide) microparticles. Biomaterials 34:3422-30