Summary: Autoimmune disorders are estimated to be among the top ten leading causes of death among women of all ages below 65, for which available treatments include systemic immunosuppressants that cause serious long-term side effects. There is hence a growing interest to engineer mechanisms of inducing target-specific immune tolerance with biomaterials particularly professional antigen presenting cells namely dendritic cells (DCs). DCs previously studied in the context of biomaterials have been discovered to elicit differential responses to biomaterials suggesting that materials on their own have the ability to stimulate specific DC phenotype. As the phenotype of DCs is a key mediator of downstream adaptive immune responses that lead to normal or aberrant immunity, there is increasing interest in delineating the underlying mechanisms of material-cell interaction. In this proposal, we initially investigate the role played by DCs in the adjuvant effect shown by certain materials such as poly lactic-co-glycolic acid (PLGA) and further exploit the differential nature of the response towards agarose compared to PLGA, to develop solely biomaterial-based methods in inducing antigen-specific immune tolerance in an in vivo mouse model. Moreover, DCs can be locally treated with specific immunomodulators rather than biomaterials to express a tolerogenic phenotype that can trigger antigen-specific immunoregulation. As a second and distinct approach, in this proposal, we examine the possibility of developing the spatiotemporally controlled delivery of immunomodulators from a single implantable biomaterial niche. The design of such a delivery device would call for not only incorporating a strategy for DC phenotype modulation but also a technique for promoting endogenous DC recruitment upon in vivo implantation; thus it would enable the localized delivery of factors while promoting systemic circulation of in situ primed DCs for effective downstream immune function, a feature commonly lacking in existing treatments of autoimmune diseases. Finally, the efficacy of this technique will be assessed in the context of an autoimmune disease model, to explore its potential use as a therapeutic cure for individuals with autoimmune disorders.

Advisor:

Julia E. Babensee, PhD

Wallace C. Coulter Department of Biomedical Engineering

Georgia Institute of Technology and Emory University

Thesis Committee:

Julie Champion, PhD

School of Chemical and Biomolecular Engineering

Georgia Institute of Technology and Emory University

Edward Botchwey, PhD

Wallace C. Coulter Department of Biomedical Engineering

Georgia Institute of Technology and Emory University

Susan Thomas, PhD

George W. Woodruff School of Mechanical Engineering

Georgia Institute of Technology and Emory University

 Krishnendu Roy, PhD

Wallace C. Coulter Department of Biomedical Engineering

Georgia Institute of Technology and Emory University