Combination products can combine biomaterials with cells, DNA or proteins; e.g. tissue engineered constructs and non-viral polymeric carriers for vaccines. The biological component of combination products can be immunogenic either by design (e.g., DNA vaccine) or by selection (e.g., allogeneic or xenogeneic cells in a tissue engineered construct). Since biomaterials are used as vehicles in such combination products it is important to clarify the role of the biomaterial component in potentiating the immune responses towards the biological component due to the adjuvant effect of the biomaterial. Dendritic cells (DCs) function in innate immunity to recognize foreign pathogens and 'danger signals' to initiate an adaptive immune response. The goal of this research is to understand the effect of biomaterial contact on DC phenotype, the role of biomaterial chemistry and the mechanism involved. The long-term goal of this project is to design biomaterials on a molecular level to control DC phenotype and in this way control immune responses. Specifically, biomaterials will be designed to not support DC maturation where immune responses are undesirable, as for tissue engineered devices, while designed to support DC maturation where immune responses are desired, as for non-viral delivery vehicles for vaccines. The research plan is comprised of the following specific aims: (1) Demonstrate that biomaterial contact is sufficient for DC maturation into efficient antigen presenting cells (APCs) and T cell stimulators, and that maturation is differentially regulated depending on the type and form of the biomaterial. (2) Elucidate the mechanism of DC maturation by biomaterials, particularly the receptors involved focusing on Toll-like receptors (TLRs) of the innate immune system. (3) Show that biomaterial chemistry influences the process of DC maturation through an adsorbed protein layer. (4) Evaluate the extent of DCs maturation in the presence of biomaterials such that they act as professional APCs in mediating an adaptive immune response to device-associated antigens. ? ?
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