Biomolecular assemblies that modulate host immune responses have widespread potential in immunotherapy and tissue engineering applications. For example, self-assembled peptides that boost host immune responses may provide chemically well-defined vaccine adjuvants with precise mechanisms of action. On the other hand, self-assembled peptides that diminish host immune responses may improve the efficacy of tissue engineering therapies by alleviating the potential for tissue or implant rejection. This project is guided by the hypothesis that self-assembled peptides decorated with foreign proteins will elicit robust immune responses, while self-assembled peptides engineered to mimic mechanisms that inhibit immune responses within natural systems will diminish the immunogenicity of these biomaterials. This project is based on the well-defined immune response to peptide antigen- decorated self-assembled peptide biomaterials, which are non-immunogenic in the absence of antigen.
Aim 1 will engineer immunogenic self-assembled peptide biomaterials presenting protein antigens. The model protein antigen green fluorescent protein (GFP) will be immobilized on a self-assembled peptide biomaterial through formation of a covalent bond between an enzyme fused to GFP and a ligand presented by the material. The immunogenicity of GFP-modified self-assembled peptide biomaterials will then be characterized in vivo in a mouse model. These studies are designed to provide proof-of-principle that self- assembled peptide biomaterials decorated with a protein antigen elicit robust and long-lived immune responses. The outcomes of this aim will provide the basis for developing biomaterial-based vaccines against clinically-relevant pathogens, such as methicillin-resistant staphylococcus aureus.
Aim 2 will engineer self-assembled peptide biomaterials that diminish anti-material immune responses by mimicking native immune privilege mechanisms. In this aim, the GFP-modified self- assembled peptide biomaterials developed in S.A.1 will be further modified with a disaccharide that non- covalently binds to the protein galectin-1. The choice of galectin-1 as a negative modulator of immune response is based on the wel-established role of galectins in tumor immune privilege and fetal-maternal tolerance. Self-assembled peptide biomaterials decorated with GFP and a galectin-binding disaccharide will then be injected into mice in the presence or absence of soluble galectin-1. The immune response to these materials will be analyzed using the same models and approaches as in S.A.1. These studies are designed to provide proof-of-principle that biomaterials engineered to mimic native mechanisms of immune privilege diminish the immune response to the material. The outcomes of this aim will provide the basis for developing biomaterials that diminish host immune responses to limit rejection of tissues or implants for tissue engineering and regenerative medicine therapies.
Biomolecular assemblies that boost immune response are promising in immunotherapy applications, while biomolecular assemblies that diminish immune response can improve the efficacy of tissue engineering therapies by alleviating the potential for implant or tissue rejection. This project proposes that assemblies decorated with foreign proteins wil elicit robust immune responses;while assemblies that mimic mechanisms to down-regulate immune responses observed in natural systems will diminish the immunogenicity of these materials. By establishing mechanisms to modulate immune response that can be generalized to a variety of different biomaterials, this study will provide fundamental design rules to develop biomaterials that modulate immune responses for diverse tissue engineering and immune therapy applications. !
|Hudalla, Gregory A; Sun, Tao; Gasiorowski, Joshua Z et al. (2014) Gradated assembly of multiple proteins into supramolecular nanomaterials. Nat Mater 13:829-36|
|Hudalla, Gregory A; Modica, Justin A; Tian, Ye F et al. (2013) A self-adjuvanting supramolecular vaccine carrying a folded protein antigen. Adv Healthc Mater 2:1114-9|