Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity

Abstract

Autoimmune diseases occur when the immune system incorrectly recognize self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLR), pathways usually involved in generating immune response again pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR-signaling, and in primary DC and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease.

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…Thus, local reprogramming of the LN environment led to tolerance that was systemic, but antigen-specific. Self-assembly has been used for co-delivery as well, promoting tolerance with carrier-free vaccines that eliminate the intrinsic immunogenic effects of biomaterials discussed earlier [86,87]. TLR signaling is overactive in many human autoimmune diseases, yet bio-materials can activate TLRs.…”

Phage display as a tool for vaccine and immunotherapy development

“…Host cells express pattern recognition receptors (PRRs) that detect danger signals known as pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). 10 Interestingly, phages can interact with a variety of TLRs, which activates innate immune pathways. One set of PRRs, toll-like receptors (TLRs), is specifically known to recognize bacterial and viral products.…”

Engineering Biomaterials to Direct Innate Immunity

“…[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The hypothesis for this type of strategy is that inhibiting inflammatory signaling or promoting regulatory signaling while antigen is being processed and presented by APCs will promote presentation of antigen in a manner that polarizes effector cells toward tolerance. [88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The hypothesis for this type of strategy is that inhibiting inflammatory signaling or promoting regulatory signaling while antigen is being processed and presented by APCs will promote presentation of antigen in a manner that polarizes effector cells toward tolerance.…”