W121 - Modulating Innate Immune Signaling with Nanomaterials to Drive Antigen-Specific Tolerance

Autoimmune diseases like multiple sclerosis (MS) occur when the immune system targets self-antigens, attacks and damages host tissues. Therapies that promote antigen-specific tolerance are a transformative goal to specifically counter this attack while leaving protective immunity intact. One exciting possibility to promote antigen-specific tolerance is to modulate innate immune signaling pathways and regulate the immune response against self-antigens delivered as a therapeutic. Toll-like receptors (TLRs) control innate signaling pathways that direct the first line of defense against invading pathogens. Remarkably, activation of TLR pathways has also been observe in MS. Thus, control of TLRs by MS therapeutics during antigen-delivery may promote tolerance. We hypothesized that therapeutics self-assembled from a TLR9 regulatory cue (GpG) and myelin self-antigen (MOG) would promote tolerance and counter autoimmunity. To test this hypothesis, a small library of therapeutics was self-assembled through electrostatic interactions to form nanostructured microcapsules. Excitingly, therapeutics containing both MOG and GpG reversed established paralysis in a pre-clinical model of MS, while leaving healthy immunity intact (Oakes RS, et al., ACS Nano, 2021). We then isolated MOG and GpG into separate formulations, which showed that MOG was required for therapeutic efficacy and GpG enhanced efficacy. Gene expression analysis of disease and treatment draining lymph nodes showed that GpG inclusion in microcapsules decreased Tnf and Myd88 (a TLR master regulator) expression in vivo, but soluble GpG alone did not. These data indicate that composition and biophysical presentation (soluble vs. microcapsule) are important design parameters for manipulation of immune signaling to drive therapeutic tolerance.