Tunable Assembly of Regulatory Immune Signals to Promote Myelin-specific Tolerance

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During autoimmune disease, the body identifies and attacks “self” molecules. Current therapies are not curative and require life-long compliance. Further, existing therapies – while beneficial, are broadly acting and can leave patients immunocompromised. These challenges have sparked great interest in controlling autoimmunity with vaccine-like specificity to preserve normal immune function. Both pre-clinical and clinical studies are testing this idea in multiple sclerosis (MS), a disease that disproportionality impacts Veterans. MS is a neurodegenerative disease driven by mistaken attack of myelin in the central nervous system (CNS). Thus, an experimental therapy idea involves co-administration of myelin peptide and tolerizing cues to promote myelin-specific regulatory T cells (TREG) that control MS. In some recent trials, small sets of 6-8 myelin epitopes are being tested as a route to span the range of myelin reactivity in many - though not all - patients. Interestingly, one set of pathways newly- associated with myelin-driven inflammation are toll-like receptors (TLRs). In healthy people, TLRs detect pathogen-associated patterns to mobilize innate immunity. However, new work shows TLR signaling - such as TLR9 - is elevated in MS patients and MS models (e.g., EAE, RR-EAE). In the latter, suppressing TLR9 function reduces inflammation, while also promoting TREG and improving disease. Lymph nodes (LNs) and spleen are key tissues that control polarization of myelin-reactive T cells toward either inflammatory T cells (e.g., TH17) or TREG. Thus, strategies that guide T cell differentiating when myelin is presented in LNs – for example, co-delivery of regulatory cues – could generate large populations of myelin-specific TREG that stop pathogenic immune cells without broad suppression. Nanotechnology offers unique capabilities for this goal, including co-delivery of self- antigen and regulatory cues, targeting, and tunable release. However, many polymer particles and other biomaterials exhibit intrinsic features that trigger inflammatory signaling, which could exacerbate autoimmunity. Strategies that mimic attractive features of biomaterials, while eliminating inflammatory “carrier” effects could be transformative for new therapies for MS. This Renewal VA Merit application uses polyionic immune signals to advance novel nanostructured capsules built entirely from regulatory immune cues and myelin antigen. These immune polyelectrolyte multilayers (“iPEMs”) are assembled through electrostatic interactions on a template, which is removed to leave capsules that juxtapose myelin with a regulatory TLR ligand against TLR9 (GpG). Since there is no carrier, the density of signals in iPEMs is very high relative to polymer or lipids encapsulating cargo (e.g., nanoparticles). During the initial award, this high density juxtaposition of self-antigen and regulatory cue (GpG) was shown to promote differentiation of myelin-specific T cells toward TREG and away from inflammatory T cells. Likewise, pilot studies with MS patient samples reveal myelin/GpG iPEMs restrain myelin- driven inflammation. In relapsing-remitting (RR-EAE) and progressive (EAE) models of MS, iPEMs reverse disease-driven paralysis. With continued VA support, this project will generate the remaining pre-clinical data needed to motivate future clinical development of a therapy that could offer Veterans and their families a safe and effective vaccine-like immunotherapy for MS. The broad goal is to define the role of TLR signaling in T cell polarization and efficacy, and show these effects are durable and robust across disease models and a set of existing, de-identified male and female Veteran MS patient samples. Our plan is supported by a multidisciplinary team of bioengineers, immunologists, and MS clinicians with a history of effective collaboration on this and other projects focused on antigen-specific tolerance. The specific aims are 1) Confirm iPEMs alter TLR signaling & function in APCs and link changes to T cell polarization, 2) Define iPEM-driven structural and functional changes associated with tolerance in LNs & spleen, 3) Ascertain the durability of efficacy and changes in CNS pathology during EAE/RR-EAE, 4) Show iPEMs regulate TLR signaling & antigen-specific response in MS patient samples.