Exploiting Rational Assembly to Map Distinct Roles of Regulatory Cues during Autoimmune Therapy

Abstract

Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune complexes. Complexes containing self-peptides and regulatory nucleic acids reverse established paralysis in a preclinical MS model. Importantly, mice responding to immunotherapy maintain healthy, antigen-specific B and T cell responses during a foreign antigen challenge. A therapeutic library isolating specific components reveals that regulatory nucleic acids suppress inflammatory genes in innate immune cells, while disease-matched peptide sequences control specificity of tolerance. Distinct gene expression profiles in cells and animals are associated with the immune signals administered in particulate and soluble forms, highlighting the impact of biophysical presentation of signals. This work provides insight into the rational manipulation of immune signaling to drive tolerance.

Self‐Assembly of Immune Signals to Program Innate Immunity through Rational Adjuvant Design

“…However, many cytokines have multifaceted roles in other disease settings that could also create immunotherapeutic opportunities. [ 31 , 32 , 33 , 34 , 35 ] For example, although IL‐10 has anti‐inflammatory features that can favor tumor escape, IL‐10 has also been reported to mediate regression of established melanoma and breast cancer metastases in preclinical models. [ 31 ] As another illustration, IL‐6 can promote Th2 differentiation and simultaneously inhibit Th1 polarization through independent mechanisms.…”

“…All images were acquired in Airyscan super-resolution (SR) mode using a 32channel GaAsP-PMT Airyscan detector. Zeiss ZEN 2.3 [ 35 ] software was used for collection and postprocessing of the images. Airyscan processing was done using a 6.3-strength 3D method.…”

“…[53] RT-qPCR for Intracellular Cytokine Gene Quantification: Gene expression analysis was performed as previously described. [35] Briefly, RNA was isolated from splenic DCs treated with iPEMs, PBS as a negative control, or soluble dose-matched TLRa as a positive control, using the Quick-RNA Microprep kit (Zymo Research). Cells were lysed in their wells using a lysis buffer, genomic material was harvested in a silica-based matrix, and DNA was degraded with DNase I.…”

Mapping the Mechanical and Immunological Profiles of Polymeric Microneedles to Enable Vaccine and Immunotherapy Applications

“…Biomaterialsincluding polymer and lipid nanoparticles, engineered scaffolds, and biodegradable materialsare being intensely investigated for vaccines and immunotherapies across infectious disease (5,6), cancer (7)(8)(9), and autoimmunity (10)(11)(12). These materials can be either naturally occurring, fully synthetic, or hybrid in composition.…”

Biomaterial-enabled induction of pancreatic-specific regulatory T cells through distinct signal transduction pathways

“…Biomaterials offer distinct advantages for the delivery of immune cargo, allowing for cargo protection, codelivery, and targeting specific tissues and cell populations. These technologies -including self-assembled constructs and microparticles/nanoparticles (MP/NPs) -have recently been intensely studied for both proimmune and tolerance contexts [24][25][26][27][28][29][30][31]. For example, delivery of cargo in MP/NPs can increase targeting of particular tissues and cell populations such as lymph nodes 32.…”