Kwiatkowski, A. J. | bioRxiv Science

bioRxiv2022

Treatment with an Antigen-Specific Dual Microparticle System Reverses Advanced Multiple Sclerosis in Mice

Antigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression. In this study, an antigen-specific dual-sized microparticle (dMP) immunotherapy reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells and microglia, not only in the draining lymph nodes, but strikingly also in the spinal cord. CD74 and cathepsin S were among the common genes downregulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses, and capably reversed paralysis in advanced EAE without the use of broad immunosuppressant. Significance StatementMultiple sclerosis (MS) is a debilitating autoimmune disease that can lead to paralysis. We demonstrate an antigen-specific microparticle treatment can reverse hind limb paralysis when administered in advanced EAE. Single-cell RNA-sequencing and flow cytometry analysis provide evidence the treatment acts by diminishing Ag presentation in APCs, including B cells in the CNS and the draining lymph nodes. Thus, the antigen-specific dual-sized microparticle treatment is a promising therapy even in advanced EAE, and potentially MS.

bioengineering↗

bioRxiv2021

Galectin-anchored indoleamine 2,3-dioxygenase suppresses local inflammation

Summary paragraphChronic inflammation underlies the onset, progression and associated pain of numerous diseases.(1) Current anti-inflammatory treatments administered systemically are associated with moderate-to-severe side effects, while locally administered drugs have short-lived efficacy, and neither approach successfully modifies the underlying causality of disease.(2) We report a new way to locally modulate inflammation by fusing the enzyme indoleamine 2,3-dioxygenase 1 (IDO) to galectin-3 (Gal3). A general regulator of inflammation(3), IDO is immunosuppressive(4), catabolizing the essential amino acid tryptophan into kynurenine.(5) Recently we demonstrated that extracellular exogenous IDO regulates innate immune cell function(6), and envisioned delivering IDO into specific tissues would provide control of inflammation. However, proteins problematically diffuse away from local injection sites. Addressing this, we recently established that fusion to Gal3 anchors enzymes to tissues(7) via binding to extracellular glycans. Fusion protein IDO-Gal3 was retained in injected tissues and joints for up to a week or more, where it suppressed local inflammation in rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis. Amelioration of local inflammation, disease progression and inflammatory pain were concomitant with homeostatic preservation of tissues without global immune suppression. Thus, IDO-Gal3 presents a new concept of anchoring immunomodulatory enzymes for robust control of focal inflammation in multiple disease settings.

bioengineering↗