Multiple sclerosis is an autoimmune disease where myelin – a protein that insulates neurons in the central nervous system – is attacked by the immune system. Experimental therapies for MS aim to expand regulatory T cells (TREGS) that control inflammation and self-reactivity against myelin without the broad suppression associated with currently-approved MS therapies. The polarization of T cells into inflammatory subsets or TREGS is controlled by lymph nodes (LNs) and spleen. Thus, new understanding of the link between the immune signals present in these tissues, and the extent and specificity of tolerance elicited, could support therapies that control autoimmunity without broad suppression. We combined degradable polymer particles with direct intra-LN injection (i.LN.) to probe the dependence of tolerance on immune signal combinations and locations (Panel a). These particles were loaded with combinations of rapamycin (rapa), a drug known to promote TREGS, and either myelin or irrelevant antigens. Mice were induced with a model of MS (EAE) then each particle formulations was administered using i.LN. or intra-muscular (i.m.) routes. While i.m. delivery of particles loaded with myelin and rapa conferred no therapeutic effect, a single i.LN. dose reversed disease-induced paralysis. Strikingly, these effects were permanent and curative, even when particles were administered at the peak of disease to a non-CNS draining LN (Panel b). Mechanistic studies revealed that i.LN. delivery of myelin and rapa particles restrained inflammation, promoted reorganization of local LN structure, and expanded TREGS in the treated node. Further, distal (i.e., untreated) nodes and the spleen exhibited reduced inflammation and enhanced polarization of T cells towards TREGS. In contrast, particles incorporating irrelevant antigen and rapa caused local suppression, but did not impact disease or TREG frequency compared with control groups. Together, these results help create design guidelines for antigen-specific tolerance and demonstrate that local signaling in non-CNS draining LNs can promote systemic, but specific efficacy.

Reprogramming the local lymph node environment to promote myelin-specific tolerance

251st National Meeting (2016)

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