Tolerogenic nanoparticles suppress central nervous system inflammation

Abstract

Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG)35–55 induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG35–55-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff cells). Notably, NLPs induced bystander suppression in the EAE model established in C57BL/6 × SJL F1 mice. Moreover, NLPs ameliorated chronic progressive EAE in nonobese diabetic mice, a model which resembles some aspects of secondary progressive MS. In summary, these studies describe a platform for the therapeutic induction of antigen-specific tolerance in autoimmune diseases.

Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy

“…For example, MBP 1-9 -specific Tregs partially inhibit EAE induced with PLP 139-151 (222). Likewise, PLP 139-151 -specific Tregs were able to restrain EAE induced with a disparate epitope of PLP [178][179][180][181][182][183][184][185][186][187][188][189][190][191] (223). Together these studies support the development of antigen-specific Treg therapy for autoimmunity.…”

“…AHR ligand 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an adjuvant that activates the aryl hydrocarbon receptor and promoted the differentiation of tDCs. DC targeted gold nanoparticles (60 nm) coated with disease-specific autoantigen, ITE, and PEG suppressed rodent models of EAE and T1D ( 171 , 172 , 182 ). The ITE-antigen-NP induced the differentiation of tDCs in vitro , that expressed low levels of the co-stimulatory molecules (MHCII, CD40, and CD86) and proinflammatory cytokines (IL-6 and IL-12) and increased the production of anti-inflammatory cytokines (TGF-β and IL-10) ( 171 , 182 ).…”

“…SC administration of the NP increased the percentage of MOG 35-55 -specific (tetramer + ) FOXP3 + Tregs and IL-10 producing Tr1 cells in addition to reducing the percentage of MOG 35-55 -specific (tetramer + ) IL-17 and IFN-γ producing Tcons in the spleen ( 182 ). The NP loaded with ITE and MOG 35-55 suppressed MOG-induced EAE when administered IP, IV, or SC and were effective when administered prophylactically or therapeutically ( 171 , 182 ). Tregs transferred tolerance from vaccinated donor mice to recipient mice and prevented the subsequent induction of EAE ( 171 ).…”

“…Tregs transferred tolerance from vaccinated donor mice to recipient mice and prevented the subsequent induction of EAE ( 171 ). The NP vaccine elicited bystander suppression because NP containing ITE and MOG 35-55 suppressed PLP 139-151 -induced EAE in C57BL/6 x SJL F1 mice ( 182 ).…”

The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

“…In this context, the targeting of AHR is no different. In order to address the potential issue of cellular toxicity, the use of nanoparticles as a vehicle to deliver AHR modulators to specific cell types has been proposed ( 138 , 139 ). This approach has been shown to minimize toxicity and maximize the therapeutic effect in the target cell types.…”