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Tolerogenic Nanoparticles Suppress Central Nervous System Inflammation

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Tolerogenic Nanoparticles Suppress Central Nervous System Inflammation Tolerogenic nanoparticles suppress central nervous system inflammation Jessica E. Kenisona,b, Aditi Jhaveric, Zhaorong Lid, Nikita Khadsec, Emily Tjond, Sara Tezzac, Dominika Nowakowskac, Agustin Plasenciac, Vincent P. Stanton Jrc, David H. Sherra,b, and Francisco J. Quintanad,e,1 aDepartment of Pathology, Boston University School of Medicine, Boston, MA 02118; bDepartment of Environmental Health, Boston University School of Public Health, Boston, MA 02118; cAnTolRx, Inc., Cambridge, MA 02139; dAnn Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard University Medical School, Boston, MA 02115; and eBroad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142 Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved October 6, 2020 (received for review August 4, 2020) Therapeutic approaches for the induction of immune tolerance activation with natural or synthetic ligands ameliorates disease in remain an unmet clinical need for the treatment of autoimmune preclinical models of multiple sclerosis (MS) (15, 16), type 1 diabetes diseases, including multiple sclerosis (MS). Based on its role in the (23), and inflammatory bowel disease (14, 24), among others, sug- control of the immune response, the ligand-activated transcription gesting that AhR is a potential target for the therapeutic reestab- factor aryl hydrocarbon receptor (AhR) is a candidate target for lishment of antigen-specific tolerance in autoimmune diseases. novel immunotherapies. Here, we report the development of AhR- Nanomaterials, including nanoparticles and nanoliposomes activating nanoliposomes (NLPs) to induce antigen-specific toler- (NLPs), provide novel opportunities to overcome the limitations ance. NLPs loaded with the AhR agonist ITE and a T cell epitope associated with immunosuppressive drugs currently in use (25). from myelin oligodendrocyte glycoprotein (MOG)35–55 induced tol- NanoparticlesandNLPscanbeusedasplatformstodeliverdrugsof erogenic dendritic cells and suppressed the development of exper- interest to target APCs while protecting these drugs from degradation imental autoimmune encephalomyelitis (EAE), a preclinical model of and clearance. Indeed, NLPs are already in use for the delivery of the MS, in preventive and therapeutic setups. EAE suppression was as- + Food and Drug Administration (FDA)-approved therapeutic agents, sociated with the expansion of MOG35–55-specific FoxP3 regulatory with well-characterized safety and tolerability profiles (26, 27). Here, T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concom- we report the use of NLPs to codeliver the tolerogenic AhR ligand 2- IMMUNOLOGY AND INFLAMMATION itant with a reduction in central nervous system-infiltrating effector (1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester T cells (Teff cells). Notably, NLPs induced bystander suppression in (ITE) and a T cell epitope from myelin oligodendrocyte protein the EAE model established in C57BL/6 × SJL F1 mice. Moreover, NLPs ameliorated chronic progressive EAE in nonobese diabetic mice, a (MOG35–55). ITE and MOG35–55 coadministration via NLPs model which resembles some aspects of secondary progressive MS. modulated myelin-specific T cells and suppressed disease devel- In summary, these studies describe a platform for the therapeutic opment in mouse preclinical models of relapsing-remitting and induction of antigen-specific tolerance in autoimmune diseases. secondary progressive MS. In summary, we describe an NLP- based platform for the induction of antigen-specific tolerance in EAE | MS | autoimmunity | nanoparticles | antigen-specific therapy autoimmune diseases. Results utoimmune diseases are driven by dysregulated adaptive Characterization of the Transcriptional Response of DCs to AhR Activation immunity against self-antigens. Current approaches for the A by ITE. DCs, as well as other APCs, control T cell activation and treatment of autoimmune diseases rely on nonspecific immu- polarization in vivo (28–31). AhR signaling modulates the ability of nosuppression, and are associated with adverse side effects. Thus, there is an unmet clinical need for therapies that rees- tablish immune tolerance in an antigen-specific manner (1). Significance Multiple mechanisms enforce immunologic tolerance. Mech- anisms of central tolerance eliminate self-reactive lymphocytes in Current treatments for autoimmune diseases rely on nonspecific the thymus and bone marrow, but do not remove all of the autor- immunosuppression, risking important complications and limit- eactive T cells and B cells (2, 3). However, additional immuno- ing the long-term use of these approaches for the treatment of regulatory mechanisms are in place to prevent the development of chronic human autoimmunity. Thus, there is an unmet need for pathogenic autoimmunity. Among these additional mechanisms are therapeutic approaches to reestablish immune tolerance in au- specialized thymic-derived regulatory FoxP3+ T cells (natural toimmune disorders in an antigen-specific manner. Here, we Tregs, nTregs) and peripherally induced regulatory cells which in- describe a nanoliposome (NLP)-based platform for the induction clude FoxP3+ Tregs as well as IL-10+ type 1 regulatory cells (Tr1 of antigen-specific tolerance via the modulation of signaling by cells) (4–6). Autoimmune diseases have been linked to reduced the aryl hydrocarbon receptor. These NLPs suppress disease pa- numbers, function, and stability of multiple regulatory T cell pop- thology and pathogenic autoimmunity in preclinical models of ulations, and/or the resistance of effector T cells to Treg modulation multiple sclerosis, providing a candidate antigen-specific thera- (7). Thus, the expansion of the Treg compartment is a potential peutic approach for the management of autoimmune disorders. approach for the treatment of autoimmunity (8). Author contributions: J.E.K., A.J., S.T., D.N., A.P., V.P.S., D.H.S., and F.J.Q. designed re- The aryl hydrocarbon receptor (AhR) is a ligand-activated search; J.E.K., A.J., N.K., S.T., D.N., and A.P. performed research; A.J. and N.K. contributed transcription factor with important roles in the control of the im- new reagents/analytic tools; J.E.K., A.J., Z.L., E.T., S.T., D.N., A.P., V.P.S., D.H.S., and F.J.Q. mune response (9–11). AhR signaling can modulate the differentia- analyzed data; and J.E.K., D.H.S., and F.J.Q. wrote the paper. tion of T cell subsets (12–15) as well as the function of antigen Competing interest statement: J.E.K, A.J., N.K., S.T., D.N., A.P., V.P.S. are/were employees presenting cells (APCs), including dendritic cells (DCs) and macro- at AnTolRx; F.J.Q. is a consultant at AnTolRx. This work was partially funded by AnTolRx. phages (16, 17). Indeed, we and others showed that AhR controls the This article is a PNAS Direct Submission. differentiation of DCs and their ability to activate and polarize reg- Published under the PNAS license. ulatory T (Treg) and effector T (Teff) cells (16, 18–22). In support of 1To whom correspondence may be addressed. Email: [email protected]. the potential therapeutic relevance of these observations, AhR First published November 25, 2020. www.pnas.org/cgi/doi/10.1073/pnas.2016451117 PNAS | December 15, 2020 | vol. 117 | no. 50 | 32017–32028 Downloaded by guest on October 4, 2021 DCs to control T cell responses (16, 20–22).However,littleisknown from three separate pools of 10 mice with ITE for 6, 18, or 72 h, about the kinetics of AhR-driven transcriptional programs in DCs. and performed RNA sequencing. We found that, similar to what To address this point, we first analyzed the effect of AhR activation was observed in human DCs, the number of genes differentially in human DCs on the expression of the AhR transcriptional target regulated by ITE decreased over time (595 genes at 6 h, 512 genes genes CYP1A1 and CYP1B1 (32). We found that the mucosa- at 18 h, and 290 genes at 72 h) (Fig. 2D). The analysis of known associated AhR agonist ITE (33) induced maximal CYP1A1 and AhR-regulated genes showed that the expression of most genes CYP1B1 expression at a dose similar to the prototypical AhR ag- was up-regulated at the early timepoint (6 h) and decreased by onist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Fig. 1A, CYP1A1 72 h, a small subset of genes was up-regulated at both the early effective concentration [EC]50ITE = 8.101 nM, EC50TCDD = and late timepoints, while another small gene subset was only up- 4.166 nM; CYP1B1 EC50ITE = 1.462 nM, EC50TCDD = 2.178 nM). regulated at intermediate or late timepoints (Fig. 2E). Indeed, both ITE and TCDD induced CYP1A1 and CYP1B1 ex- Gene set enrichment analysis determined that genes associ- pression at concentrations 3 to 4 log folds lower than other AhR ated with regulation of the innate immune response, response to agonists such as laquinimod (Laq) (34), indoxyl-3-sulfate (I3S), and type 1 IFN, and cytokine stimuli were significantly altered over L-kynurenine (Kyn) (Fig. 1A, CYP1A1 EC50Laq = 9.117 μM, time (Fig. 2F), similar to what was observed in human DCs. EC50I3S = 47.781 μM, EC50Kyn = 236.711 μM; CYP1B1 EC50Laq = AhR-driven early (6 h) transcriptional modules were associated 2.783 μM, EC50I3S = 19.322 μM, EC50Kyn = 47.249 μM). While with the suppression of DC maturation and IFN signaling and CYP1A1 expression showed an early peak followed by a return to the promotion of PD-1/PD-L1 signaling (Fig. 2G). AhR-driven baseline (Fig. 1B), the expression of IDO1 and IDO2,whichencode “mid” (18 h) transcriptional modules were associated with the immunosuppressive enzymes involved in tryptophan catabolism (35), down-regulation of IL-15 and NF-κB signaling (Fig. 2G). AhR- peaked early on and remained above baseline over the next 48 h. driven late (72 h) transcriptional modules were associated with These data suggest that different transcriptional modules characterize down-regulation of PPARα signaling and the promotion of the early, intermediate, and late responses to AhR activation in DCs.
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