Nanoparticles engineered for antigen-specific immunotherapy

Current therapeutics for autoimmune conditions are usually nonspecific and induce general immune suppression. Now, reporting in Nature, Clemente-Cesares and colleagues show that nanoparticles coated with autoimmune disease-relevant peptides bound to MHC class II molecules (pMHC–NPs) can induce antigen-specific T cells with regulatory function in vivo. This approach led to suppression of disease in mouse models of rheumatoid arthritis (RA), type 1 diabetes (T1D) and multiple sclerosis (MS), without affecting general immunity.

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Autoimmune disease results from chronic T cell and B cell responses to autoantigens. Central to this process are autoantigen-responsive CD4⁺ T helper (T_H) cells, which orchestrate the function of other immune cells. Conversely, CD4⁺ T cells with regulatory function, including FOXP3⁺CD4⁺CD25⁺ T_Reg cells and FOXP3⁻CD4⁺CD25⁻ T_R1 cells, can dampen the inflammatory process.

Based on the hypothesis that chronic autoantigen exposure may convert autoreactive T cells into regulatory T cells in a negative feedback loop, the authors engineered nanoparticles coated with the pMHC complex 2.5mi/IA^g7, which is a known antigenic target in the development of T1D in non-obese diabetic (NOD) mice. After intravenous injection with these pMHC–NPs twice weekly for 5 weeks, the animals developed antigen-specific CD4⁺ T cells of the memory-like (CD44^hiCD62L^low) FOXP3⁻ T_R1-like phenotype and reverted to stable normoglycaemia. Similar results were achieved when the nanoparticles were coated with pMHC complexes that contained sub-dominant (non-disease causing) NOD-specific autoantigenic peptides — but uncoated nanoparticles, pMHC monomers, peptides, peptide-coated nanoparticles or peptide-coated microparticles had no effect.

A similar strategy was used to reverse paralysis in mice with experimental autoimmune encephalomyelitis (EAE; a model of MS) and to reduce joint inflammation in collagen-induced arthritis (CIA; a model of RA). The effect was strictly dependent on the presence of the disease-specific autoantigen–MHC complex — that is, the nanoparticles that were effective in the EAE model had no effect in the CIA model, and vice versa. However, disease-specific autoantigens besides the ones used to induce disease had therapeutic activity, indicating that the therapeutic effects of pMHC–NPs are disease-specific but dissociated from the pathogenic role of the antigenic epitope that is presented.

pMHC–NPs promote the differentiation of rare pre-activated autoreactive CD4⁺ T cells into T_R1-like cells

Further in vitro and adoptive transfer experiments indicated that pMHC–NPs promote the differentiation of rare pre-activated autoreactive CD4⁺ T cells into T_R1-like cells, followed by their systemic expansion. The T_R1-like cells suppressed autoreactive helper and cytotoxic T cells through the secretion of interleukin-10 (IL-10), transforming growth factor-β (TGFβ) and IL-21. Moreover, T_R1-like cells induced the formation and clonal expansion of regulatory B cells and downregulated the production of pro-inflammatory mediators by antigen-presenting cells. Importantly, this did not impair general immunity, as pMHC–NP-treated mice cleared acute viral infections as efficiently as untreated mice. The potential translatability of the approach to human disease was demonstrated by using human T1D-relevant pMHC–NPs in NOD scid Il2rg^−/− mice reconstituted with peripheral blood mononuclear cells from T1D patients.

The authors suggest that pMHC–NPs may form a new class of therapeutics capable of resolving complex autoimmune disease in a disease- and organ-specific manner, without compromising systemic immunity.

This article is modified from the original in Nat. Rev. Drug Discov. (http://dx.doi.org/10.1038/nrd.2016.62)