An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy

Abstract

Tolerogenic nanoparticles (NPs) are rapidly being developed as specific immunotherapies to treat autoimmune disease. However, many NP-based therapies conjugate antigen (Ag) directly to the NP posing safety concerns due to antibody binding or require the co-delivery of immunosuppressants to induce tolerance. Here, we developed Ag encapsulated NPs comprised of poly(lactide-co-glycolide) [PLG(Ag)] and investigated the mechanism of action for Ag-specific tolerance induction in an autoimmune model of T helper type 1/17 dysfunction – relapse-remitting experimental autoimmune encephalomyelitis (R-EAE). PLG(Ag) completely abrogated disease induction in an organ specific manner, where the spleen was dispensable for tolerance induction. PLG(Ag) delivered intravenously distributed to the liver, associated with macrophages, and recruited Ag-specific T cells. Furthermore, programmed death ligand 1 (PD-L1) was increased on Ag presenting cells and PD-1 blockade lessened tolerance induction. The robust promotion of tolerance by PLG(Ag) without co-delivery of immunosuppressive drugs, suggests that these NPs effectively deliver antigen to endogenous tolerogenic pathways.

An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis

“…Similarly, disease was only blocked with dMP-MOG 35-55 treatment, but not by treatment with an irrelevant antigen, dMP-Ova 323-339 . These are hallmarks of successful antigen-specific immunotherapy approaches, and correspond to such demonstrations by previous reports utilizing nanoparticles encapsulating EAE-specific antigens and tolerogenic factors [51, 52, 88]. This antigen-specificity in a newly developed microparticle-based immunotherapy is especially important since the safety profile of the MS antigen-specific tolerogenic drug glatiramer acetate, an FDA approved therapy for MS, is significantly superior to that of other approved immunotherapies, such as Natalizumab and Fingolimod, which do not rely on antigen-specificity [19, 89-91].…”

“…This antigen-specificity in a newly developed microparticle-based immunotherapy is especially important since the safety profile of the MS antigen-specific tolerogenic drug glatiramer acetate, an FDA approved therapy for MS, is significantly superior to that of other approved immunotherapies, such as Natalizumab and Fingolimod, which do not rely on antigen-specificity [19, 89-91]. Our observation that CD4 + T cells isolated from EAE mice treated with dMP-MOG 35-55 were not responsive to stimulation by MOG 35-55 -loaded splenocytes whereas EAE mice treated with dMP Ova 323-339 proliferated, showed that T cell anergy is effectively induced by the dMP-MOG 35-55 therapy in an antigen-specific manner, which is similar to other PLGA-based nanoparticle encapsulated EAE therapies [51, 52, 88]. …”

Tolerogenic Nanoparticles to Treat Islet Autoimmunity

“…Both antigen-conjugated and antigen-encapsulating particles have been used in Th1/Th17-mediated EAE [116••, 117••, 118••], Th2-mediated allergic airway inflammation [98•], and minor antigen mismatched bone marrow transplant [119•]. The exact mechanisms behind the tolerance induction in this model are still under investigation, but it is thought that intravenous administration leads to uptake of the carboxylated PLG nanoparticles by splenic marginal zone macrophages via the MARCO scavenger receptor, thereafter triggering various tolerogenic pathways including cell-intrinsic anergy and the activation of Foxp3 + Tregs and IL-10-producing Tr1 cells.…”

“…The exact mechanisms behind the tolerance induction in this model are still under investigation, but it is thought that intravenous administration leads to uptake of the carboxylated PLG nanoparticles by splenic marginal zone macrophages via the MARCO scavenger receptor, thereafter triggering various tolerogenic pathways including cell-intrinsic anergy and the activation of Foxp3 + Tregs and IL-10-producing Tr1 cells. A recent study, however, has highlighted the importance of liver macrophages in addition to those in the spleen [118••]. …”

“…a Nanoparticles targeting APCs. Top : MARCO receptor dependent uptake of antigen-coupled and antigen-encapsulating PLG [98•, 116••, 117••, 118••, 119•, 120••, 121•, 122]. Middle : PLG encapsulating both antigen and rapamycin [109, 110].…”