A Suppressive Oligodeoxynucleotide Enhances the Efficacy of Myelin Cocktail/IL-4-Tolerizing DNA Vaccination and Treats Autoimmune Disease

Abstract

Targeting pathogenic T cells with Ag-specific tolerizing DNA vaccines encoding autoantigens is a powerful and feasible therapeutic strategy for Th1-mediated autoimmune diseases. However, plasmid DNA contains abundant unmethylated CpG motifs, which induce a strong Th1 immune response. We describe here a novel approach to counteract this undesired side effect of plasmid DNA used for vaccination in Th1-mediated autoimmune diseases. In chronic relapsing experimental autoimmune encephalomyelitis (EAE), combining a myelin cocktail plus IL-4-tolerizing DNA vaccine with a suppressive GpG oligodeoxynucleotide (GpG-ODN) induced a shift of the autoreactive T cell response toward a protective Th2 cytokine pattern. Myelin microarrays demonstrate that tolerizing DNA vaccination plus GpG-ODN further decreased anti-myelin autoantibody epitope spreading and shifted the autoreactive B cell response to a protective IgG1 isotype. Moreover, the addition of GpG-ODN to tolerizing DNA vaccination therapy effectively reduced overall mean disease severity in both the chronic relapsing EAE and chronic progressive EAE mouse models. In conclusion, suppressive GpG-ODN effectively counteracted the undesired CpG-induced inflammatory effect of a tolerizing DNA vaccine in a Th1-mediated autoimmune disease by skewing both the autoaggressive T cell and B cell responses toward a protective Th2 phenotype. These results demonstrate that suppressive GpG-ODN is a simple and highly effective novel therapeutic adjuvant that will boost the efficacy of Ag-specific tolerizing DNA vaccines used for treating Th1-mediated autoimmune diseases.

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

“…In vivo treatment of mice with CIA with imatinib reduced epitope spreading of the autoantibody response ( Figure 5C), and we have observed similar reductions in epitope spreading in other models of autoimmunity following effective therapy (27,43,44). c-Abl phosphorylates and…”

Tolerance and Autoimmunity in Type 1 Diabetes

“…TLR3, TLR7, TLR8 and TLR9 are all equally possible, although the effect of chloroquine on IL-7 production would suggest an endosomal TLR with TLR9 being the most likely candidate ( Figure 5) (Di Caro & Giannoukakis, unpublished data). Indeed, the data indicating that CpG oligonucleotide-triggered TLR9 signaling confers immunosuppressive capacity to DC that can treat autoimmunity in vivo strengthens our hypothesis (Ho PP et al, 2005). A) Western blot analysis of protein extracts from DC treated with AS-ODN for CD40, CD80 and CD86 over time, using the indicated antibodies, shows activation of NFkB after 1 hour and activation of p38 MAP kinase and TRAF6 after 3 hours.…”

“…AS-ODN DCs, but not control DC, produce IL-7, in response to a secondary action of the antisense oligonucleotides on Toll Like Receptor (TLR) signaling. It is known that CpG oligonucleotides, like the AS-ODN we use to make tolerogenic DCs, can activate TLR signaling and confer an immunoregulatory phenotype to DCs (Roberts et al, 2005;Jarnicki et al, 2008) and are thus useful for treatment of autoimmune conditions (Ho et al, 2005). It is possible that the oligonucleotides act in a sequence-nonspecific manner when interacting with TLRs, TLR9 in particular, based on conformation and higher order multistrand structures (Guiducci et al, 2008;Kindrachuk et al, 2008).…”

Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

“…In EAE, systemic administration of myelin antigens either prevented or treated EAE, but the delivery of repeated massive doses of these proteins were required for the therapeutic effect [14][15][16]. This problem has been overcome by DNA-based vaccines encoding the myelin antigens alone or in combination with immunomodulatory molecules, such as IL-4 or IL-10, that act as "adjuvants" for T REG function [17,18]. The EAE results were so promising that they prompted a first clinical trial in MS patients, that showed some positive results in reducing the MRI-measured disease activity and inducing antigen-specific tolerance to myelin antigens in patients with relapse-remitting (RR) MS [19].…”