Immune tolerance: DNA vaccine as strategy in autoimmune diseases

Abstract

Autoimmune diseases (AID) affect 5–8% of occidental populations. Theses AID are characterized by the destruction of self-tissue following activation of autoimmune responses mediated by T cells or B cells, or both. Manipulations of immune responses to protect against autoimmunity as potential immunotherapeutic implications using DNA vaccination could help to treat and/or prevent AID. Recently, we have generated an animal model to study the role of the molecular mimicry in breaking tolerance to a neo-antigen in the liver. Transgenic (Tg) mice expressing the nucleoprotein (NP) gene from lymphocytic choriomingitis virus (LCMV) as neo-self antigen in their hepatocytes develop an autoimmune hepatitis after immunization with plasmids coding for intracellular or secreted LCMV-NP forms [1]. Four groups of transgenic mice (Tg-NP) were immunized via the intramuscular route with both these plasmids (pNP) alone or co-injected with IL-12-expressing plasmid (pIL-12). NP-specific serum antibody titres were detected in an ELISA test. All animals injected with different plasmid-based gene expression vectors showed different anti-NP antibody profiles. The IgG1 subclass is an indication of Th2 immune response, whereas IgG2 subclass production reflects a Th1 immune response. Mice vaccinated with intracellular form-coding plasmid alone or with pIL-12 developed an antibody response characterized by more pronounced Th2 profiles (IgG1 isotype). In contrast, those injected with the secreted form injections alone or with pIL-12 produced exclusively IgG2 isotypes indicative of a Th1 response. These results suggest that immune response profiles provoked by DNA vaccine seem to be dependent on the protein form rather than on the cytokine adjuvant or on the administration route of the DNA vaccine. Even if cytokine (IL-12) driving B cells and T cells to a Th1 phenotype response was added, specific serum antibody titres were significantly higher in mice co-injected with the intracellular form compared with those co-immunized with the secreted form. The form of autoantigen used in DNA vaccination may induce protection from autoimmunity by inducing a cytokine shift in the immune response to the antigens responsible for the disease. Moreover, the induction of shift strategies could orient the profile of T cells responding to disease target antigens from Th1 to Th2 or Th2 to Th1 according to the autoimmune process involved in each AID in order to induce a selective protective immune response.