Suppressive DNA vaccination in experimental autoimmune encephalomyelitis

<p>This thesis describes the development of a novel method to suppress an organ-specific autoimmune disease, experimental autoimmune encephalomyelitis (EAE), by vaccination with DNA encoding autoantigenic peptides. DNA vaccination can produce long-term immunity and generate antigen-specific CD8+ and CD4+ T cells. EAE is an autoimmune disease of the central nervous system (CNS), and an animal model for multiple sclerosis (MS). We used myelin basic protein (MBP)-EAE, in which Lewis (LEW) rats are immunized with MBP or encephalitogenic MBP-peptides. The disease is considered to be T1-mediated.</p><p>We vaccinated LEW rats with DNA encoding the irnmunodominant T cell epitope MBP-peptide 68-85 (MBP68-85) targeted to IgG, before challenge with MBP68-85. The clinical and histopathological signs of EAE were reduced in the DNA vaccinated group, compared to controls. We observed a reduced production of IFN-[gamma] in the vaccinated group, compared to controls, but we measured no induction of type 2 immunity.</p><p>DNA sequences in DNA vaccine constructs may function as immunomodulators, such as immunostimulatory DNA sequences (ISS). ISS are non-coding, unmethylated CpG motifs of bacterial or viral origin that promote type 1 immunity. Treatment with a DNA vaccine encoding MBP68-85 and containing three ISS suppressed clinical signs of EAE, while a corresponding DNA vaccine without such ISS had no effect. Furthermore, coinjection of IL-4 or IL-10-coding cDNA with the ISS-positive DNA vaccine, inhibited the suppressive effect of the vaccine.</p><p>We studied the requirements for dominant expression of TCRBV8S2 in LEW rats, after immunization with MBP63-88. The preferential recruitment of TCRBV8S2+ T cells was strictly dependent on MHC haplotype and heterologous MBP-peptide. Then, we demonstrated that a single aminoacid exchange in position 79 from serine (non-self) to threonine (self) in MBP68-85 dramatically altered the protective effect of DNA vaccine encoding MBP68-85. Furthermore, the DNA vaccine encoding MBP68-85 did not protect against MBP89-101-induced EAE and vise versa. Thus, the protective effect was highly specific.</p><p>To study if DNA vaccination also is feasible with other important encephalitogenic peptide autoantigens, we used myelin oligodendrocyte glycoprotein (MOG)-EAE. Vaccination with DNA encoding MOG91-108 suppressed clinical signs of EAE, after MOG91-108-challenge.</p><p>In conclusion, vaccination with DNA encoding autoantigenic peptides suppresses EAE. Presence of ISS and a local type 1 cytokine milieu is decisive for specific, protective DNA vaccination in EAE, and the effect is highly specific.</p>