Development of a novel mouse model of vitiligo and inhibition of autoreactive CD8+ T cells by competitive peptides

Abstract

The immune responses against self-antigens caused by failure of self-tolerance develop autoimmune diseases which affect approximately 5-8 % of the population or 14 to 22 million persons in the United States. However, current treatments are not curative and induce general immunosuppression which can result in serious infections, cancer, and other adverse outcomes. Therefore, it is necessary to develop new therapies to selectively tolerize the autoreactive immune cells. The binding of peptides to major histocompatibility complex (MHC) molecules is mediated by the interaction between the residue of peptide and the cleft of MHC molecule. This noncovalent binding is formed by hydrophobic or charge interaction. If other peptides are added into extracellular space, MHC binding peptides can be replaced with different peptides that bind to the same MHC molecule. Consequently, the autoimmune response induced by autoreactive T cells specific to self-peptide could be inhibited by the addition of an excess of other peptides that competitively inhibit the presentation of self-peptide. In the present study, we established a novel murine model of vitiligo by sequential prime/ boost immunizations into the hind footpad and tail dermis with tyrosinase-related protein 2 (TRP2)-180 (SVYDFFVWL) peptide, lipopolysaccharides and CpG oligodeoxynucleotides. This new model of vitiligo, characterized by skin depigmentation without hair depigmentation, is more similar to human disease than previous murine models. Furthermore, the extent of skin depigmentation correlated with the frequency of TRP2-180-specific splenic CD8+ effector T cells. Therefore, this model is well-suited to analyze how efficiently the addition of competitive peptides for MHC binding inhibits the activation of autoreactive CD8+ T cells. The competitive peptides for Kb binding inhibited the IFN-γ production and proliferation of TRP2-180-specific CD8+ T cells upon ex vivo peptide restimulation, compared to non-competiti...