We have generated a mutant version of inducible HSP70i with treatment potential for vitiligo. The resulting protein inhibits dendritic cell activaton and gene gun vaccinated mice exhibit markedly reduced depigmentation over time, associated with tolerized dendritic cell profiles and reduced T cell infiltration to the skin. Under the curret application, we want to learn about the underlying mechanism whereby mutant HSP70i affects immune activation. We propose that the remarkable changes observed in response to a single amino acid modification in human HSP70i relate to relative activation via CLRs versus TLRs. Differential APC activation may be conserved throughout evolution, as the microbial homolog of HSP70 elicits APC activation and inflammation, and conserved functions of the molecule may explain infection induced autoimmunity. Moreover, mutant HSP70i may impact the development of autoimmune disease beyond vitiligo. We propose to generate a manageable peptide of use for patient treatment, and to test the safety and efficacy of purified peptide treatment in a substrain of Sinclair swine with human-like skin and spontaneous vitiligo. These studies will greatly extend our knowledge of HSP70-induced vitiligo and provide preclinical data of use for translating our findings towards the treatment of human autoimmune disease.
We have introduced a mutation into HSP70i that renders a molecule with therapeutic activity towards vitiligo. Besides studying the underlying mechanism, we also propose to generate HSP70i derived peptides containing the resulting, modified peptide and test its safety and activity towards vitiligo development in Sinclair swine.
