Targeting HSP70 in autoimmune vitiligo

描述（由申请人提供）：我们已经产生了具有白癜风治疗潜力的可诱导HSP 70 i的突变形式。所得的蛋白质抑制树突状细胞活化，并且基因枪接种的小鼠表现出随时间推移明显减少的脱色，这与耐受化的树突状细胞谱和减少的T细胞对皮肤的浸润有关。在当前的应用中，我们希望了解突变型HSP70 i影响免疫激活的潜在机制。我们提出，在响应于人HSP70 i中的单个氨基酸修饰中观察到的显著变化与通过CLRs与TLR的相对活化有关。差异APC活化可能在整个进化过程中是保守的，因为HSP 70的微生物同系物激发APC活化和炎症，并且该分子的保守功能可以解释感染诱导的自身免疫。此外，突变型HSP 70 i可能影响白癜风以外的自身免疫性疾病的发展。我们提出产生用于患者治疗的可管理的肽，并在具有类人皮肤和自发性白癜风的Sinclair猪亚系中测试纯化肽治疗的安全性和功效。这些研究将极大地扩展我们对HSP70诱导的白癜风的认识，并为将我们的研究结果转化为人类自身免疫性疾病的治疗提供临床前数据。

DESCRIPTION (provided by applicant): 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.