title: Mutant HSP70 reverses autoimmune depigmentation in vitiligo.
abstract: Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell-mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substrate-binding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, and mutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A-encoding DNA applied months before spontaneous depigmentation prevented vitiligo in mice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70iQ435A therapeutically in a different, rapidly depigmenting model after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift from quiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo.
authors: Department of Pathology, Immunology/Oncology Institute, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Jeffrey A
authors: JA
authors: Mosenson
authors: Andrew
authors: A
authors: Zloza
authors: John D
authors: JD
authors: Nieland
authors: Elizabeth
authors: E
authors: Garrett-Mayer
authors: Jonathan M
authors: JM
authors: Eby
authors: Erica J
authors: EJ
authors: Huelsmann
authors: Previn
authors: P
authors: Kumar
authors: Cecele J
authors: CJ
authors: Denman
authors: Andrew T
authors: AT
authors: Lacek
authors: Frederick J
authors: FJ
authors: Kohlhapp
authors: Ahmad
authors: A
authors: Alamiri
authors: Tasha
authors: T
authors: Hughes
authors: Steven D
authors: SD
authors: Bines
authors: Howard L
authors: HL
authors: Kaufman
authors: Andreas
authors: A
authors: Overbeck
authors: Shikhar
authors: S
authors: Mehrotra
authors: Claudia
authors: C
authors: Hernandez
authors: Michael I
authors: MI
authors: Nishimura
authors: Jose A
authors: JA
authors: Guevara-Patino
authors: I Caroline
authors: IC
authors: Le Poole
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D018450:Disease Progression; D015316:Genetic Therapy; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D017496:Hypopigmentation / Q000276:immunology*; D007249:Inflammation / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D012867:Skin / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection; D014611:Vaccination; D014820:Vitiligo / Q000276:immunology* / Q000473:pathology / Q000628:therapy*
chemical_list: D000941:Antigens; D018840:HSP70 Heat-Shock Proteins; D050505:Mutant Proteins; D010455:Peptides