Abstract
Human HSP70iQ435A carries a single amino-acid modification within the dendritic cell activating region and tolerizes dendritic cells in vitro. The underlying DNA was used to prevent and treat disease in vitiligo mouse models through reduced dendritic cell activation and diminished skin T-cell infiltration, suggesting the same may be useful for patients. Physiologic differences between mouse and human skin then called for studies in large animals with human-like skin. We established the efficiency of DNA jet injection into swine skin before subcloning HSP70iQ435A into clinically suitable vector pUMVC3. Vitiligo lesions in Sinclair swine were treated with plasmid DNA to measure changes in depigmentation, T-cell infiltration, expression of HSP70i in skin, serum HSP70i, and anti-HSP70i serum titers. Remarkable repigmentation following HSP70iQ435A-encoding DNA treatment persisted throughout the 6-month follow-up period. Repigmentation was accompanied by an initial influx of T cells accompanied by increased CD4/CD8 ratios, waning by week 15. Melanocytes spanned the border of repigmenting skin, suggesting that melanocyte repopulation precedes skin melanization. Serum titer fluctuations were not treatment-associated. Importantly, treatment did not interfere with melanoma immunosurveillance. These data encourage clinical testing of HSP70iQ435A.
Original language | English (US) |
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Pages (from-to) | 2531-2539 |
Number of pages | 9 |
Journal | Journal of Investigative Dermatology |
Volume | 138 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2018 |
Funding
Sinclair Bioresources is acknowledged for careful prescreening and handling of animals. We appreciate help from Levi Barse to generate a macro that measures lesional area. All authors corrected and approved of the manuscript. Funding was provided by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant 1R44AR065866 to AS and by National Institutes of Health/National Cancer Institute grant R01CA191317 to CLP. International Patent Application No. PCT/US12/53139 was filed related to the application of HSP70iQ435A to treat autoimmune disease. Sinclair Bioresources is acknowledged for careful prescreening and handling of animals. We appreciate help from Levi Barse to generate a macro that measures lesional area. All authors corrected and approved of the manuscript. Funding was provided by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases grant 1R44AR065866 to AS and by National Institutes of Health/National Cancer Institute grant R01CA191317 to CLP. International Patent Application No. PCT/US12/53139 was filed related to the application of HSP70i Q435A to treat autoimmune disease. These studies were supported in part by NIH funding for an SBIR phase I study to Radikal Therapeutics.
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Dermatology
- Cell Biology