Ocular Examinations for Uveitis in S1 Sinclair Swine in Response to HSP70i_Q435A

Abstract

Purpose : A subset of S1 Sinclair swine who develop cutaneous melanoma and spontaneous tumor regression may develop depigmentation of the skin, hair, and eyes (thought to be due to T cell mediated destruction of melanocytes) and uveal inflammation (due to immunologic cross reaction). Heat shock protein 70 (HSP70i) plays an important role in vitiligo development, and an HSP70i_Q435A construct has been shown to support repigmentation. Ocular examinations were conducted to detect any pigmentary or inflammatory changes that may occur during observation or treatment of vitiligo lesions.

Methods : The treatment group (n=3) underwent jet injection of HSP70i_Q435A encoding DNA into vitiligo lesions weekly for 4 weeks, and vitiligo lesions in the control group (n=3) were injected with phosphate-buffered saline. Ocular exams, blood draws (to monitor anti-HSP70i titers), and peri-lesional skin biopsies were conducted under isoflurane anesthesia. Examinations were performed at 4-week intervals during each swine’s 26-week observation cycle and included videos of each eye and external, anterior segment, and funduscopic examinations. The observing ophthalmologist was blinded to the swine’s treatment randomization but was aware of which swine was being examined.

Results : The presence of conjunctival plaques (2 controls), dilated iris vessels (2 treatment, 1 control), and hypopigmented retinal lesions (2 treatment) were deemed normal variants. A round, bluish lesion (choroidal nevus) was noted in the retina of one swine (treatment). One swine (control) exhibited dilated conjunctival vessels on initial examination that significantly increased in size at the 24-week examination and then stabilized. Another swine (treatment) developed multiple nummular perivascular areas of retinal hypopigmentation in both eyes at the 4-week examination (6 examinations remaining). A significant reduction in cutaneous depigmentation was observed in HSP70i_Q435A -treated lesions: +2.8 cm² in untreated lesions compared to -6.2 cm² in DNA treated lesions at 26 weeks.

Conclusions : HSP70i_Q435A–treated vitiligo lesions in S1 Sinclair swine showed cutaneous repigmentation without ocular inflammatory side effects or changes in tumor growth, suggesting that HSP70i_Q435A may suppress autoimmunity without impacting anti-tumor responses. Numerous ocular normal variants were observed, and the significance of nummular perivascular hypopigmentation remains to be elucidated.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.