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Elliott H Sohn, Chunhua Jiao, Robert Mullins, Edwin M Stone, Budd A Tucker; Allogenic iPSC-derived RPE cell transplants induce immune response in pigs. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1368.
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Stem cell strategies focused on replacement of RPE cells for the treatment of geographic atrophy are under intense investigation. Although the eye has long been considered immune privileged, a limited number of large animal studies focused on the post-transplant immune response have been performed. The purpose of this study was to determine if allogenic iPSC-derived RPE cells delivered to the subretinal space of the pig would survive and fail to induce an immune response in non-diseased eyes.
250,000 iPSC-derived RPE cells, generated from GFP-positive outbred domestic swine, were injected subretinally into 12-week-old vitrectomized Yucatan mini swine (a subset of eyes received BSS vehicle control only). Eyes were enucleated at 3 weeks post-op, fixed in 4% paraformaldehyde, cryosectioned and immunostained with antibodies targeted against GFP, ZO1, macrophages (BA4D5), CD45, GFAP, nestin, Ki67, and PCNA. Vitreous samples extracted at the time of vitrectomy and again at post-op week 3 were assayed for cytokine levels using a swine cytokine Quantibody array kit (RayBiotech, Inc). Data were analyzed using Student’s t-test and one-way ANOVA followed by Fisher’s LSD test.
GFP-positive cells expressing the RPE marker ZO-1 were identified in the subretinal space at 3 weeks post-injection. Accompanying GFP-negative cells positive for CD45 and macrophage markers were also identified. All cells were negative for GFAP as well as the cell cycle markers nestin, Ki67, and PCNA. At post-op week 3, vitreous TGF-beta1 levels were elevated in the iPSC-RPE group compared to BSS controls and native vitreous. IL-12 levels were greater in post-op week 3 compared to native vitreous but not post-op week 3 BSS controls.
Subretinal injection of allogenic iPSC-RPE cells into wild-type mini-pigs can induce a positive immune response. These findings suggest that immunologically matched or autogenic donor cells may be required for clinical RPE cell replacement.
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