April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Induced Pluripotent Stem Cell-derived Tissues Elicit Selective Immunogenicity
Author Affiliations & Notes
  • Daniel Feitelberg
    Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
  • Peter D Westenskow
    Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
  • Stephen Bravo
    Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
  • Tongbiao Zhao
    Molecular Biology, University of California, San Diego, La Jolla, CA
  • Zhili Rong
    Molecular Biology, University of California, San Diego, La Jolla, CA
  • Carli M Wittgrove
    Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
  • Liliana P Paris
    Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
  • Dennis O Clegg
    Molecular, Cell and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA
  • Yang Xu
    Molecular Biology, University of California, San Diego, La Jolla, CA
  • Martin Friedlander
    Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
  • Footnotes
    Commercial Relationships Daniel Feitelberg, None; Peter Westenskow, None; Stephen Bravo, None; Tongbiao Zhao, None; Zhili Rong, None; Carli Wittgrove, None; Liliana Paris, None; Dennis Clegg, None; Yang Xu, None; Martin Friedlander, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2673. doi:
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      Daniel Feitelberg, Peter D Westenskow, Stephen Bravo, Tongbiao Zhao, Zhili Rong, Carli M Wittgrove, Liliana P Paris, Dennis O Clegg, Yang Xu, Martin Friedlander; Induced Pluripotent Stem Cell-derived Tissues Elicit Selective Immunogenicity. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2673.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Age-Related Macular Degeneration (AMD) is the leading cause of vision loss in the elderly. While no cure exists, evidence suggests that stem cell-derived retinal pigment epithelium (RPE) grafts can prevent photoreceptor degeneration in atrophic retinas. Clinical trials utilizing embryonic stem (ES) cell-derived RPE are ongoing, but require immune suppression; this may be unnecessary if autologous induced pluripotent stem cells (iPS) are employed. However, some studies suggest that reprogramming may actually make naïve iPS cells more immunoreactive.

Methods: Mice with humanized immune systems were generated and fibroblasts were collected from the same human source. iPSCs were generated using episomal vectors and were either directly injected into the host to generate teratomas, or converted into RPE or smooth muscle cells (SMCs) and characterized. These iPSCs were then transplanted directly into the muscle or eyes of humanized mice (HuSCID) as “autografts.” (RPE were injected in muscle since eyes are relatively immune privileged). ES-RPE and ES-SMCs were generated as allograft controls. The grafted regions of the muscle and eyes were examined for T-cell infiltration using immunohistochemistry.

Results: After injecting naïve autologous iPSCs into HuSCID mice, unusually small teratomas formed which lacked specific cell types like smooth muscle, but contained RPE. iPS-RPE and iPS-SMCs that strongly resemble their primary counterparts (based on expression of terminal differentiation genes and functional assays) were injected as autologous grafts. While significant T-cell infiltration was observed around allografts, none of the iPS-RPE lines elicited obvious T-cell infiltration. However, all of the autologous iPS-derived SMC lines examined had significant T-cell infiltration in HuSCID mice. No T-cell infiltration was observed in eyes injected with iPS- or ES-RPE.

Conclusions: The presence of small teratomas lacking smooth muscle and other cell types (but containing RPE) in HuSCID mice suggested that cells derived from iPS may elicit selective immunogenicity. This was confirmed by injecting autologous RPE cells and SMC cells and observing pronounced differences in T-cell infiltration. While this represents a promising outcome for RPE cell transplantation studies, it also serves as a warning against using other iPS-derived cells without first doing adequate pre-screening to ensure that they are not immunoreactive.

Keywords: 721 stem cells • 412 age-related macular degeneration • 553 immune tolerance/privilege  
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