Induced Pluripotent Stem Cell-derived Tissues Elicit Selective Immunogenicity

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