Transplanted terminally differentiated induced pluripotent stem cells are accepted by immune mechanisms similar to self-tolerance

Abstract

The exact nature of the immune response elicited by autologous induced pluripotent stem cell (iPSC) progeny is still not well understood. Here we show in murine models that autologous iPSC-derived endothelial cells (iECs) elicit an immune response that resembles the one against a comparable somatic cell, the aortic endothelial cell (AEC). These cells exhibit long-term survival in vivo and prompt a tolerogenic contexture of intra-graft characterized by elevated IL-10 expression. In contrast, undifferentiated iPSCs elicit a very different immune response with high lymphocytic infiltration and elevated IFN-γ, granzyme-B, and perforin intra-graft. Furthermore, the clonal structure of infiltrating T cells from iEC grafts is statistically indistinguishable from that of AECs, but is different from that of undifferentiated iPSC grafts. Taken together, our results indicate that the differentiation of iPSCs results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC-derived versus original somatic cells.

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

“…NSCs isolated from syngeneic C57BL/6 mice and allogeneic ICR mice were transplanted into EAE mice, and used as positive and negative controls respectively. (Araki et al, 2013;de Almeida et al, 2014). To investigate whether NSCs derived from iPSCs can elicit immune rejection responses and thus affect their clinical applications, T cell stimulation assays were performed.…”

Hurdles to clinical translation of human induced pluripotent stem cells

“…By contrast, autologous iPSCs may avoid the costs and side effects associated with lifelong immunosuppression required for allogeneic cell transplantation (16). Despite some controversy over the immunogenicity of undifferentiated iPSCs (40), recent work has demonstrated that the differentiation of iPSCs results in the loss of immunogenicity (41). Pending further validation, this is a potentially important finding, because it could lead to induction of tolerance similar to the tolerance elicited by a corresponding self-somatic cell.…”

Methods of induced pluripotent stem cells for clinical application

“…Subsequently, experiments with isogenic transplantation of mouse iPSCs revealed the successful engraftment of iPSCderived tissue without immunosuppressive treatment and verified the advantages of using auto-transplantation of iPSCs for avoiding immunosuppressive treatment [112,113] . However, a recent study demonstrated immune rejection upon transplanting autologous undifferentiated mouse iPSCs in vivo, and rejection was imperceptible upon transplanting autologous terminally differentiated mouse iPSCs [114] . Although this report supports the presence of immunogenicity in undifferentiated iPSCs [91] and conflicts with the successful autologous engraftment of undifferentiated iPSCs in other reports [93,94] , it supports the advantages of using auto-transplantation of iPSCderived terminally differentiated cells for avoiding immunosuppressive treatment.…”