Immunogenicity and Engraftment of Mouse Embryonic Stem Cells in Allogeneic Recipients

Abstract

Embryonic stem cells (ESCs) are pluripotent and therefore able to differentiate both in vitro and in vivo into specialized tissues under appropriate conditions, a property that could be exploited for cellular therapies. However, the immunological nature of these cells in vivo has not been well understood. In vitro, mouse-derived ESCs fail to stimulate T cells, but they abrogate ongoing alloresponses by a process that requires cell-cell contact. We further show that despite a high expression of the NKG2D ligand retinoic acid early inducible-1 by mouse ESCs, they remain resistant to natural killer cell lysis. In vivo, allogeneic mouse ESCs populate the thymus, spleen, and liver of sublethally irradiated allogeneic host mice, inducing apoptosis to T cells and establishing multilineage mixed chimerism that significantly inhibits alloresponses to donor major histocompatibility complex antigens. Immunohistochemical imaging revealed a significant percentage of ESC-derived cells in the splenic marginal zones, but not in the follicles. Taken together, the data presented here reveal that nondifferentiated mouse embryonic stem cells are non-immunogenic and appear to populate lymphoid tissues in vivo, leading to T-cell deletion by apoptosis.

Low immunogenicity of endothelial derivatives from rat embryonic stem cell-like cells

“…In some studies mouse ES cells exhibited a strong humoral and cellular immune response after in vivo application into injured myocardium in allogeneic settings [4,5]. In contrast, Bonde et al [3] described the inhibition of allo-responses to donor MHC antigens and the development of a multi-lineage mixed chimerism after in vivo administration of mouse ES cells into sublethally irradiated allogeneic hosts.…”

“…There are several reports of a robust immune-privileged ('tolerogenic') state of ESC of mice, humans and rats after engraftment [1][2][3], while others described an increase of immunogenicity following transplantation with proceeding differentiation [4,5]. Expression of structures recognized by the host immune system varies between the species, e.g.…”

“…MHC class II and costimulatory molecules are generally not expressed by ESC. Another 'tolerogenic' feature of these cells is the profound expression of Fas ligand (FasL) that would induce T-cell apoptosis via Fas-FasL interaction [1,3]. The major obstacle following transplantation is the recognition of donor antigens on the graft by the recipient's immune cells.…”

Stem Cell Therapies for Type I Diabetes

“…It appears that HoxB4-ES-HP-derived T cells are actively "tolerized" to donor antigens in the thymus, and that if not, they can cause lethal GVHD (Kim, Stultz et al 2011). In line with this, recipients of allogeneic ES-HP lacked evidence of GVHD (Burt, Verda et al 2004;Bonde and Zavazava 2006;Bonde, Chan et al 2008). Finally, another study has shown that non-HoxB4 transduced ES-HP can prevent onset of TID in mice (Verda, Kim et al 2008), but the method of ES-HP production in this study is quite different from the other more recent protocols.…”

“…Recent studies have provided proof-of-principle that the induction of immunological tolerance to ESC-derived tissues can be achieved, but the mechanisms of tolerance induction to ESC-derived hematopoietic-progenitors (ES-HP), as well as the ability of ES-HP themselves to induce immunological tolerance across allogeneic barriers, are still not well understood (reviewed in (Thompson and Manilay 2011)). Transplantation of HoxB4-transduced ES-HP resulted in mixed hematopoietic chimersm and the induction of specific transplantation tolerance to allogeneic cardiac grafts (Bonde and Zavazava 2006;Bonde, Chan et al 2008). It appears that HoxB4-ES-HP-derived T cells are actively "tolerized" to donor antigens in the thymus, and that if not, they can cause lethal GVHD (Kim, Stultz et al 2011).…”