An analysis of the adaptive immune response towards an embryonic stem cell grafts

Background: Although clinical transplantation has had enormous impact on the treatment of premature organ failure, shortage of donor organs continues to be a crucial limiting factor. Embryonic stem cells represent an attractive potential source of replacement tissue because of their inherent pluripotentiality and ability to self-renew. However, before any ES cell-based cellular replacement strategies can be considered, many issues must be addressed. Among these is an evaluation of the potential immune response elicited by any ES cell graft. Because ES cells express very low levels of MHC class I and no MHC class II, their immunogenicity has been questioned. Here we utilize a BM3 TCR transgenic model to analyze the adaptive immune response against an ES cell graft in vivo. Methods: BM3 CD8 TCR-tg T cells (H2K background) specific for the MHC class I molecule H2Kb were labelled with CFSE and adoptively transferred into CBA rag recipients. The following day, ES cells derived from a CBA, B6, or CBK background were implanted beneath the kidney capsule of adoptively transferred mice. Response of the CD8 T cells was measured via CSFE division profiling and graft infiltration. Results: CFSE division profile of naïve BM3 CD8 T cells was unaltered by the presence of either a syngeneic or an allogeneic ES cell graft. These naïve cells were also unable to recognize and infiltrate either a syngeneic or allogeneic ES cell graft on days 5 and 10 post-implantation, despite strong expression of the MHC class I molecule H2Kb by engrafted allogeneic ES cells. On the other hand, H2Kb+ islets begun to be infiltrated by day 5, and were obliterated by a vigorous allogeneic response by day 10. When H2Kb+ islets were implanted into the same kidney as allogeneic ES cells (opposite poles), islet grafts were rapidly infiltrated by CD4 and CD8 T cells and destroyed, but ES cell grafts exhibited markedly reduced cellular infiltrate. In contrast to naïve BM3 CD8 T cells, however, activated cells recognized and mounted an aggressive cytotoxic response against an allogeneic ES cell graft which could be detected by day 6 and resulted in complete graft destruction by day 10. Conclusions: Under certain circumstances, an ES cell graft may have reduced immunogenicity as compared with other conventional tissue or solid organ allografts. This may be due to their lack of passenger APC, which may in turn cripple their ability to elicit a robust allogeneic response via the direct pathway of allorecognition. However, because of their strong upregulation of allogeneic MHC class I molecules after transplantation, they are still likely to elicit a significant rejection response when transplanted into recipients replete with both CD4 and CD8 T cells