Under certain conditions, foreign haematopoietic stem cells can engraft in a new host, giving rise to a chimaeric immune system. One benefit of this is that the donor-derived immune cells induce tolerance to the donor major histocompatibility complex (MHC) antigens. This tolerance allows acceptance of organ and tissue grafts from the same donor. However, contaminating T cells in the transfusion can respond to the recipient's MHC antigens and cause a lethal graft-versus-host reaction. Also, allogeneic haematopoietic stem cells are usually rejected outright unless the recipient's immune system is depleted and suppressed ('host conditioning'). Embryonic stem (ES) cell transfusions, however, carry no risk of contaminating T cells and, as Fred Fändrich and colleagues show in the February issue of Nature Medicine, they have a crucial immunological advantage over haematopoietic stem cells.

An implanted embryo is, in essence, an allograft: half of the MHC antigens expressed are paternal. Studies indicate that the implantation-stage embryo — from which ES cells can be derived — has intrinsic mechanisms of avoiding rejection by the maternal immune system. This new study investigated whether ES cells also have a special immune-privilege status that might allow them to engraft in an allogeneic host.

Stable ES-cell lines were derived from rat blastocysts. These stem cells express few or no MHC molecules. The stem cells were then labelled with a fluorescent dye and transferred by intravenous injection into fully MHC-disparate rats. Seven days after injection, fluorescent cells were detected in the liver, spleen, thymus and mesenteric lymph nodes. A proportion of these cells had become positive for MHC-class-II molecules, indicating that differentiation had commenced. In the blood, staining for a donor MHC-class-I molecule revealed that 5–8% of leukocytes were now derived from the implanted stem cells. This proportion stabilized at 6–12%. The leukocytes of donor origin included B cells and monocytes but, strikingly, no T or NK cells.

What mechanism might account for the survival of embryonic stem cells in allogeneic hosts in the absence of host conditioning? Expression of the death receptor ligand Fas ligand (FasL), seems to be high on the rat ES cells. Also, the rat ES cells were shown to trigger Fas-dependent killing of activated T cells in vitro. This indicates that there is a role for FasL, but other tolerance mechanisms also need to be investigated.

So, does the stable chimaerism permit acceptance of an organ transplant? To test this, heart allografts of the same genotype as the ES cells were transplanted into the abdominal cavity of the chimaeric rats. As expected, the transplants were permanently accepted.

This study has important implications for both transplantation and stem-cell therapies in general. If resistance to immune rejection is unique to specialized ES cells then they might become the stem cell of choice for therapeutic purposes. In organ transplantation, ES-cell-induced tolerance could eliminate the requirement for immunosuppression and tissue matching of recipient and organ donor. However, organ and stem cell would of course have to be MHC matched. This would require a large bank of human ES-cell lines of known MHC haplotype, which raises substantial logistical and ethical concerns.