Abstract
BackgroundBone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES) cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs). Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells.Methodology/Principal FindingsHere, we derived CD45+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts.ConclusionsOur data show, for the first time, the efficacy of ES-derived CD45+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.
Highlights
Five decades ago Medawar and colleagues published an article in Nature [1] demonstrating that transplantation tolerance can be acquired; in these studies tolerance was strongly associated with donor leukocyte chimerism [1,2]
HOXB4-transduced embryonic stem (ES) cells differentiate into hematopoietic progenitor cells (HPCs) The derivation of multilineage hematopoietic cells from ES cells has remained difficult, limiting their use in large-scale functional studies
ES cells transduced with HOXB4 were analyzed for the expression of hematopoietic markers after 26 days of differentiation
Summary
Five decades ago Medawar and colleagues published an article in Nature [1] demonstrating that transplantation tolerance can be acquired; in these studies tolerance was strongly associated with donor leukocyte chimerism [1,2]. It has been appreciated that engrafting allogeneic bone marrow into irradiated hosts can give the host lifelong donor-specific chimerism [3] These hosts have hematolymphoid systems that are derived wholly or in part from donor stem cells. Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. Their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. It has been difficult to generate stable hematopoietic cells from ES cells
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