*Purpose: Modulation of the immune system using cellular therapy is an increasingly attractive option to prevent solid organ graft rejection, while at the same time maintaining immune function, sufficiently so to prevent most complications associated with general immunosuppression. We have previously shown that murine myeloid progenitor cells (mMPC), cryopreserved after expansion in vitro, not only induce robust tolerance for matched organ grafts when preconditioning included lethal whole body irradiation and third party hematopoietic stem cell transplantation (HSC), but also when non-lethal pre-conditioning is used.

*Methods: BALB/c mice were pre-conditioned with a combination of depleting antibodies, chemotherapeutic agents and immunosuppressants as well as infusion of 3 to 6 million mMPC expanded from HSC in vitro using a 10-day expansion protocol. mMPC were injected i.v. one week after skin graft placement. Skin grafts were either matched or not matched to the mMPC. These experiments looked at survival following the treatment without HSC transplantation, engraftment by mMPC-derived cells, tolerance to mMPC-matched, but not unmatched, skin grafts, generation of anti-graft MHC antibodies and anti-graft T cell responses in blood.

*Results: A preconditioning protocol that combines anti-thymocyte serum, anti-CD3 antibodies, busulfan, and rapamycin over a two week period allowed mMPC to be infused up to two weeks after the skin transplants. 40 out of 44 mMPC-matched grafts tested using this protocol survived for more than 5 months. mMPC mismatched grafts were all rejected. When looking at the effects on T and B cell responses, results shows that administration of mMPC under these conditions significantly reduces the T-cell response against mMPC-matched stimulator cells, but not against third party stimulator cells in MLR assays. Circulating antibody levels directed against mMPC-matched MHC molecules did not change following mMPC administration, compared to untreated controls. Animals that received a mMPC-matched skin graft did not show increased levels of anti-graft MHC circulating antibodies. However, when animals received third-party skin grafts, mismatched to both mMPC and host, a significant increase in the levels of circulating antibodies recognizing the skin graft MHC was seen.

*Conclusions: mMPC administration can contribute to tolerance induction without the need for lethal preconditioning or allogeneic hematopoietic stem cell transplantation. Under these non-lethal conditions mMPC can induce tolerance for solid organ grafts by modulating the T and B cell response directed against the graft.

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