Crucial role of donor-derived stromal cells in successful treatment for intractable autoimmune diseases in MRL/lpr mice by BMT via portal vein

We have recently established a new bone marrow transplantation (BMT) method for the treatment of intractable autoimmune diseases in MRL/lpr mice; the method consists of fractionated irradiation (5.5 Gy x 2), followed by BMT o f whole bone marrow cells (BMCs) from allogeneic C57BL/6 mice via the porta l vein (abbreviated as 5.5 Gy x 2 + PV), In the present study, we investiga te the mechanisms underlying the early engraftment of donor-derived cells i n MRL/lpr mice by this method. In the mice treated with this method, the nu mber of donor-derived cells possessing the mature lineage (Lin) markers rap idly increased in the BM, spleen, and Liver; almost 100% were donor-derived cells by 14 days after the treatment. The number of donor-derived hemopoie tic progenitor cells (defined as c-kit(+)/Lin(-) cells) increased in the BM Cs, hepatic mononuclear cells, and especially spleen cells by 14 days after the treatment. Simultaneously, hemopoietic foci adjoining donor-derived st romal cells were observed in the liver when injected via the PV, but not vi a the peripheral vein (i.v.), When adherent cell-depleted BMCs were injecte d via the PV, recipients showed a marked reduction in the survival rate. Ho wever, when mire were transplanted with adherent cell-depleted BMCs with cu ltured stromal cells, all the recipients survived. These findings suggest that not only donor hematopoietic stem cells (HSCs) but also donor stromal cells administered via the PV were trapped in the li ver, resulting in the early engraftment of donor HSCs in cooperation with d onor-derived stromal cells. This new strategy to facilitate the early recov ery of hemopoiesis would therefore be of great advantage in human applicati on.