Treatment of autoimmune diseases by portal venous bone marrow transplantation

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A new bone marrow transplantation (BMT) method for treating severe autoimmune diseases in MRL/lpr mice without using immunosuppressants has been established. The method consists of fractionated irradiation (5.5 Gy x 2) followed by the portal venous (PV) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice and intravenous (IV) injection of whole B6 BMCs 5 days after the PV injection. Al recipients survived more than 1 year after this treatment. Abnormal T cells (B220+/Thy1.2+/CD3+/CD4-/CD8-) present in untreated MRL/lpr mice disappeared. In the mice thus treated, the number of donor-derived cells possessing the mature lineage (Lin) markers rapidly increased in the bone marrow, spleen, and liver, indicating that hematolymphoid cells are completely reconstituted with donor-derived cells. The number of donor-derived hemopoietic progenitor cells (c-kit+Lin- cells) increased in the BMCs, hepatic mononuclear cells, and spleen cells. Simultaneously, homopoietic foci adjoining donor-derived stromal cells were observed in the liver when injected via PV, but not IV. Furthermore, donor-derived stromal cells were detected in the BMCs after the culture. This indicates that the donor-derived stromal cells are not only trapped in the liver but also migrate into the bone marrow where they construct the hemopoietic environment.These findings suggest that not only donor hemopoietic stem cells (HSCs) but also donor stromal cells administered via the PV were trapped in the liver, resulting in the early engraftment of donor HSCs in cooperation with donor-derived stromal cells.