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Induction of Tolerance in Quadruple Chimeric Mice

^a Department of Pathology,
^b Transplantation Center,
^c Regeneration Research Center for Intractable Diseases, and
^d Department of Neurosurgery, Kansai Medical University, Moriguchi, Osaka, Japan;
^e Laboratory of Cell Pathobiology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Osaka, Japan;
^f Department of Ophthalmology and
^g Department of Toxicology, Norman Bethune Medical University, Changchun, China

Key Words. Cord blood cells • Bone marrow transplantation • Reconstitution

Correspondence: Susumu Ikehara, M.D., First Department of Pathology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570-8506, Japan. Telephone: 81-66-993-8283; Fax: 81-66-884-8283; e-mail: ikehara{at}takii.kmu.ac.jp

Human cord blood (CB) contains hematopoietic stem cells and progenitors. Because the major limitation to a widespread use of CB for transplantation lies in its limited volume, it is necessary to combine the CB from several donors. In this study, we show that lethally irradiated mice can be reconstituted with the injection of a mixture of T cell–depleted bone marrow cells (BMCs; total, 3 x 10⁶) obtained from three fully allogeneic mouse strains in two different mouse combinations. A higher survival rate was obtained in the triple injection group than in mice injected with BMCs (1 x10⁶) obtained from a single mouse strain. In the mixed chimeric mice, three kinds of donor-type and recipient-type cells were detected in all the hematopoietic organs 1 month after bone marrow transplantation (BMT). Mixed-lymphocyte reaction showed that the tolerance to both recipient-type and donor-type major histocompatibility complex determinants was induced in the chimeric mice. In the peripheral blood (PB) of these mice, only one type of cells from the three different donor strains became dominant in most chimeric mice and reached a stable level about 4 months after BMT. Polymerase chain reaction analyses, however, revealed that the skins from all the donors were accepted even when no cells with their phenotypes could be detected in the PB. These results suggest that both hemato-lymphoid reconstitution and stable tolerance to not only the recipient strain but also all the donor strains can be achieved in chimeric mice, indicating the possibility of mixed CB transplantation in humans.