Induction of donor-specific tolerance with splenocytes-for clinical application to organ transplantation

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Allogeneic chimerism has been established in the graft-accepting recipients and the donor cells in the host may act in a major role to facilitate the induction of tolerance. In the present study, we investigated effects of allogeneic splenocytes (SPLCs) mixture, which we usually procure at cadaveric organ donor surgery, to the bone marrow cells on the tolerance induction.1) Injection of 3x10^6 BMCs did not establish effective mixed chimerism. Donor cells were completely rejected by single 10x10^6 SPLCs injection. In a group of a mixture of very low dose of 3x10^6 BMCs and 10x10^6 SPLCs, however, mice were successfully induced chimerism. These chimeric mice showed donor-specific tolerance in vivo; skin grafting. T-cell enriched SPLCs could induce effective chimerism when mixed with a small amount of BMCs, but a mixture of B-cell enrich population of SPLCs and BMCs failed to establish effective chimerism. SPLCs without macrophages were as effective as naive SPLCs to induce tolerance. Even low dose of BMCs can establish a state of allogeneic chimerism and donor specific tolerance if combined with vigorous SPLCs. T-cells in SPLCs may play a important role to support BMCs for induction of donor-specific tolerance.2) Efficacy of a donor splenocytes mixed with stem cells in the peripheral blood were also investigated. Granulocyte stimulating factor was given and stem cell from peripheral blood was examined. Effective chimerism was established with a low dose of stem cell with a mixture of splenocytes. This results indicates the possibility of clinical usage of a chimerism induction because of safe procurement of stem cell in PBL instead of bone marrow cells.3) GVHD remains as a great concern. T-cells may play a major role for GVHD, however, they do for establishment of chimerism. It is necessary to establish a method to prevent GVHD without eliminating T-cells.