Prevention of Graft-versus-Host Disease by Intra-Bone Marrow －Bone Marrow Transplantation plus Intra-Bone Marrow －Donor Lymphocyte Infusion

Abstract

We have recently found that intra-bone marrow - bone marrow transplantation (IBM-BMT) can be used to prevent graft-versus-host disease (GvHD), even when intensive donor lymphocyte infusion (DLI) is carried out. In the present study, in conjunction with IBM-BMT, allogeneic splenic T cells as DLI were also injected into the bone marrow cavity of lethally irradiated (8.5Gy) recipients. The extent of GvHD was compared with that of recipients that had received allogeneic IBM-BMT plus intravenous injection of allogeneic T cells (IV-DLI). GvHD in recipients treated with allogeneic IBM-BMT plus IBM-DLI was far milder than in those treated with allogeneic IBM-BMT plus IV-DLI. This was confirmed macroscopically and histopathologically. The frequency of regulatory T cells (Tregs) detected as CD4⁺ CD25⁺ or CD4⁺ Foxp3⁺ cells was significantly higher in recipients treated with IBM-BMT plus IBM-DLI than in those treated with IBM-BMT plus IV-DLI. Donor-derived helper T (Th) cells polarized to Th2 type in recipients treated with IBM-BMT plus IBM-DLI, while Th1 cells were dominant in recipients treated with IBM-BMT plus IV-DLI. Furthermore, the production of TGF-ß and HGF from bone marrow stromal cells (BMSCs) was enhanced after IBM-DLI. Thus, IBM-BMT plus IBM-DLI seem to preferentially induce Tregs and Th2, and also induce the production of TGF-ß and HGF from BMSCs, thereby resulting in the prevention of GvHD. These findings indicate that IBM-BMT is an excellent way of BMT not only for facilitating donor engraftment but also for preventing GvHD even when T cells are contained in BMCs or intensive donor lymphocyte infusion is carried out.