Prevention of graft-versus-host disease by intrabone marrow injection of donor T cells: involvement of bone marrow stromal cells.
We have developed a new and effective method for bone marrow transplantation (BMT): bone marrow cells (BMCs) are injected directly into the bone marrow (BM) cavity of recipient mice. The intrabone marrow injection of BMCs (IBM-BMT) greatly facilitates the engraftment of donor-derived cells, and IBM-BMT can attenuate graft-versus-host reaction (GVHR), in contrast to conventional intravenous BMT (i.v.-BMT). Here, we examine the mechanisms underlying the inhibitory effects of IBM-BMT on GVHR using animal models where GVHR is elicited. Recipient mice (C57BL/6) were irradiated and splenic T cells (as donor lymphocyte infusion: DLI) from major histocompatibility complex-disparate donors (BALB/c) were injected directly into the BM cavity (IBM-DLI) or injected intravenously (i.v.-DLI) along with IBM-BMT. The BM stromal cells (BMSCs) from these recipients were collected and related cytokines were examined. The recipient mice that had been treated with IBM-BMT + i.v.-DLI showed severe graft-versus-host disease (GVHD), in contrast to those treated with IBM-BMT + IBM-DLI. The suppressive activity of BMSCs in this GVHD model was determined. The cultured BMSCs from the recipients treated with IBM-BMT + IBM-DLI suppressed the proliferation of responder T cells remarkably when compared with those from the recipients of IBM-BMT + i.v.-DLI in mixed leucocyte reaction. Furthermore, the level of transforming growth factor-beta and hepatocyte growth factor in cultured BMSCs from IBM-BMT + IBM-DLI increased significantly when compared with those from the recipients of IBM-BMT + i.v.-DLI. Thus, the prevention of GVHD observed in the recipients of IBM-BMT + IBM-DLI was attributable to the increased production of immunosuppressive cytokines from BMSCs after interaction with host reactive T cells (in DLI).
Miyake
T
T
First Department of Pathology, and Department of Surgery, Kansai Medical University, Osaka, Japan.
Inaba
M
M
Fukui
J
J
Ueda
Y
Y
Hosaka
N
N
Kamiyama
Y
Y
Ikehara
S
S
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000379:methods*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D007377:Interleukin-3 / Q000096:biosynthesis; D017710:Lymphocyte Transfusion / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017154:Stromal Cells / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D007377:Interleukin-3; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma