Recovery from established graft-vs-host disease achieved by bone marrow transplantation from a third-party allogeneic donor.
OBJECTIVE
We investigated whether established graft-vs-host disease (GVHD) could be successfully treated by a second allogeneic bone marrow transplantation (BMT) through elimination of first donor-derived lymphocytes responsible for GVHD.


METHODS
In a murine GVHD model of BDF1 (H-2(b/d))-->B6C3F1(H-2(b/k)), GVHD mice underwent a second BMT using a graft (1 x 10(7) bone marrow and 3 x 10(7) spleen cells) from a major histocompatibility complex (MHC) antigen haploidentically mismatched (to host and also to first donor) mouse strain, B6B10F1(H-2(b/s)), following low-dose total body irradiation (TBI) 2 to 3 weeks after the first BMT.


RESULTS
Results demonstrated that severe GVHD could be successfully and stably treated by a second allogeneic BMT. For successful treatment of GVHD, rapid achievement of full second-donor T-cell chimerism was required. Furthermore, we showed that mice with GVHD could easily accept MHC haploidentically mismatched second-donor hematopoietic cells even after minimal conditioning (2-4 Gy TBI) because they were in a profoundly immunosuppressed state, and that the mice were relatively resistant to new development of GVHD by second-donor grafts. Furthermore, the timing of the second BMT, the intensity of conditioning treatment (GVHD mice are very sensitive), and donor selection were also found to be important for obtaining successful outcomes. Increased regulatory T cells and reduction of interferon-gamma levels may be involved in tolerance induction.


CONCLUSIONS
We demonstrated that established GVHD in a murine GVHD model could be successfully treated by a second BMT from a third-party allogeneic donor.
Taniguchi
Yuki
Y
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Yoshihara
Satoshi
S
Hoshida
Yoshihiko
Y
Inoue
Takayuki
T
Fujioka
Tatsuya
T
Ikegame
Kazuhiro
K
Kawakami
Manabu
M
Masuda
Tomoki
T
Aozasa
Katsuyuki
K
Kawase
Ichiro
I
Ogawa
Hiroyasu
H
D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000601:surgery*; D006648:Histocompatibility; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D011828:Radiation Chimera; D012086:Reoperation; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014019:Tissue Donors; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma