Taniguchi Yuki, Yoshihara Satoshi, Hoshida Yoshihiko, Inoue Takayuki, Fujioka Tatsuya, Ikegame Kazuhiro, Kawakami Manabu, Masuda Tomoki, Aozasa Katsuyuki, Kawase Ichiro, Ogawa Hiroyasu
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Exp Hematol. 2008 Sep;36(9):1216-25. doi: 10.1016/j.exphem.2008.03.018. Epub 2008 Jul 2.
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.
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 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.
We demonstrated that established GVHD in a murine GVHD model could be successfully treated by a second BMT from a third-party allogeneic donor.
我们研究了通过消除负责移植物抗宿主病（GVHD）的首个供体来源的淋巴细胞，第二次同种异体骨髓移植（BMT）是否能够成功治疗已确立的GVHD。
在BDF1（H-2(b/d)）→B6C3F1（H-2(b/k)）的小鼠GVHD模型中，在首次BMT后2至3周进行低剂量全身照射（TBI），然后用来自主要组织相容性复合体（MHC）抗原单倍体不匹配（与宿主以及首个供体均不匹配）的小鼠品系B6B10F1（H-2(b/s)）的移植物（1×10⁷骨髓细胞和3×10⁷脾细胞）对患有GVHD的小鼠进行第二次BMT。
结果表明，第二次同种异体BMT能够成功且稳定地治疗严重GVHD。为成功治疗GVHD，需要快速实现完全的第二个供体T细胞嵌合。此外，我们发现患有GVHD的小鼠即使在经过最小预处理（2 - 4 Gy TBI）后也能够轻易接受MHC单倍体不匹配的第二个供体造血细胞，因为它们处于深度免疫抑制状态，并且这些小鼠对第二个供体移植物新引发的GVHD相对具有抗性。此外，还发现第二次BMT的时机、预处理治疗的强度（GVHD小鼠非常敏感）以及供体选择对于获得成功结果也很重要。调节性T细胞增加和干扰素-γ水平降低可能参与了耐受性诱导。
我们证明，在小鼠GVHD模型中已确立的GVHD可以通过来自第三方同种异体供体的第二次BMT成功治疗。
