Storb R, Yu C, Barnett T, Wagner J L, Deeg H J, Nash R A, Kiem H P, McSweeney P, Seidel K, Georges G, Zaucha J M
Clinical Research Division and Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WA, USA.
Blood. 1999 Aug 1;94(3):1131-6.
Stable mixed donor/host hematopoietic chimerism can be accomplished in dog leukocyte antigen (DLA)-identical littermate dogs given sublethal (200 cGy) total-body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) after transplant (Blood 89:3048, 1997). Studies were based on the hypothesis that drugs that prevent graft-versus-host disease (GVHD) after transplant also suppress host-versus-graft (HVG) reactions and thereby enhance engraftment. Here, we asked whether pretransplant TBI provided marrow space for the graft to home or caused host immunosuppression. To address the questions, recipients were given pretransplant irradiation to cervical, thoracic, and abdominal lymph nodes (except pelvis), DLA-identical littermate marrow grafts, and MMF/CSP posttransplant. Six dogs that received 450 cGy irradiation showed initial engraftment. Two rejected their grafts after 8 and 18 weeks, 1 died with GVHD and engraftment, and 3 are alive as mixed chimeras after 57 to 97 weeks. Four dogs given 200 cGy irradiation also showed initial engraftment, but rejected their grafts after 10 to 18 weeks. Mixed chimerism was present in nonirradiated marrow and lymph node spaces and involved granulocytes, T cells, and monocytes. While other explanations are possible, results seem consistent with the hypothesis that pretransplant radiation provides host immunosuppression, and grafts can create their own marrow space. These data set the stage for the development of novel transplant regimens that substitute immunosuppressive for cytotoxic agents.
在移植前给予亚致死剂量（200 厘戈瑞）的全身照射（TBI），并在移植后用霉酚酸酯（MMF）和环孢素（CSP）进行免疫抑制的情况下，可在犬白细胞抗原（DLA）相同的同窝犬中实现稳定的混合供体/宿主造血嵌合体（《血液》89:3048，1997）。研究基于这样的假设，即移植后预防移植物抗宿主病（GVHD）的药物也会抑制宿主抗移植物（HVG）反应，从而增强植入。在此，我们探讨移植前的 TBI 是为移植物提供了归巢的骨髓空间，还是导致宿主免疫抑制。为解决这些问题，对受体进行移植前照射，照射部位为颈部、胸部和腹部淋巴结（骨盆除外），给予 DLA 相同的同窝骨髓移植，并在移植后使用 MMF/CSP。接受 450 厘戈瑞照射的 6 只犬出现了初始植入。2 只在 8 周和 18 周后排斥了移植物，1 只死于 GVHD 且伴有植入，3 只在 57 至 97 周后作为混合嵌合体存活。接受 200 厘戈瑞照射的 4 只犬也出现了初始植入，但在 10 至 18 周后排斥了移植物。混合嵌合体存在于未照射的骨髓和淋巴结空间，涉及粒细胞、T 细胞和单核细胞。虽然可能有其他解释，但结果似乎与以下假设一致，即移植前照射导致宿主免疫抑制，移植物可创造自身的骨髓空间。这些数据为开发用免疫抑制剂替代细胞毒性药物的新型移植方案奠定了基础。
