Ishii E, Gengozian N, Good R A
Department of Pediatrics, All Children's Hospital, University of South Florida, St. Petersburg 33701.
Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8435-9. doi: 10.1073/pnas.88.19.8435.
To study murine major histocompatibility complex (MHC)-haploidentical bone-marrow transplantation (BMT), B6C3F1 mice (H-2b/k) underwent BMT using syngeneic [B6C3F1 (H-2b/k)], haploidentical [CB6F1 (H-2d/b)], or fully allogeneic [DBA/2 (H-2d)] donor mice. As pretreatment, dimethyl myleran (DMM), an alkylating agent that produces effective myeloablation but little immunosuppression, was used with total body irradiation (TBI). Four conditioning regimens were studied: TBI 800 rads (1 rad = 0.01 Gy), TBI 950 rads, TBI 800 rads plus DMM (0.2 mg per mouse), and TBI 950 rads plus DMM. Survival rates, chimerism, proliferative responses in mixed-lymphocyte culture, specific cell-mediated lympholysis, and in vivo plaque-forming cell responses to several antigens were compared. TBI 800 rads plus DMM was maximally effective. Haploidentical BMT was as successful in inducing long-term survival and immune and hematologic reconstitution as was syngeneic BMT. This regimen plus haploidentical BMT of T-cell-purged marrow yielded survivors tolerant of donor and recipient major histocompatibility complex. Such myeloablation and immunosuppression prevented graft rejection, immunodeficiency due to histoincompatibility, and damage to a radiosensitive cell population. A microenvironmental influence crucial to some antibody responses was thus revealed. Delayed recovery of antibody production after BMT in humans may be due partly to suboptimal myeloablation or excess irradiation.
为研究小鼠主要组织相容性复合体（MHC）单倍型相合的骨髓移植（BMT），对B6C3F1小鼠（H-2b/k）进行了BMT，供体小鼠分别采用同基因的[B6C3F1（H-2b/k）]、单倍型相合的[CB6F1（H-2d/b）]或完全异基因的[DBA/2（H-2d）]小鼠。作为预处理，使用了二甲基马利兰（DMM），一种产生有效骨髓消融但几乎不产生免疫抑制的烷化剂，并联合全身照射（TBI）。研究了四种预处理方案：TBI 800拉德（1拉德 = 0.01戈瑞）、TBI 950拉德、TBI 800拉德加DMM（每只小鼠0.2毫克）以及TBI 950拉德加DMM。比较了生存率、嵌合率、混合淋巴细胞培养中的增殖反应、特异性细胞介导的淋巴细胞溶解以及对几种抗原的体内空斑形成细胞反应。TBI 800拉德加DMM效果最佳。单倍型相合的BMT在诱导长期生存以及免疫和血液学重建方面与同基因BMT一样成功。该方案联合T细胞清除的骨髓进行单倍型相合的BMT产生了耐受供体和受体主要组织相容性复合体的存活者。这种骨髓消融和免疫抑制防止了移植物排斥、因组织不相容导致的免疫缺陷以及对放射敏感细胞群体的损伤。由此揭示了对某些抗体反应至关重要的微环境影响。人类BMT后抗体产生的延迟恢复可能部分归因于骨髓消融不足或照射过度。
