Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, 20892, MD, USA.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, 02115, MA, USA.
Nat Commun. 2019 Feb 6;10(1):616. doi: 10.1038/s41467-018-08202-w.
Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non-genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.
异基因骨髓移植后的造血嵌合可能会建立供体抗原特异性耐受状态。然而，目前的同种异体移植方案涉及基因毒性调理，具有有害的副作用，并易导致感染和癌症。在这里，我们描述了一种非基因毒性调理方案，用于在小鼠中进行完全 MHC 错配的骨髓同种异体移植，该方案涉及短暂的免疫抑制和用 CD117 抗体药物偶联物 (ADC) 选择性耗尽受体造血干细胞。与不进行调理的情况下从 5000 万个总骨髓细胞中获得的≤2.1%的造血嵌合相比，该方案导致在移植 2000 万个总骨髓细胞后多谱系、高水平（高达 50%）、持久的供体来源造血嵌合。此外，在没有慢性免疫抑制的情况下，在 CD117-ADC 调理的嵌合小鼠中可实现骨髓供体类型但不是第三方皮肤同种异体移植物的长期存活。唯一观察到的不良事件是调理后第一周内肝酶短暂升高。这些结果为 CD117-ADC 在同种异体移植和耐受方案中作为非基因毒性、高度靶向调理剂提供了原理证明。
