Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance
Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance
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DOI：
10.1016/j.stem.2019.05.018
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发表时间：
2019-08-01
期刊：
影响因子：
23.9
通讯作者：
Weissman, Irving L.
中科院分区：
文献类型：
--
作者：
George, Benson M.;Kao, Kevin S.;Weissman, Irving L.
造血细胞移植可以通过用健康的血液系统替换患病的血液系统来纠正血液学和免疫学疾病，但目前这需要用毒性和非特异性化疗、放疗或两者来耗尽患者现有的造血系统。在这里，我们报告了一种基于抗体的预处理方案，具有降低的毒性和增强的特异性，用于受体小鼠中的稳健造血干细胞（HSC）移植和植入。用靶向CD47、T细胞、NK细胞和HSC的六种单克隆抗体进行宿主预处理，然后进行供体HSC移植，使得在一半（单倍性）或全部主要组织相容性复合体（MHC）基因错配的受者中能够稳定造血系统重建。这种方法允许在单倍相合的受体中对来自HSC供体株的心脏组织产生耐受，显示出在没有免疫抑制的情况下用于实体器官移植的潜在应用。完全错配的嵌合小鼠对标称抗原产生抗体应答，显示出保留的功能性免疫。这些发现提示了移植免疫不匹配的HSC和具有有限毒性的实体器官的方法。
Hematopoietic cell transplantation can correct hematological and immunological disorders by replacing a diseased blood system with a healthy one, but this currently requires depleting a patient's existing hematopoietic system with toxic and non-specific chemotherapy, radiation, or both. Here we report an antibody-based conditioning protocol with reduced toxicity and enhanced specificity for robust hematopoietic stem cell (HSC) transplantation and engraftment in recipient mice. Host pre-treatment with six monoclonal antibodies targeting CD47, T cells, NK cells, and HSCs followed by donor HSC transplantation enabled stable hematopoietic system reconstitution in recipients with mismatches at half (haploidentical) or all major histocompatibility complex (MHC) genes. This approach allowed tolerance to heart tissue from HSC donor strains in haploidentical recipients, showing potential applications for solid organ transplantation without immune suppression. Fully mismatched chimeric mice developed antibody responses to nominal antigens, showing preserved functional immunity. These findings suggest approaches for transplanting immunologically mismatched HSCs and solid organs with limited toxicity.