Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
San Raffaele-Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy; Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cambridge, Mass.
J Allergy Clin Immunol. 2024 Jan;153(1):341-348.e3. doi: 10.1016/j.jaci.2023.07.017. Epub 2023 Aug 9.
Mutations in the recombinase-activating genes 1 and 2 (RAG1, RAG2) cause a spectrum of phenotypes, ranging from severe combined immune deficiency to combined immune deficiency with immune dysregulation (CID-ID). Hematopoietic cell transplantation is a curative option. Use of conditioning facilitates robust and durable stem cell engraftment and immune reconstitution but may cause toxicity. Transplantation from haploidentical donors is associated with poor outcome in patients with CID-ID.
We sought to evaluate multilineage engraftment and immune reconstitution after conditioning with CD45-antibody drug conjugate (CD45-ADC) as a single agent in hypomorphic mice with Rag1 mutation treated with congenic and haploidentical hematopoietic cell transplantation.
Rag1-F971L mice, a model of CID-ID, were conditioned with various doses of CD45-ADC, total body irradiation, or isotype-ADC, and then given transplants of total bone marrow cells from congenic or haploidentical donors. Flow cytometry was used to assess chimerism and immune reconstitution. Histology was used to document reconstitution of thymic architecture.
Conditioning with CD45-ADC as a single agent allowed robust engraftment and immune reconstitution, with restoration of thymus, bone marrow, and peripheral compartments. The optimal doses of CD45-ADC were 1.5 mg/kg and 5 mg/kg for congenic and haploidentical transplantation, respectively. No graft-versus-host disease was observed.
Conditioning with CD45-ADC alone allows full donor chimerism and immune reconstitution in Rag1 hypomorphic mice even following haploidentical transplantation, opening the way for the implementation of similar approaches in humans.
重组激活基因 1 和 2（RAG1、RAG2）突变可引起一系列表型，从严重联合免疫缺陷到联合免疫缺陷伴免疫失调（CID-ID）。造血细胞移植是一种有治愈可能的选择。使用预处理可促进强大且持久的干细胞植入和免疫重建，但可能会引起毒性。亲缘半相合供者的移植与 CID-ID 患者的不良预后相关。
我们试图评估 Rag1 突变的低功能小鼠在接受同源和半相合造血细胞移植后，使用 CD45 抗体药物偶联物（CD45-ADC）作为单一药物进行预处理后的多谱系植入和免疫重建。
Rag1-F971L 小鼠，一种 CID-ID 模型，用不同剂量的 CD45-ADC、全身照射或同型 ADC 预处理，然后接受同源或半相合供者的总骨髓细胞移植。流式细胞术用于评估嵌合体和免疫重建。组织学用于记录胸腺结构的重建。
CD45-ADC 作为单一药物的预处理可实现强大的植入和免疫重建，恢复了胸腺、骨髓和外周区室。CD45-ADC 的最佳剂量分别为 1.5mg/kg 和 5mg/kg 用于同源和半相合移植。未观察到移植物抗宿主病。
CD45-ADC 单独预处理可使 Rag1 低功能小鼠即使在接受半相合移植后也能实现完全供者嵌合体和免疫重建，为在人类中实施类似方法开辟了道路。
