Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:147

Article

Castiello, Maria Carmina^1,2,3  Bosticardo, Marita⁴  Sacchetti, Nicolo¹  Calzoni, Enrica^1,4  Fontana, Elena^2,3  Yamazaki, Yasuhiro^4,5  Draghici, Elena¹  Corsino, Cristina⁴  Bortolomai, Ileana¹  Sereni, Lucia¹  Yu, Hsin-Hui⁴  Uva, Paolo⁶  Palchaudhuri, Rahul^7,8,9  Scadden, David T.^7,8  Villa, Anna^1,2,3  Notarangelo, Luigi D.⁴ 

[1] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy SR Tiget, Milan, Italy

[2] CNR, Inst Genet, Milan, Italy

[3] CNR, Biomed Res Milan Unit, Milan, Italy

[4] NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[5] Humanitas Clin & Res Ctr, Human Genome Lab, Milan, Italy

[6] Sci & Technol Pk Polaris, CRS4, Pula, Italy

[7] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[8] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[9] Magenta Therapeut, Cambridge, MA USA

关键词: RAG deficiency;    conditioning;    anti-CD45-saporin;    immunotoxin;    engraftment;    immune reconstitution;    hematopoietic stem cell transplantation;    thymic epithelial cells;   

DOI  :  10.1016/j.jaci.2020.04.033

来源: Elsevier

【 摘 要 】

Background: Mutations in the recombinase-activating genes cause severe immunodeficiency, with a spectrum of phenotypes ranging from severe combined immunodeficiency to immune dysregulation. Hematopoietic stem cell transplantation is the only curative option, but a high risk of graft failure and poor immune reconstitution have been observed in the absence of myeloablation. Objectives: Our aim was to improve multilineage engraftment; we tested nongenotoxic conditioning with anti-CD45 mAbs conjugated with saporin CD45 (CD45-SAP). Methods: Rag1-KO and Rag1-F971L mice, which represent models of severe combined immune deficiency and combined immune deficiency with immune dysregulation, respectively, were conditioned with CD45-SAP, CD45-SAP plus 2 Gy of total body irradiation (TBI), 2 Gy of TBI, 8 Gy of TBI, or no conditioning and treated by using transplantation with lineage negative bone marrow cells from wild-type mice. Flow cytometry and immunohistochemistry were used to assess engraftment and immune reconstitution. Antibody responses to 2,4,6-trinitrophenyl-conjugated keyhole limpet hemocyanin were measured by ELISA, and presence of autoantibody was detected by microarray. Results: Conditioning with CD45-SAP enabled high levels of multilineage engraftment in both Rag1 mutant models, allowed overcoming of Band T-cell differentiation blocks and thymic epithelial cell defects, and induced robust cellular and humoral immunity in the periphery. Conclusions: Conditioning with CD45-SAP allows multilineage engraftment and robust immune reconstitution in mice with either null or hypomorphic Rag mutations while preserving thymic epithelial cell homeostasis.

【 授权许可】

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