Efficacy and safety of anti-CD45–saporin as conditioning agent for RAG deficiency - 09/01/21
, Luigi D. Notarangelo, MD c, ⁎ Abstract |
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 B- and 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : RAG deficiency, conditioning, anti-CD45–saporin, immunotoxin, engraftment, immune reconstitution, hematopoietic stem cell transplantation, thymic epithelial cells
Abbreviations used : ADC, BM, CD45-SAP, CID-ID, DN, HSC, HSCT, HSPC, Lin–, LSK, mTEC, MZ, PB, RAG, SCID, TBI, TEC, TNP, WBC, WT
Plan
| Supported by a grant from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (to L.D.N.); the National Institutes of Health Bench to Bedside grant RAG Deficiency: From Pathophysiology to Precise Gene Editing (to L.D.N. and A.V.); and grants Tiget E2 (to A.V.), Italian Ministry of Health PE-2016-02363691 (to E.F. and L.D.N.), EU2020 (SCIDNET) No. 666908 (to A.V.), and MIUR 2017-5XHBPN (to A.V.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 1
P. 309 - janvier 2021 Retour au numéro
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