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.
Il testo completo di questo articolo è disponibile in 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
Mappa
| 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 - Gennaio 2021 Ritorno al numero
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