Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency.
J Allergy Clin Immunol
; 147(1): 309-320.e6, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-32387109
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transplante de Medula Óssea
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Imunodeficiência Combinada Severa
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Antígenos Comuns de Leucócito
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Imunoconjugados
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Proteínas de Homeodomínio
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Condicionamento Pré-Transplante
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Saporinas
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Anticorpos Monoclonais
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article