Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency.
Allografts
Animals
Antibodies, Monoclonal
/ adverse effects
Bone Marrow Transplantation
Homeodomain Proteins
/ genetics
Immunoconjugates
/ adverse effects
Leukocyte Common Antigens
/ antagonists & inhibitors
Mice
Mice, Knockout
Saporins
/ adverse effects
Severe Combined Immunodeficiency
/ genetics
Transplantation Conditioning
RAG deficiency
anti-CD45–saporin
conditioning
engraftment
hematopoietic stem cell transplantation
immune reconstitution
immunotoxin
thymic epithelial cells
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
28
01
2020
revised:
08
04
2020
accepted:
10
04
2020
pubmed:
11
5
2020
medline:
27
7
2021
entrez:
11
5
2020
Statut:
ppublish
Résumé
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. Our aim was to improve multilineage engraftment; we tested nongenotoxic conditioning with anti-CD45 mAbs conjugated with saporin CD45 (CD45-SAP). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32387109
pii: S0091-6749(20)30629-1
doi: 10.1016/j.jaci.2020.04.033
pmc: PMC8322962
mid: NIHMS1727108
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Homeodomain Proteins
0
Immunoconjugates
0
RAG-1 protein
128559-51-3
Leukocyte Common Antigens
EC 3.1.3.48
Ptprc protein, mouse
EC 3.1.3.48
Saporins
EC 3.2.2.22
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
309-320.e6Subventions
Organisme : Intramural NIH HHS
ID : ZIA AI001222
Pays : United States
Informations de copyright
Published by Elsevier Inc.
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