title: Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients.
abstract: Severe combined immunodeficiency (SCID) caused by mutation of the recombination-activating gene 1 (RAG1) or Artemis gene lead to the absence of B- and T-cell differentiation. The only curative treatment is allogeneic bone marrow (BM) transplantation, which displays a high survival rate when an HLA compatible donor is available but has a poorer prognosis when the donor is partially compatible. Consequently, gene therapy may be a promising alternative strategy for these diseases. Here, we report that lentiviral gene-corrected BM CD34(+) cells (isolated from Artemis- or RAG1-deficient patients) sustain human B-cell differentiation following injection into non-obese diabetic/SCID (NOD-SCID) mice previously infused with anti-interleukin-2 receptor beta chain monoclonal antibody. In most of the mice BM, engrafted with Artemis-transduced cells, human B-cell differentiation occurred until the mature stage. The B cells were functional as human immunoglobulin M (IgM) was present in the serum. Following injection with RAG1-transduced cells, human engraftment occurred in vivo but B-cell differentiation until the mature stage was less frequent. However, when it occurred, it was always associated with human IgM production. This overall approach represents a useful tool for evaluating gene transfer efficiency in human SCID forms affecting B-cell development (such as Artemis deficiency) and for testing new vectors for improving in vivo RAG1 complementation.
authors.affiliation: Institut National de la Santé et de Recherche Médicale, Unit 768, Necker site, Paris, France. lagresle@necker.fr
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.forename: Fatine
authors.initials: F
authors.lastname: Benjelloun
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.forename: Isabelle
authors.initials: I
authors.lastname: Andre-Schmutz
authors.forename: Delphine
authors.initials: D
authors.lastname: Bonhomme
authors.forename: Monique
authors.initials: M
authors.lastname: Forveille
authors.forename: Kheira
authors.initials: K
authors.lastname: Beldjord
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: De Villartay
authors.forename: Pierre
authors.initials: P
authors.lastname: Charneau
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018952:Antigens, CD34 / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins; D004720:Endonucleases; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000276:immunology; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007075:Immunoglobulin M; D053646:Interleukin-2 Receptor beta Subunit; D009687:Nuclear Proteins; C064658:RAG-1 protein; C426344:DCLRE1C protein, human; D004720:Endonucleases