title: Correction of defective expression in MHC class II deficiency (bare lymphocyte syndrome) cells by retroviral transduction of CIITA.
abstract: Retrovirus-mediated gene transfer was used to restore expression to MHC class II-negative patient cells from complementation group A(II) of MHC class II immunodeficiency or bare lymphocyte syndrome (BLS). The cells of these patients do not transcribe MHC class II genes due to a defect in the trans-acting factor, CIITA. We constructed a vector, pGAG/Ii-CIITA, with the MHC class II-associated invariant chain promoter driving CIITA expression. Cocultivation with the virus producer line was consistently shown to be the optimal method for infection of all cell types. The induction of MHC class II expression after virus infection was rapid, and high levels of expression were achieved in cell lines within 1 wk of infection. In addition, expression was easily detectable even in peripheral blood cells of a BLS patient within a few days. Cell lines maintained in vitro for several months remained positive, and the proportion of cells with surface expression of DR was correlated with the number of integrated proviruses. Moreover, transduced B lymphoblastoid cell lines readily established tumors in CB17-scid/scid mice, and the MHC class II-positive cells demonstrated a clear competitive advantage in vivo. Ultimately, we hope to use this transduction system to restore normal immune function to a BLS patient for which no other therapeutic option currently exists.
authors.affiliation: Sloan-Kettering Institute, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Bradley
authors.forename: J M
authors.initials: JM
authors.lastname: Fernandez
authors.forename: G
authors.initials: G
authors.lastname: Ungers
authors.forename: T
authors.initials: T
authors.lastname: Diaz-Barrientos
authors.forename: V
authors.initials: V
authors.lastname: Steimle
authors.forename: B
authors.initials: B
authors.lastname: Mach
authors.forename: R
authors.initials: R
authors.lastname: O'Reilly
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D015683:Gene Products, gag / Q000096:biosynthesis / Q000235:genetics; D018014:Gene Transfer Techniques; D005802:Genes, MHC Class II; D015316:Genetic Therapy; D005822:Genetic Vectors; D006684:HLA-DR Antigens / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D015683:Gene Products, gag; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; C045084:invariant chain