title: Genetically modified human CD4(+) T cells can be evaluated in vivo without lethal graft-versus-host disease.
abstract: Adoptive cell immunotherapy for human diseases, including the use of T cells modified to express an anti-tumour T-cell receptor (TCR) or chimeric antigen receptor, is showing promise as an effective treatment modality. Further advances would be accelerated by the availability of a mouse model that would permit human T-cell engineering protocols and proposed genetic modifications to be evaluated in vivo. NOD-scid IL2rγ(null) (NSG) mice accept the engraftment of mature human T cells; however, long-term evaluation of transferred cells has been hampered by the xenogeneic graft-versus-host disease (GVHD) that occurs soon after cell transfer. We modified human primary CD4(+) T cells by lentiviral transduction to express a human TCR that recognizes a pancreatic beta cell-derived peptide in the context of HLA-DR4. The TCR-transduced cells were transferred to NSG mice engineered to express HLA-DR4 and to be deficient for murine class II MHC molecules. CD4(+) T-cell-depleted peripheral blood mononuclear cells were also transferred to facilitate engraftment. The transduced cells exhibited long-term survival (up to 3 months post-transfer) and lethal GVHD was not observed. This favourable outcome was dependent upon the pre-transfer T-cell transduction and culture conditions, which influenced both the kinetics of engraftment and the development of GVHD. This approach should now permit human T-cell transduction protocols and genetic modifications to be evaluated in vivo, and it should also facilitate the development of human disease models that incorporate human T cells.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Riyasat
authors.initials: R
authors.lastname: Ali
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Babad
authors.affiliation: Department of Health Sciences, University of Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Gebe
authors.affiliation: Program in Molecular Medicine, Diabetes Center of Excellence™, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Program in Molecular Medicine, Diabetes Center of Excellence™, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Teresa P
authors.initials: TP
authors.lastname: DiLorenzo
mesh_terms: D000818:Animals; D002460:Cell Line; D005818:Genetic Engineering; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006086:Graft vs Host Disease / Q000517:prevention & control*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014183:Transplantation, Heterologous
chemical_list: D015804:HLA-DR4 Antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D005968:Glutamate Decarboxylase
keywords: human CD4+ T cells; immunodeficient mice; lentiviral transduction