title: Tolerance induction using lentiviral gene delivery delays onset and severity of collagen II arthritis.
abstract: The treatment of rheumatoid arthritis remains suboptimal; thus there is considerable interest in the development of strategies that mediate tolerance to autoantigens. Using lentiviral gene transfer in vivo, we expressed the immunodominant epitope of collagen type II (CII) on major histocompatibility complex class II molecules (MHC II) in a mouse model of destructive arthritis. A sequence corresponding to amino acids 259-270 of CII was fused into the class II-associated invariant chain peptide (CLIP) position of the invariant chain to achieve efficient binding to MHC II. Transduction of cloned cells and primary antigen-presenting cells (APCs) in vitro demonstrated successful presentation of the peptide on MHC II, and a physiological glycosylation pattern. Compared with controls, mice intravenously injected with lentiviral vectors encoding this epitope displayed significantly less frequent, less severe, and less destructive arthritis, decreased lymphocyte proliferation in response to restimulation with CII, and lower CII-specific antibody levels. This was associated with an increased production of transforming growth factor-beta (TGF-beta) in vitro. We suggest that overexpression of the immunodominant CII epitope on MHC II induces T cell production of TGF-beta and leads to inhibition of arthritis by means of both antigen-specific and bystander mechanisms. Thus, antigen-specific tolerance induction using lentiviral gene delivery can ameliorate arthritis.
authors.affiliation: Department of Rheumatology and Inflammation Research, Göteborg University, Gothenburg, Sweden. nger.gjertsson@rheuma.gu.se
authors.forename: Inger
authors.initials: I
authors.lastname: Gjertsson
authors.forename: Karen L
authors.initials: KL
authors.lastname: Laurie
authors.forename: James
authors.initials: J
authors.lastname: Devitt
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Kenth
authors.initials: K
authors.lastname: Gustafsson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001323:Autoantibodies / Q000276:immunology; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D024043:Collagen Type II / Q000276:immunology*; D017931:DNA Primers; D015316:Genetic Therapy; D005822:Genetic Vectors; D006031:Glycosylation; D007108:Immune Tolerance; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D016133:Polymerase Chain Reaction; D012720:Severity of Illness Index; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection
chemical_list: D001323:Autoantibodies; D024043:Collagen Type II; D017931:DNA Primers