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Tolerance Induction Using Lentiviral Gene Delivery Delays Onset and Severity of Collagen II Arthritis

Gjertsson, Inger; Laurie, Karen L.; Devitt, James; Howe, Steven J.; Thrasher, Adrian J.; Holmdahl, Rikard LU and Gustafsson, Kenth (2009) In Molecular Therapy 17(4). p.632-640
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Therapy
volume
17
issue
4
pages
632 - 640
publisher
Nature Publishing Group
external identifiers
  • wos:000264748000009
  • scopus:63949083969
ISSN
1525-0024
DOI
10.1038/mt.2009.299
language
English
LU publication?
yes
id
38556a95-bf18-42c3-a45d-19f2a4f3b29d (old id 1400995)
date added to LUP
2009-06-15 12:49:13
date last changed
2017-05-21 03:35:11
@article{38556a95-bf18-42c3-a45d-19f2a4f3b29d,
  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.},
  author       = {Gjertsson, Inger and Laurie, Karen L. and Devitt, James and Howe, Steven J. and Thrasher, Adrian J. and Holmdahl, Rikard and Gustafsson, Kenth},
  issn         = {1525-0024},
  language     = {eng},
  number       = {4},
  pages        = {632--640},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Tolerance Induction Using Lentiviral Gene Delivery Delays Onset and Severity of Collagen II Arthritis},
  url          = {http://dx.doi.org/10.1038/mt.2009.299},
  volume       = {17},
  year         = {2009},
}