Collagen II-pulsed antigen-presenting cells genetically modified to secrete IL-4 down-regulate collagen-induced arthritis.
We explored the possibility that pulsed antigen-presenting cells (APC) provide a model vector system for site-specific delivery of immunosuppressive proteins during collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. Thus, mice were treated with either B cells or macrophages engineered to secrete IL-4 and loaded (or not) with type II collagen (CII). Systemic injection of an IL-4-producing B cell hybridoma resulted in a reduction of arthritis severity which was further improved when APC were incubated with CII before their transfer. Unmanipulated B cells loaded with CII also exerted a potent suppressive effect. Likely, clinical amelioration was observed in mice given at priming syngeneic bone marrow-derived macrophages producing IL-4 and pulsed with CII in comparison to the other groups. When the same dose of cells was transferred at disease onset, a moderate beneficial effect was observed. Whatever the APC inoculated, the beneficial effect did not rely upon an IL-4-driven shift towards Th2 phenotype. Systemic administration of fluorescent dye labeled macrophages to arthritic mice has shown that some of these cells rapidly migrate to joints. Moreover, IL-4 transfected macrophages retained their potent capacity to present CII peptides to T cells. These findings validate the use of CII peptide-loaded engineered APC as therapeutic vector cells in CIA and allow consideration of this strategy for the administration of various anti-inflammatory proteins.
Guéry
L
L
INSERM U477, Université René Descartes, Paris, France.
Chiocchia
G
G
Batteux
F
F
Boissier
M C
MC
Fournier
C
C
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism* / Q000637:transplantation*; D001169:Arthritis, Experimental / Q000628:therapy*; D001402:B-Lymphocytes / Q000378:metabolism; D003094:Collagen; D024043:Collagen Type II / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA
D024043:Collagen Type II; D015847:Interleukin-4; D003094:Collagen