Rheumatoid arthritis is the most common chronic inflammatory disease targeting peripheral joints. It causes progressive cartilage destruction and bone erosion around joints (Palmer, 1995). CIA is an experimental mouse model used for the study of human RA and is induced in genetically predisposed mice by immunization with bovine collagen II (bCII) emulsified in CFA as mentioned before. CD4+ T cells play a central role in disease induction in arthritis (Ranges et al., 1985). Both antigen specific helper T cells and antibodies isolated from arthritic animals are capable of transferring disease within susceptible mouse strains (Seki etal., 1988;Taylor etal., 1995). Suggesting both B and T lymphocytes are involved in the pathogenesis of CIA.
As previously mentioned, CD137/CD137L interaction blockade showed only mild effect in preventing the development of CIA, however, CD137 agonist was capable to both prevent and treat established CIA. Similar as SLE, CD137 engagement with agonistic monoclonal antibodies (3H3) not only suppressed the development of CIA, but also reversed disease progression in mice already afflicted with disease (Foell et al., 2004; Seo et al., 2004). Administration of agonistic anti-CD137 prevents arthritis development in a dose dependent manner when treatment started on the day of first immunization with bCII emulsified with CFA. Three to five doses of200 ^g 3H3 treatment completely prevented the development of arthritis with ablated clinical sign and joint pathology, anti-bCII autoantibody production was absent as well (Foell et al., 2004; Seo et al., 2004). Moreover, such treatment generated a long-term tolerance that protected the mice from subsequent rechallenge with the same antigen (Foell et al., 2004). Most strikingly, anti-CD137 treatment improves established CIA with quick and almost complete clearance of anti-bCII autoantibodies in sera. CD4+ T cells isolated from draining lymph node of bCII immunized and 3H3 treated mice lost recall response to bCII re-stimulation ex vivo as the control IgG treated mice did. These studies suggest that CD137 engagement induces potent immunosuppression in autoantibody production and autoreactive helper T cell function.
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