J Immunol 2002 Feb 1;168(3):1457-65
Sun Y, Lin X, Chen HM, Wu Q, Subudhi SK, Chen L, Fu YX.
Departments of. Pathology and Neurology, and Committee in Immunology, University of Chicago, Chicago, IL 60637. Department of Immunology, Mayo Clinic, Rochester, MN 55905.
4-1BB, a member of the TNFR superfamily, is a costimulatory receptor primarily expressed on activated T cells.
It has been shown that the administration of agonistic anti-4-1BB Abs enhances tumor immunity and allogenic immune responses.
Paradoxically, we found that the administration of an agonistic anti-4-1BB mAb (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE).
Adoptive transfer of T cells from such treated mice failed to induce EAE, whereas anti-4-1BB treatment following adoptive transfer of encephalitogenic T cells did not prevent EAE pathogenesis.
These results suggest that anti-4-1BB treatment during the induction phase inhibits autoreactive T cell immune responses rather than preventing T cell trafficking into the CNS.
This was substantiated by the observations that draining lymph node cells from anti-4-1BB-treated mice failed to respond to Ag stimulation in vitro.
In addition, we found that such treatment initially promotes the activation and proliferation of Ag-specific CD4(+) T cells but subsequently increases their probability of undergoing activation-induced cell death, thereby inhibiting effector T cell responses.
More importantly, 2A treatment also inhibits the relapse of EAE in a clinically relevant murine model of multiple sclerosis.
This study indicates that the agonistic Ab against 4-1BB can potentially be used as a novel immunotherapeutic agent for treating autoimmune diseases.