BACKGROUND: The modulation of costimulatory pathways represents an original therapeutic approach to regulate T cell-mediated autoimmune diseases by preventing or reducing autoantigen-driven T-cell activation in humans. Autoreactive CD4(+) T cells play a critical role in initiating the immune response leading to the chronic inflammation and demyelination characteristic of multiple sclerosis (MS). METHODS: We used IV infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway in a phase 1 dose-escalation study in MS. Sixteen patients with relapsing-remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. In an extension study, four additional subjects received four doses of CTLA4Ig. RESULTS: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon-gamma production by MBP-specific lines. CONCLUSIONS: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.
BACKGROUND: The modulation of costimulatory pathways represents an original therapeutic approach to regulate T cell-mediated autoimmune diseases by preventing or reducing autoantigen-driven T-cell activation in humans. Autoreactive CD4(+) T cells play a critical role in initiating the immune response leading to the chronic inflammation and demyelination characteristic of multiple sclerosis (MS). METHODS: We used IV infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway in a phase 1 dose-escalation study in MS. Sixteen patients with relapsing-remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. In an extension study, four additional subjects received four doses of CTLA4Ig. RESULTS: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon-gamma production by MBP-specific lines. CONCLUSIONS: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.
Authors: Jeffrey A Bluestone; Hugh Auchincloss; Gerald T Nepom; Daniel Rotrosen; E William St Clair; Laurence A Turka Journal: Nat Rev Immunol Date: 2010-11 Impact factor: 53.106