CTLA4Ig treatment in patients with multiple sclerosis

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Abstract
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-γ 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. GLOSSARY: 1M = 1 month after infusion; 2M = 2 months after infusion; 3M = 3 months after infusion; 8D = 8 days after infusion; AE = adverse event; AI = Ambulation Index; APC = antigen-presenting cell; BL = baseline; BL2 = second baseline; BPF = brain parenchymal fraction; CTLA-4 = cytotoxic T lymphocyte–associated gene 4; EDSS = Expanded Disability Status Scale; FDA = Food and Drug Administration; Gd+ = gadolinium-enhanced; hMBP = human myelin basic protein; IDO = indolamine 2,3-dioxygenase; IFN = interferon; IL = interleukin; MBP = myelin basic protein; MS = multiple sclerosis; MSFC = Multiple Sclerosis Functional Composite; PBMC = peripheral blood mononuclear cell; RA = rheumatoid arthritis; TE = echo time; TR = repetition time; URI = upper respiratory infection; UTI = urinary tract infection; WBC = white blood cell.

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