CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial.
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.
Viglietta
V
V
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Bourcier
K
K
Buckle
G J
GJ
Healy
B
B
Weiner
H L
HL
Hafler
D A
DA
Egorova
S
S
Guttmann
C R G
CR
Rusche
J R
JR
Khoury
S J
SJ
D000069594:Abatacept; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007107:Immune System / Q000187:drug effects; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D008279:Magnetic Resonance Imaging; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000037:antagonists & inhibitors; D013997:Time Factors
D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D000069594:Abatacept; D007371:Interferon-gamma