Abstract showing anti-CD40L (Biogen Phase II compound) as potential MS treatment:
J Clin Invest 1999 Jan;103(2):281-90
Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154)
antibody in an animal model of multiple sclerosis.
Howard LM, Miga AJ, Vanderlugt CL, Dal Canto MC, Laman JD, Noelle RJ, Miller SD
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
[Medline record in process]
Relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse is a Th1-mediated autoimmune demyelinating disease model for human multiple sclerosis and is characterized by infiltration of the central nervous system (CNS) by Th1 cells and macrophages. Disease relapses are mediated by T cells specific for endogenous myelin epitopes released during acute disease, reflecting a critical role for epitope spreading in the perpetuation of chronic central CNS
pathology. We asked whether blockade of the CD40-CD154 (CD40L) costimulatory pathway could suppress relapses in
mice with established R-EAE. Anti-CD154 antibody treatment at either the peak of acute disease or during remission
effectively blocked clinical disease progression and CNS inflammation. This treatment blocked Th1 differentiation and
effector function rather than expansion of myelin-specific T cells. Although T-cell proliferation and production of interleukin
(IL)-2, IL-4, IL-5, and IL-10 were normal, antibody treatment severely inhibited interferon-gamma production, myelin
peptide-specific delayed-type hypersensitivity responses, and induction of encephalitogenic effector cells. Anti-CD154
antibody treatment also impaired the expression of clinical disease in adoptive recipients of encephalitogenic T cells,
suggesting that CD40-CD154 interactions may be involved in directing the CNS migration of these cells and/or in their
effector ability to activate CNS macrophages/microglia. Thus, blockade of CD154-CD40 interactions is a promising
immunotherapeutic strategy for treatment of ongoing T cell-mediated autoimmune disea |
