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 |
