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Treatment
of Multiple sclerosis with CTLA4Ig
Principal Investigator: Samia Khoury, Brigham &
Women's Hospital
Abstract | Investigators
| Background
| Resources
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the
central nervous system initiated by autoreactive CD4+
T cell recognizing and responding to myelin antigens.
Our understanding of the immunopathogenesis of MS implicates
T cell activation as an important step in the pathogenesis
of this autoimmune disease. In experimental autoimmune
encephalomyelitis (EAE), the animal model of MS, treatment
of animals with CTLA4Ig, a fusion protein that binds and
blocks B7 interaction with CD28, suppresses EAE.
We also found that expression of CD28
in the CNS of mice undergoing EAE correlated with disease
activity. More importantly, B7 molecules are expressed
in plaques from MS brain. Initial studies in humans
with CTLA4Ig for the treatment of psoriasis showed that
this treatment could safely be administered to patients
and appeared to be efficacious.
Our hypothesis is that treatment with
CTLA4Ig will arrest the disease if administered early
in the course of MS and provides a novel conceptual
approach to treat MS with the intent to abort the
disease.
Our primary objective in this study is to evaluate
the safety and immunologic effects of CTLA4Ig therapy
in
MS. The study will include 3 dose groups (4 patients
each) starting with an induction therapy of 3 daily
doses followed by 2 monthly treatments of CTLA4Ig with
a total duration of study of 4 months. This phase
1
study is not designed to test efficacy but only safety
and immunologic responses in treated patients. MRI
measures
of disease activity (T2 lesion volume, number of gadolinium
(GD) enhancing lesions and progression of atrophy)
will
also serve as safety measures and may provide hints
for efficacy information to help design Phase II studies.
This clinical study will be accompanied by extensive
immunologic studies in order to understand the immunomodulatory
functions of CTLA4Ig in MS patients. The immunologic
studies will focus on 4 areas of investigation: 1)
to
look for change in activation state of I cells before
and after treatment, 2) to investigate the effect
of
treatment on markers of inflammation that have been
associated with disease activity in MS, 3) to investigate
the efect of treatment on the precursor frequency of
myelin reactive cells, 4) to investigate the effect
of treatment on immune function in vivo.
 Participating
Investigators
|
Samia J. Khoury,
Brigham & Women’s Hospital |
|
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David A. Hafler,
Brigham & Women’s Hospital |
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Charles R.G. Guttmann,
Brigham & Women’s Hospital |
|
Michael A. Panzara,
Brigham & Women’s Hospital |
Background
Articles
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Longitudinal
MRI in multiple sclerosis - Neurology [go ] |
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Changes
in serum levels of ICAM and TNF-R correlate with
disease activity in multiple sclerosis - Neurology
[go]
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Paradoxical
inhibition of T-cell function in response to CTLA-4
blockade - Nature Med
[go] |
Resources
& Interesting Links
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CTLA4 is
associated with susceptibility to multiple sclerosis
- J Neuroimmunol [go] |
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