DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

A CASE STUDY: IMMUNOTHERAPY
FOR MULTIPLE SCLEROSIS
Clinical Features and Pathology. MS is a demyelinating
inflammatory disease of the CNS white matter that displays
a triad of pathogenic symptoms: mononuclear cell
infiltration, demyelination, and scarring (gliosis). The
peripheral nervous system is uninvolved. The disease,
which may be episodic or progressive, occurs in early to
middle adulthood with prevalence increasing from late
adolescence to 35 years of age and then declining. MS is
roughly 3-fold more common in females than in males
and occurs mainly in higher latitudes of the temperate climates.
Epidemiologic studies suggest a role for environmental
factors in the pathogenesis of MS; despite many
suggestions, associations with infectious agents have
proven inconclusive, even though several viruses can
cause similar demyelinating diseases in laboratory animals
and humans. A stronger linkage is the genetic one:
people of northern European ancestry have a higher susceptibility
to MS, and studies in twins and siblings suggest
a strong genetic component of susceptibility to MS.
Specifically, MS is a complex genetic disease in
which multiple allelic variants lead to disease susceptibility.
Although there is long-range linkage disequilibrium
in the MHC region, HLA-DR2 clearly is associated
with risk of developing MS (p = 10 228 ), as is HLA-
B*4402. Genome-wide association studies have identified
predominantly immune-related variants associated
with disease risk, including the IL-2RA chain (p = 10 27 ),
IL-7R chain (p = 10 20 ), CLEC16A (p = 10 15 ), CD58
(LFA-3, p = 10 10 ), and CD226 (p = 10 8 ) (IMSGC,
2007; IMSGC, 2008; Hafler, 2008). It is estimated that
>200 common allelic variants will be uncovered as
genome-wide association studies become properly powered.
Interestingly, these variants are strikingly common
among the different auto-immune diseases.
There also is substantial evidence of an autoimmune
component to MS: in MS patients, there are
activated T cells that are reactive to different myelin
antigens, including myelin basic protein (MBP). In
addition, there is evidence for the presence of autoantibodies
to myelin oligodendrocyte glycoprotein
(MOG) and to MBP that can be eluted from the CNS
plaque tissue, although it appears unlikely that highaffinity
auto-antibodies are present in the circulation.
These antibodies may act with pathogenic T cells to
produce some of the cellular pathology of MS. The neurophysiological
result is altered conduction (both positive
and negative) in myelinated fibers within the CNS
(cerebral white matter, brain stem, cerebellar tracts,
optic nerves, spinal cord); some alterations appear to
result from exposure of voltage-dependent K + channels
that normally are covered by myelin.
Attacks are classified by type and severity and
likely correspond to specific degrees of CNS damage
and pathological processes. Thus, physicians refer to
relapsing-remitting MS (the form in 85% of younger
patients), secondary progressive MS (progressive neurological
deterioration following a long period of
relapsing-remitting disease), and primary progressive
MS (~15% of patients, wherein deterioration with
relatively little inflammation is apparent at onset). De
Jager and Hafler (2007) have reviewed current concepts
of the etiology, natural history, and current therapy
of MS.
Pharmacotherapy for MS. Specific therapies are aimed at
resolving acute attacks, reducing recurrences and exacerbations,
and slowing the progression of disability
(Table 35–3). Nonspecific therapies focus on maintaining
function and quality of life. For acute attacks, pulse
glucocorticoids often are employed (typically, 1 g/day
of methylprednisolone administered intravenously for
3-5 days). There is no evidence that tapered doses of
oral prednisone are useful or even desirable.
For reducing the recurrence of relapsingremitting
attacks, immunomodulatory therapies are
approved: β-1 interferons [IFN-β-1a, IFN-β-1b], and
glatiramer acetate (GA; COPAXONE). The interferons
suppress the proliferation of T lymphocytes, inhibit their
movement into the CNS from the periphery, and shift the
cytokine profile from pro- to anti-inflammatory types.
Random polymers that contain amino acids commonly
used as MHC anchors and T cell–receptor contact
residues have been proposed as possible “universal
APLs (altered peptide ligands).” GA is a randomsequence
polypeptide consisting of four amino acids
[alanine (A), lysine (K), glutamate (E), and tyrosine (Y)
at a molar ratio of A:K:E:Y of 4.5:3.6:1.5:1] with an
average length of 40-100 amino acids. Directly labeled
GA binds efficiently to different murine H2 I-A molecules,
as well as to their human counterparts, the MHC
class II DR molecules, but does not bind MHC class II
DQ or MHC class I molecules in vitro. In phase III
clinical trials, GA, administered subcutaneously to
patients with relapsing-remitting MS, decreased the rate
of exacerbations by ~30% (De Jager and Hafler, 2007).
In vivo administration of GA induces highly crossreactive
CD4 + T cells that are immune deviated to
secrete Th2 cytokines and prevents the appearance of
new lesions detectable by magnetic resonance imaging.
This represents one of the first successful uses of an
1025
CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS