Download existing immunomodulatory therapy and potential neuroprotective

PROCEEDINGS
EXISTING IMMUNOMODULATORY THERAPY
AND POTENTIAL NEUROPROTECTIVE ROLES*
—
Olaf Stüve, MD, PhD†
ABSTRACT
Six disease-modifying therapies are approved
for the treatment of multiple sclerosis: glatiramer
acetate, 2 formulations of interferon (IFN) β-1a
(one administered by subcutaneous injection and
one administered by intramuscular injection),
IFNβ-1b, natalizumab, and mitoxantrone. These
agents are thought to act primarily by suppressing
central nervous system (CNS) inflammation, which
may also produce secondary neuroprotective
effects. Inflammatory CNS demyelination requires
a sequence of tightly controlled immune processes,
including antigen presentation to T cells, additional cell-cell contacts between antigen-presenting
cells and T cells that are required for full T-cell activation, the migration of T cells through the
endothelial lining, and the release of several proinflammatory or anti-inflammatory chemical mediators. IFNβ and glatiramer acetate (GA) interrupt
several of these process, resulting in decreased
CNS infiltration of lymphocytes and inflammation.
GA may also produce neuroprotective effects by
modulating the release of neurotrophic factors,
chemical mediators that are produced by several
cell populations that promote neuronal development and survival. Natalizumab blocks specific
cell-surface receptor molecules that are required
for lymphocytes to migrate from the circulation to
*Based on a presentation given by Dr Stüve at the 5th
Annual Johns Hopkins MS Symposium held in Washington,
DC, on April 26, 2008.
†
Assistant Professor of Neurology, University of Texas
Southwestern Medical Center at Dallas, Dallas, Texas.
Address correspondence to: Olaf Stüve, MD, PhD,
Assistant Professor of Neurology, University of Texas
Southwestern Medical Center at Dallas, 5323 Harry Hines
Boulevard, Dallas, TX 75390.
E-mail: [email protected].
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the CNS, producing long-lasting suppression of
the infiltration of CD4+ and CD8+ T lymphocytes.
Natalizumab may produce a rebound increase in
the number of T2 lesions on magnetic resonance
imaging after discontinuation. Mitoxantrone is an
antineoplastic agent that interferes with DNA
replication in rapidly dividing cells, resulting in
lymphocyte depletion. It is not known to produce
neuroprotective effects.
(Adv Stud Med. 2008;8(9):315-321)
ll of the disease-modifying therapies
that are currently approved for the
treatment of multiple sclerosis (MS)
act primarily by suppressing central
nervous system (CNS) inflammation.
However, recent evidence suggests that these agents
may also possess secondary neuroprotective properties.
This paper reviews the immunomodulatory and neuroprotective mechanisms by which current therapies
improve outcomes in patients with MS.
A
MS TREATMENT OPTIONS: THE ROLE OF CNS
INFLAMMATION
Six medications are currently approved by the US
Food and Drug Administration for the treatment of
MS. First-line treatments include glatiramer acetate
(GA) and 3 formulations of interferon (IFN) β (IFNβ1a for intramuscular injection once weekly; IFNβ-1a
for subcutaneous injection 3 times weekly; and IFNβ-
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1b for subcutaneous injection every other day).
Mitoxantrone and natalizumab are generally reserved
for patients who cannot tolerate or do not respond
adequately to GA or IFNβ. Although mitoxantrone
and natalizumab are similar in efficacy to the first-line
agents, they are associated with potentially serious safety concerns. Natalizumab has been associated with an
increased risk of progressive multifocal leukoencephalopathy, an opportunistic CNS infection that is
potentially fatal.1-4 Mitoxantrone is associated with an
increased risk of cardiotoxicity.5
Nearly all of the approved or investigational therapies for MS are based on a model of MS pathogenesis
in which an important early step is the interaction
between antigen-presenting cells (APCs; especially dendritic cells, but also monocytes or B cells) and T lymphocytes in secondary lymphoid organs (Figure 1).6,7
This interaction results in the activation and clonal
expansion of T cells. The activating antigen might be a
foreign (eg, viral) peptide or a CNS autoantigen that
has escaped the brain as the result of some type of
insult. T cells that enter the CNS but do not encounter
the specific antigen to which they have been sensitized
rapidly exit the CNS. If a T cell encounters an antigen
that is identical or very similar to the antigen that it has
Figure 1. Proposed Mechanisms that Appear to Be
Germane to Trafficking, Inflammation, Demyelination,
and Ultimately Axonal Dysfunction and Loss
APC = antigen-presenting cell; CNS = central nervous system; MBP =
myelin basic protein; PLP = proteolipid protein.
Reprinted with permission from Frohman et al. Arch Neurol.
2005;62:1345-1356.7
316
been sensitized to detect, it becomes reactivated and
begins to express a range of inflammatory mediators,
cytokines, and free radicals that damage the axon and
the surrounding myelin sheath. Activated T cells may
also activate B cells, which differentiate into plasma
cells. Plasma cells are capable of secreting antibodies,
some of which bind to myelin antigens.
The activation of T cells by APCs requires 2 distinct
cell-cell signaling pathways.8 The first signal (sometimes
referred to as “signal 1”) occurs when an APC presents
antigen, complexed with major histocompatibility complex (MHC), to T cells. MHC possesses an antigenbinding cleft that holds a peptide antigen that is typically
8 to 11 amino acids in length.9 Binding of the MHCantigen complex to specific cell-surface receptor molecules on T cells provides the first signal for T-cell
activation. The second signal (sometimes referred to as
“signal 2,” or the T-cell costimulatory signal) requires the
interaction between several cell-surface costimulatory
molecules on APCs and corresponding receptor molecules on T cells. For example, one costimulatory signal
pathway involves the interaction of a specific costimulatory molecule known as B7 on APCs with its receptor
molecule (CD28) on T cells. T-cell costimulation occurs
both during the initial activation of T cells in the lymph
nodes and when T cells are reactivated by APCs in the
CNS. T cells that do not receive the appropriate costimulatory signal do not initiate inflammatory responses and
may undergo apoptotic cell death.10,11
INTERFERON β
All of the IFNβ formulations used for MS therapy
bind to IFNβ receptors on T cells and APCs.11
Engagement of IFNβ receptors initiates several intracellular events that interfere with the process of antigen presentation, including prevention of the
upregulation of MHC, costimulatory molecules, and
T-cell receptor molecules.11 IFNβ does not extensively
penetrate the CNS at the doses typically used to treat
MS, and therefore probably acts primarily on antigen
presentation in the lymph nodes.
Activated T cells in circulation also require chemoattractant molecules (chemokines) to migrate from the
vasculature into sites of inflammation. Chemokines are
expressed by several cell types, including endothelial
cells, astrocytes, and microglia.12 Two chemokines—
monocyte chemotactic protein-1 and interleukin (IL)-
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8—are especially important in T-cell infiltration to sites
of inflammation.13 Several studies have demonstrated
that IFNβ downregulates the expression of these
chemokines or blocks their activity.11 Another critical
step in the migration of T cells to sites of inflammation
is the adhesion of T cells to the vascular endothelium.
T-cell adhesion requires the interaction of specific cellsurface adhesion molecules on T cells (eg, very late antigen-4 [VLA-4]) and receptor molecules on endothelial
cells (eg, intercellular adhesion molecule-1). IFNβ
downregulates VLA-4, resulting in reduced T-cell adherence to the endothelial membrane.11
Finally, the migration of T cells from the vasculature
to the parenchyma requires the release of proteolytic
enzymes by T cells (eg, matrix metalloproteinase-9
[MMP-9]) that help to digest the endothelial lining and
the extracellular matrix. IFNβ is a potent inhibitor of
MMP-9,14-17 and therefore decreases the ability of T cells
to migrate from the circulation to the parenchyma.
There is no evidence that IFNβ produces a direct
neuroprotective effect. However, the diverse actions of
IFNβ on T-cell activation, chemoattraction, lymphocyte adhesion, and transendothelial migration may
indirectly promote neuroprotection in patients with
MS by suppressing CNS inflammation. This hypothesis is supported by studies in which IFNβ has been
shown to significantly reduce brain atrophy in patients
with MS. For example, Rudick et al examined the
effects of IFN therapy on brain atrophy in 140
patients with relapsing-remitting MS (RRMS).18
Atrophy was common among patients with MS treated with placebo: approximately 20% of patients exhibited a loss of more than 2% of brain parenchymal
volume from baseline after 2 years (Figure 2).18
Treatment with weekly intramuscular IFNβ-1a significantly reduced atrophy after the second year of treatment, but not the first year (Figure 3).18
activated by APCs bearing an appropriate antigen
complexed with MHC, CD4+ T cells differentiate into
either helper T cell (TH) 1 cells (which release several
pro-inflammatory cytokines, including IFNγ, tumor
necrosis factor-α and IL-2), or TH2 cells (which
release anti-inflammatory cytokines, such as IL-4, IL10, IL-13, and transforming growth factor-β).9,19 GA
structurally resembles myelin-derived antigen, but
promotes the maturation of anti-inflammatory TH2
cells that migrate to the CNS and suppress inflammaFigure 2. Percent Change in BPF Between Baseline
and Year 2 for Each Placebo Patient
A total of 9.8% of the patients increased and 90.2% decreased. A total of
37.5% of the patients decreased between 0% and 1%; 33.3% of the patients
decreased between 1% and 2%; 11.1% of the patients decreased between
2% and 3%; and 8.3% of the patients decreased by more than 3%.
BPF = brain parenchymal fraction.
Reprinted with permission from Rudick et al. Neurology. 1999;53:1698-1704.18
Figure 3. Change in BPF According to Treatment
Arm in the IFNβ-1a Clinical Trial
GLATIRAMER ACETATE
Glatiramer acetate is a random synthetic polymer
of 4 amino acids (L-alanine, L-glutamic acid, L-lysine,
and L-tyrosine) in a molar ratio of 4.6:1.5:3.6:1.9. GA
reduces CNS inflammation that is mediated by CD4+
and CD8+ T cells, and may also produce indirect neuroprotective effects in patients with MS.
CD4+ T cells were long believed to be the dominant T-cell subset in the pathogenesis of MS. When
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The rate of brain atrophy in year 1 (solid bars) was not affected by treatment arm, but there was significantly less brain atrophy in IFNβ-1a patients
during the second year (open bars).
BPF = brain parenchymal fraction; IFN = interferon.
Reprinted with permission from Rudick et al. Neurology. 1999;53:1698-1704.18
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tion.9 GA treatment also increases the number of circulating CD8+ T cells, a response that has been correlated with the clinical efficacy of GA.20 The precise
mechanism by which CD8+ cells suppress CNS
inflammation is not known, but may involve killing of
autoreactive CD4+ cells. Finally, GA also has been
shown to modify the development of APCs in animal
models of MS by promoting the development of antiinflammatory monocytes.16
Glatiramer acetate also may modulate the activity
of neurotrophic factors (neurotrophins). These molecules are primarily expressed during CNS development, and they also may be important in the
pathogenesis of MS and other neurodegenerative diseases. Neurotrophins are produced by immune cells
and neurons, they provide trophic support to injured
axons, and they may promote the preservation of
axons.21 Some neurotrophins (eg, brain-derived neurotrophic factor and neutrophin-3) have been shown
to stimulate oligodendrocyte proliferation and
remyelination.22 Neurotrophins also produce immunoregulatory effects that may be important in MS,
including the suppression of MHC expression by
microglia, downregulation of costimulatory molecules
B7 and CD40, and decreased monocyte migration.23-25
In animal models of MS, GA-specific T cells have been
Figure 4. Onset of Confirmed Disease Progression
by Time in Study and Sex*
*455 male and 480 female patients.
HR for male patients = 0.71 (95% CI, 0.53–0.95), P = .0193; HR for female
patients = 1.08 (95% CI, 0.79–1.46), P = .063.
CI = confidence interval; GA = glatiramer acetate; HR = hazard ratio;
PBO = placebo.
Reprinted with permission from Wolinsky et al. Ann Neurol. 2007;61:14-24.27
318
shown to cross the blood-brain barrier and release neurotrophic factors and anti-inflammatory cytokines.26
The efficacy of GA for the treatment of primary
progressive MS (PPMS), which many experts believe is
primarily a disorder of neurodegeneration rather than
inflammation, has recently been evaluated in the
PROMISE clinical trial.27 Patients with PPMS were
randomized to treatment with GA at a dose of 20 mg
per day by subcutaneous injection or placebo for up to
3 years. The primary efficacy end point (the likelihood
of disease progression) did not differ significantly
between the 2 treatment groups. This may have been
due to a much lower rate of progression in both groups
than was anticipated when the study was designed.
However, post-hoc analysis revealed that GA was associated with a significant decrease in the rate of disease
progression among men, but not among women
(Figure 4).27 This finding suggests that GA may produce neuroprotective effects in male patients with MS,
and that a larger clinical trial may be required to
demonstrate significant improvement in disease progression for men and women.
NATALIZUMAB
As previously described, infiltration of T lymphocytes into the CNS is a pivotal early step in the development of inflammation and demyelination in MS.
Natalizumab, a monoclonal antibody that blocks the
cell-surface adhesion molecule VLA-4, acts by preventing leukocyte migration. Natalizumab is an
immunoglobulin G4 antibody that does not bind
complement or induce cell killing.28 Natalizumab was
approved for the treatment of MS on the basis of 2
phase III clinical trials. The AFFIRM (Natalizumab
Safety and Efficacy in RRMS) clinical trial demonstrated that natalizumab decreased the annualized
relapse rate by 68% compared with placebo and the
risk of confirmed progression of disease by 42% over 2
years. Natalizumab also significantly reduced gadolinium-enhancing lesions, T2 lesions, and brain atrophy.29 The SENTINEL (Safety and Efficacy of
Natalizumab in Combination with IFNβ-1a in
Patients with RRMS) study compared the combination of natalizumab and IFNβ-1a versus IFNβ-1a
alone in patients with at least 1 relapse on IFNβ therapy.30 Compared with IFNβ-1a alone, combination
therapy was associated with a 24% reduction in the
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risk of sustained disability after 2 years, and also significantly reduced relapse rates and T2 lesions.
Recent research has examined the effects of natalizumab on immunosurveillance of the CNS in patients
with MS by performing lymphocyte profiles from
samples of cerebrospinal fluid (CSF) and peripheral
blood.31,32 Natalizumab markedly decreased leukocyte
infiltration into the CNS. An analysis of T-cell subsets
revealed a decrease in CD8+ T cells of approximately 5fold in patients treated with natalizumab compared
with untreated patients, but nearly a 50-fold reduction
in CD4+ T cells. Natalizumab treatment was also associated with a decrease in penetration of B cells and
plasma cells into the CNS. At an additional follow-up
evaluation 6 months later—long after natalizumab
would be expected to have completely cleared from
circulation—patients who had received natalizumab
continued to exhibit significant depletion of CD4+ and
CD8+ T cells in the CNS (Figure 5).31 Thus, at least
some pharmacologic effect of natalizumab persists for
at least 6 months after the last dose.
The optimal duration of natalizumab therapy is
not well defined, and it is unclear whether the benefits
of treatment persist after treatment is discontinued. In
one phase II clinical trial, relapse rates were significantly lower for patients who were treated with natalizumab during 6 months of therapy, but this benefit of
treatment was almost entirely lost within 6 months of
treatment discontinuation.33 More recently, an analysis
of magnetic resonance imaging outcomes for 21
patients from the AFFIRM and SENTINEL clinical
trials demonstrated that the number of new or enlarging T2 lesions increased after natalizumab was discontinued, especially among patients with the shortest
duration of natalizumab treatment.34
MITOXANTRONE
Mitoxantrone is an antineoplastic agent that is also
used to treat patients with MS who do not respond
adequately to or cannot tolerate other treatments.35
Mitoxantrone kills rapidly dividing cells by interfering
with DNA replication, resulting in the depletion of
leukocytes.36 In clinical trials of patients with secondary progressive MS or very active RRMS, mitoxantrone has been shown to significantly reduce relapses
and slow the progression of disability.37,38 It is not
known to produce neuroprotective effects.
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Figure 5. Natalizumab Decreases the Number of
Lymphocytes in CSF
At study entry, the number of (A) WBCs, (B) CD4+ T cells, (C) CD8+ T
cells, (D) CD19+ B cells, and (E) CD138+ plasma cells in CSF was compared between patients with other neurologic diseases (OND), patients
with multiple sclerosis who were not treated with natalizumab (MS), and
patients with multiple sclerosis treated with natalizumab [(MS (Nat)]. A
mild CSF pleocytosis was observed in MS patients who had not received
natalizumab therapy (A), compared with the OND patient cohort (A).
Compared with MS patients not treated with natalizumab, treatment with
natalizumab significantly reduced the numbers of T lymphocytes, CD4+ T
cells, CD8+ T cells, CD19+ B cells, and CD138+ plasma cells in the CSF
(A–E). Six months after cessation of therapy, the CSF cellular phenotype
of 14 natalizumab-treated MS patients was reanalyzed [MS (Nat) 6 Mo].
The number of CSF WBCs (A), CD4+ T cells (B), CD8+ T cells (C), CD19+
B cells (D), and CD138+ plasma cells (E) remained significantly lower than
those in MS patients not treated with natalizumab. During the 6-month
interval, 1 patient had a clinical relapse. This patient (indicated by a triangle and an arrow) had the highest WBC, CD4+, and CD8+ T-cell counts of
the cohort (A–C).
CSF = cerebrospinal fluid; WBC = white blood cell.
Reprinted with permission from Stüve et al. Ann Neurol. 2006;59:743-747.31
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CONCLUSIONS
Currently approved disease-modifying therapies for
MS act primarily by suppressing CNS inflammation.
Lymphocyte activation and migration to the CNS are
carefully regulated by numerous signaling molecules
and their receptors, many of which are modulated by
IFNβ and GA. IFNβ and GA may produce secondary
neuroprotective effects by preventing the infiltration
of autoreactive T cells into the CNS. GA may also
modulate the activity of neurotrophic factors that are
important in neuronal survival. Natalizumab, which is
used for second-line therapy of MS, may produce
long-lasting suppression of leukocyte migration to the
CNS for several months after the drug has cleared
from circulation.
QUESTION AND ANSWER SESSION
Q: You showed that CD4 and CD8 cells were barely
detectable in CSF 6 months after natalizumab treatment. But in the rebound paper that you described,
relapses were seen after 3 months. There appears to be
a disconnect between cellular and clinical events.
Dr Stüve: We were also surprised when we looked
at the 6-month data to see that there was no change.
We subsequently looked at other cell types, which I
did not show. In the original paper we looked at effector cells—T cells and B cells. But we realized that
APCs may also be affected by blocking VLA-4.
Probably the most effective APCs in the brain are from
the peripheral circulation, such as dendritic cells and B
cells, which may be impaired in their ability to enter
the CNS. If these are excluded from the brain, reactivation of T cells cannot occur. This effect may mediate the prolonged effect of natalizumab.
We also examined radiographic and clinical outcomes 14 months after the cessation of therapy in our
patients, and we did not see any rebound phenomenon. I think one difference between our patients and
those from the rebound studies is that in those studies,
patients were not treated with other immunoregulatory drugs. Most of our patients were either already on
IFNβ or were started on IFNβ or GA immediately
after cessation of natalizumab therapy.
I think that we also have to consider the biologic
half-life. In the case of natalizumab, administration of
a single dose may block VLA-4, but it probably does
320
not affect the cellular expression of VLA-4. But
chronically blocking VLA-4 over a period of years may
cause the cells to reduce their expression of VLA-4, so
that when that blockade is removed, it may take awhile
for the cell to again establish VLA-4 expression.
Dr Greenberg: There is also evidence of a similar
effect with rituximab. We have had some patients
whose B cells have not come back 1 year after dosing
with rituximab. The rituximab itself has been gone for
months, but the cells have not recovered yet. I think
that the monoclonal antibodies may produce longterm effects that we do not really understand yet.
REFERENCES
1. Berger JR. Natalizumab and progressive multifocal leucoencephalopathy. Ann Rheum Dis. 2006;65(suppl 3):iii48-iii53.
2. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal
leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J
Med. 2005;353:369-374.
3. Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005;353:375-381.
4. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for
Crohn's disease. N Engl J Med. 2005;353:362-368.
5. Martinelli Boneschi F, Rovaris M, Capra R, Comi G.
Mitoxantrone for multiple sclerosis. Cochrane Database Syst
Rev. 2005;4:CD002127.
6. McFarland HF, Martin R. Multiple sclerosis: a complicated
picture of autoimmunity. Nat Immunol. 2007;8:913-919.
7. Frohman EM, Filippi M, Stüve O, et al. Characterizing the
mechanisms of progression in multiple sclerosis: evidence
and new hypotheses for future directions. Arch Neurol.
2005;62:1345-1356.
8. Chitnis T, Khoury SJ. Role of costimulatory pathways in the
pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. J Allergy Clin Immunol.
2003;112:837-849.
9. Hopkins LM, Schall M, Leykam JF, Gerlach JA.
Characterization of major histocompatibility complex-associated peptides from a small volume of whole blood. Anal
Biochem. 2004;328:155-161.
10. Appleman LJ, Boussiotis VA. T cell anergy and costimulation.
Immunol Rev. 2003;192:161-180.
11. Yong VW. Differential mechanisms of action of interferon-beta
and glatiramer acetate in MS. Neurology. 2002;59:802-808.
12. Wu DT, Woodman SE, Weiss JM, et al. Mechanisms of
leukocyte trafficking into the CNS. J Neurovirol.
2000;6(suppl 1):S82-S85.
13. Stanimirovic D, Satoh K. Inflammatory mediators of cerebral
endothelium: a role in ischemic brain inflammation. Brain
Pathol. 2000;10:113-126.
14. Leppert D, Waubant E, Bürk MR, et al. Interferon beta-1b
inhibits gelatinase secretion and in vitro migration of human
T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol. 1996;40:846-852.
Vol. 8, No. 9
■
September 2008
PROCEEDINGS
15. Stüve O, Dooley NP, Uhm JH, et al. Interferon beta-1b
decreases the migration of T lymphocytes in vitro: effects on
matrix metalloproteinase-9. Ann Neurol. 1996;40:853-863.
16. Stüve O, Chabot S, Jung SS, et al. Chemokine-enhanced
migration of human peripheral blood mononuclear cells is
antagonized by interferon beta-1b through an effect on matrix
metalloproteinase-9. J Neuroimmunol. 1997;80:38-46.
17. Zhao X, Nozell S, Ma Z, Benveniste EN. The interferon-stimulated gene factor 3 complex mediates the inhibitory effect
of interferon-beta on matrix metalloproteinase-9 expression.
FEBS J. 2007;274:6456-6468.
18. Rudick RA, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsingremitting MS. Multiple Sclerosis Collaborative Research
Group. Neurology. 1999;53:1698-1704.
19. Weber MS, Prod’homme T, Youssef S, et al. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med. 2007;13:935-943.
20. Karandikar NJ, Crawford MP, Yan X, et al. Glatiramer
acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J Clin Invest.
2002;109:641-649.
21. Stadelmann C, Kerschensteiner M, Misgeld T, et al. BDNF
and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells?
Brain. 2002;125:75-85.
22. McTigue DM, Horner PJ, Stokes BT, Gage FH. Neurotrophin-3
and brain-derived neurotrophic factor induce oligodendrocyte
proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci. 1998;18:5354-5365.
23. Neumann H, Misgeld T, Matsumuro K, Wekerle H.
Neurotrophins inhibit major histocompatibility class II
inducibility of microglia: involvement of the p75 neurotrophin
receptor. Proc Natl Acad Sci U S A. 1998;95:5779-5784.
24. Wei R, Jonakait GM. Neurotrophins and the anti-inflammatory agents interleukin-4 (IL-4), IL-10, IL-11 and transforming
growth factor-beta1 (TGF-beta1) down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat
microglia. J Neuroimmunol. 1999;95:8-18.
25. Flügel A, Matsumuro K, Neumann H, et al. Anti-inflammatory activity of nerve growth factor in experimental autoimmune
encephalomyelitis: inhibition of monocyte transendothelial
migration. Eur J Immunol. 2001;31:11-22.
Johns Hopkins Advanced Studies in Medicine
■
26. Aharoni R, Kayhan B, Eilam R, et al. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and
brain-derived neurotrophic factor in situ. Proc Natl Acad Sci
U S A. 2003;100:14157-14162.
27. Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer
acetate in primary progressive multiple sclerosis: results of a
multinational, multicenter, double-blind, placebo-controlled
trial. Ann Neurol. 2007;61:14-24.
28. Steinman L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov.
2005;4:510-518.
29. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing
multiple sclerosis. N Engl J Med. 2006;354:899-910.
30. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus
interferon beta-1a for relapsing multiple sclerosis. N Engl J Med.
2006;354:911-923.
31. Stüve O, Marra CM, Jerome KR, et al. Immune surveillance
in multiple sclerosis patients treated with natalizumab. Ann
Neurol. 2006;59:743-747.
32. Stüve O, Marra CM, Bar-Or A, et al. Altered CD4+/CD8+ Tcell ratios in cerebrospinal fluid of natalizumab-treated patients
with multiple sclerosis. Arch Neurol. 2006;63:1383-1387.
33. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial
of natalizumab for relapsing multiple sclerosis. N Engl J Med.
2003;348:15-23.
34. Vellinga MM, Castelijns JA, Barkhof F, et al. Postwithdrawal
rebound increase in t2 lesional activity in natalizumab-treated
ms patients. Neurology. 2008;70:1150-1151.
35. Fox EJ. Management of worsening multiple sclerosis with
mitoxantrone: a review. Clin Ther. 2006;28:461-474.
36. Fox EJ. Mechanism of action of mitoxantrone. Neurology.
2004;63(12 suppl 6):S15-S18.
37. Hartung HP, Gonsette R, König N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, doubleblind,
randomised,
multicentre
trial.
Lancet.
2002;360:2018-2025.
38. Edan G, Miller D, Clanet M, et al. Therapeutic effect of
mitoxantrone combined with methylprednisolone in multiple
sclerosis: a randomised multicentre study of active disease
using MRI and clinical criteria. J Neurol Neurosurg
Psychiatry. 1997;62:112-118.
321