the immunological basis of current and novel therapies of ... · most of the actual therapies are...
TRANSCRIPT
A�
rchivum Immunologiae et Therapiae Experimentalis, 1999, 4�
7,� 7–16P�
L ISSN 0004-069X
Review
The Immunological Basis of Current and Novel Therapiesof Multiple SclerosisB. Dubois and G. Opdenakker: Multiple Sclerosis Therapy
B�
ÉNÉDICTE DUBOIS and GH�
ISLAIN OPDENAKKER
Rega Institute for Medical Research, Laboratory of Molecular Immunology, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
A�
bstract. T�
he etiology and the pathogenesis of multiple sclerosis are not yet known. There might be a role� forg enetic susceptibility, for environmental factors and for inflammatory and immunologica l changes. Most of thea ctual therapies are based on the latter two phenomena. We review here corticosteroids, int
�erferon β a nd co-
p� olymer 1 as the current drugs of choice and compare schematically the immunological basis of the mechanisms
o� f action of these three substances with those of experimental or other treatments.
Key words: multiple sclerosis; therapy; immunological network; interferon β; copolymer 1; corticosteroids.
M�
ultiple sclerosis (MS) is one of the most frequenta nd best studied neurological diseases in many coun-t
�ries22. In spite of this, the etiology and the pathogenesis
o� f this acquired, inflammatory and demyelinating cen-t
�ral nervous system disease still remain an enigma.
Multifocal white matter lesions are the histologica nd radiologic (magnetic resonance imaging, MRI)hallmarks of this disease. The white matter foci arec� aused by perivascular lymphocytic infiltrations. CD4+
T�
cells and macrophages6�
4 predominate in the lesionsa nd these inflammatory cells invade the surroundingp� arenchyma and lead to demyelination. In the acutestage of the disease, inflammation with destruction oft
�he blood brain barrier plays a central role5
�8, in the
m� ore chronic stages there is also axonopathy.T
�he current hypothesis about the pathogenesis of
MS is that an external factor, such as a viral infection,induces an abnormal immune reaction in persons who
a re genetically predisposed. This immune reaction107
leads to chemical and enzyme-mediated damage (e.g.e� xtracellular proteolysis), or vice versa, and results ind
�emyelination and axonal loss7
�5.
Most of the actual therapies are focussed on thep� revention or suppression of inflammation and de-m� yelination (Fig. 1). More experimental strategies tryt
�o promote remyelination and to prevent axonal dam-
a ge. Nevertheless, progress with novel treatmentstrategies is slow and this may be attributed to differentfactors. The variability of the first clinical symptomsa nd the lack of a diagnostic test make an early diag-n� osis nearly impossible. Moreover, the course of thed
�isease is not predictable, with exacerbations and re-
m� issions, rapid or slow progression and all combina-t
�ions of these. We also lack valid and simple parameters
t�o follow the disease activity. The exacerbation fre-
q� uency, the expended disability status score (EDSS)
Abbreviations used: ACTH – adrenocorticotrope hormone, EAE – experimental autoimmune encephalomyelitis, EDSS – expandedd�isability status score, HLA – human leukocyte antigen, IFN – interferon, I.M. – intramuscul
�ar, I.V. – intravenous, MBP – myelin basic
p� rotein, MIU – million international units, MRI – magnetic resonance imaging, MS – multiple sclerosis, P.O. – per os, TNF – tumornecrosis factor.
a nd MRI analysis are used as surrogate markers and allt
�hese parameters have serious limitations. Exacerbation
frequency is not convincingly correlated with the finale� volution and decreases with the duration of disease.T
�he EDSS is not reliable in patients who experience
little neurologic impairment. In more severe cases it isl
�imited to the evaluation of the ambulation problems of
t�he patient. Moreover, in chronic progressive MS, this
scale is not sensitive. Finally, the MRI offers the possi-b
�ility to trace more disease activity than a clinical
e� valuation. This is useful to select patients in the activestate of the disease and also to evaluate the short terme� ffect of new therapies. Moreover, the hypointense le-sions on MRI correlate rather well with the EDSS101. It
Fig. 1. Multiple sclerosis treatment within the frame of inflammatory and immunological networks. The proven useful therapies appearo� n a black background. Effective therapies, but requiring further studies, are shown on a grey background, contested and experimentalt�herapies on a white one. Black arrows indicate the targets of the treatment, open arrows indicate the cellular interactions in aspecific ands� pecific immunity. The mechanisms of action are discussed in the text. APC – antigen presenting cell; MHC – major histocompatibilityc omplex; TCR – T cell receptor; IVIG – intravenous immunoglobulin
8 B. Dubois and G. Opdenakker: Multiple Sclerosis Therapy
i!s therefore understandable that clinical trials in MS do
not always lead to unequivocal conclusions6�
5, 7�
0. In ad-d
�ition, placebo treatment leads to improvement in one
t�hird of the MS-patients, to stabilization and to worsen-
ing in two other thirds89.W
"e here review the treatments with proven effi-
c� iency in large, randomized, placebo-controlled studiesa nd those with more equivocal results. Next, the ther-a pies with a suggested beneficial effect in smallstudies, that still need confirmation, are compared. Fi-nally, we discuss some experimental treatments inw# hich the positive effects are restricted to animal mo-d
�els. For all treatment strategies, the mechanism of ac-
t�ion within inflammatory or immunological networks is
i!llustrated (Fig. 1).
P$
roven Useful Treatments
Corticosteroids as treatment of an exacerbationThere exists a considerable literature on exacerba-
t�ions, treated by corticosteroids3
%, 6
�, 9
&, 10, 18, 26, 46, 6
�8, 6
�9, 9
&9,
100, 105, 110. The exact mechanism of action of corticos-t
�eroids in MS is not known but these substances reduce
t�he inflammation and the oedema in acute demyelinat-
i!ng lesions. Corticosteroids also downregulate the intra-
t�hecal IgG synthesis and the number of T cells in thec� erebrospinal fluid.
P'
reviously, intramuscular (I.M.) adrenocorticotropehormone (ACTH) was used to accelerate remissiona fter an exacerbation. The disadvantage of this therapyw# as the unpredictability of the evoked corticosteroidp� roduction. Nowadays, intravenous (I.V.) methylpred-n� isolone or peroral (P.O.) prednisolone are mostly used.Most frequently, one uses I.V. methylprednisolone (ina dose of 500–1000 mg/day during 3 to 5 days). Thismay be followed by using decreasing doses of P.O.p� rednisolone during a couple of days. Probably the ef-fect of a higher total dose is more pronounced, as isseen by the reduction of the number of exacerbationsd
�uring the year following treatment with a higher dose
o� f methylprednisolone5�
9. Another study3% did not docu-
ment a significant difference between 500 mg I.V. orP
'.O. but the number of included patients was too low
t�o exclude a difference.
A(
s was already mentioned, corticosteroids accel-e� rate the repair after an exacerbation. However, they donot prevent new attacks and do not influence the dis-e� ase progression.
T�
he Optic Neuritis Treatment Trial11, 12, 100 showedt
�hat a monosymptomatic optic neuritis progresses twot
�imes less to MS (evaluated after two years) if P.O.
p� rednisone is preceded by a high daily dose of methyl-
p� rednisolone during some days. This effect was mostmarked for those patients who, at the time of the opticneuritis, had an MRI that was suggestive for MS. Pred-n� isolone P.O. alone – in a dose of 1 mg/kg/day during14 days – yielded more episodes of optic neuritis than int
�he placebo group and resulted in a minimal reduction oft
�he MS incidence during the two years of the study.
The influence of corticosteroids in chronic pro-g ressive MS is not pronounced. The most remarkableo� bservation is a short term reduction of spasticity18, 6
�8,
w# hich is independent of inflammation.The monthly (or another interval) use of high dose
c� orticosteroid therapy is based on the knowledge thatc� hronic progression is associated with the appearanceo� f new acute lesions. However, the clinical efficiencyh
)as never been well controlled.
The use of corticosteroids in MS has little side-ef-fects6
�9. Most frequently, transient mental changes, gas-
t�ric ulcera and urinary or respiratory infections are ob-
served. The higher incidence of osteoporosis in MSp� atients is more correlated with the reduced mobilityt
�han with the short use of high doses corticosteroids.
The long term use of low doses, however, has to bea voided because of no beneficial effect on the numbero� f exacerbations and disease progression and becauseo� f the occurrence of side-effects.
Interferons as prevention of exacerbationsRecent studies have confirmed the partial effect of
interferon β (IFN-β)* on reducing exacerbations.
T�
he interferons that are used in the treatment of MSa re produced by genetic engineering. Besides theirk
+nown antiviral activity, interferons4, 6
�, 7
�, 9
&, 19, 3
%0, 3
%1, 3
%3,
3%5, 4
,6, 4
,8, 4
,9, 6
�2, 6
�7, 7
�6, 7
�7, 80, 83, 85, 9
&7, 9
&9, 105, 110, 113 possess
o� ther biological effects, e.g. inhibition of cell growth,immunomodulation, enhancement of the functions ofm� acrophages, natural killer and killer cells and alsoneutrophils. They also induce cell differentiation andm� ay possess adjuvant antitumoral activity.
IFN-γ-
In contrast with the effect of INF-γ - o� n experimentala utoimmune encephalomyelitis (EAE), in man IFN-γ- 7
�6,
7�7 increases the number of exacerbations. In the future,
n� ovel molecules with an inhibitory effect on IFN-γ - p� ro-d
�uction (e.g. IL-10) or a blocking effect on IFN-γ- (re-
c� eptors) may be used in the treatment of MS.
I.FN-α-2A (Roferon-A®
/)
*
The first studies with IFN-α w# ere rather disappoint-i
!ng. However, the use of higher doses3
%3, 46 (9 million
international units (MIU) every 2 days during 6 months)
20
– Archivum Immunologiae... 1/99
B. Dubois and G. Opdenakker: Multiple Sclerosis Therapy 91
r2 esulted in a beneficial clinical and radiological effectin 20 relapsing-remitting MS patients. After the treat-ment, the original disease process was restored3
%3.
L3
arger studies on this interferon are needed.
IFN-βI
.n a small study6
�7 of 16 patients an increase of the
number of exacerbations was seen with the intrathecala dministration of natural IFN-β during 6 months whilet
�he disability was not influenced. The purpose of the
intrathecal way is mainly local delivery in the centralnervous system.
I.FN-β i
!s a cytokine of 166 amino acids. There exist
t�wo forms49 of recombinant IFN-β, IFN-β-1a (Avo-
n� ex®/, Rebif®
/)
* is expressed in a mammalian cell line
a nd is glycosylated. IFN-β-1b (Betaseron®/)
* is ex-
p� ressed in bacteria, is not glycosylated, misses the ami-noterminal methionine and has a serine substitution forc� ysteine on position 17.
In relapsing-remitting MS the subcutaneous admin-i
!stration of IFN-β-1b leads to a reduction of 1/3 in the
e� xacerbations and 50% in severe exacerbations. Thenumber of exacerbation-free patients increases duringt
�he first 3 years. The total lesion load on MRI and then� umber of new lesions is smaller in IFN-β-treated pa-t
�ients6
�3, 9
&7. All these effects persisted during a 5-year
f ollow-up3
%0, except the reduction in the number of
e� xacerbation-free patients. The latter did not showa significant difference anymore after two years. Theree� xists also a clear dose effect: 8 MIU every two daysi
!s more effective than 1.6 MIU. In the latter patient
g roup there was no marked effect of IFN-β-1b on dis-e� ase progression.
A subcutaneous dose of 3 resp. 9 MIU IFN-β-1a83
t�hree times a week during 6 months, leads to a reduc-t
�ion of the number of gadolinium enhancing lesions
(gadolinium enhancement means a disruption of theb
�lood-brain barrier) with 40 resp. 64% and of the
n� umber of exacerbations with 1/3. Six MIU oncea week intramuscularly4
,8 has a similar effect and also
d�elays disease progression. However, the patients in-
c� luded in this study were part of a functionally betterg roup and there was no influence on the total lesionb
�urden on MRI. IFN-β-1a, subcutaneously and 3 times
a week, at dosages of 6 MIU and 12 MIU has signi-ficant effects on the 3 major categories of outcomemeasures in MS: progression in disability, exacerba-t
�ions, and MRI disease burden and activity23. Both IFN-
β-1a and -1b80 are currently being tested in chronicp� rogressive MS. The preliminary results show encour-a ging effects.
The most important side-effects of IFN-β a re red-
n� ess and pain at the injection sites, flu-like symptoms,rarely lymphopenia and liver dysfunction. Mostly theseside-effects are transient. More important is the devel-o� pment of neutralizing antibodies in approximately 1/3o� f the treated patients. Possibly this goes along with thed
�isappearance of the beneficial effect3
%2, 7
�8.
A(
dditional studies are needed to determine the mostb
�eneficial administration way, the optimal dose and the
long term effect on exacerbations and progression.
Copolymer 1 as prevention of exacerbationsThis synthetic mixture of oligopeptides6
�, 8, 9
&, 13, 14, 46,
4,
7, 5�0, 5
�1, 82, 9
&5, 9
&9, 115 consists of 4 amino acids (L-lysine,
L-tyrosine, L-alanine and L-glutamic acid). It was syn-t
�hetized as an analogue of myelin basic protein to in-
d�uce EAE in animals. However, it was found to protect
t�he animals from developing EAE, presumably by bind-
ing to antigen presenting cells and consequently block-i
!ng the activation of T cells.
C4
opolymer 1 reduces the number of exacerbationsw# ith 29–32% in 2 years if one starts the therapy earlyi
!n the disease process5
�1. The number of exacerbation-
-free patients is increased. Although a similar numbero� f patients deteriorate, the progression of disability inr2 elapsing remitting patients is less pronounced with co-p� olymer 1 therapy5
�1. The influence on the MRI lesions
i!s not as convincing as with IFN-β. However, this
e� xamination was limited to a small number of pa-t
�ients2
00. A new study to evaluate the effect on MRI has
b�een started. In chronic progressive MS so far, there is
l�ittle effect on evolution13, 15.
C4
opolymer 1 has to be injected every day subcuta-n� eously in a dose of 20 mg/day. Besides some localreactions on the injection sites there are little side-ef-fects. Some patients experience flushing, dyspnoe andp� alpitations. The latter last for 30 s to 30 min butu5 sually occur just once in a patient. The elicited anti-b
�odies against copolymer 1 do not have clinical conse-
q� uences5�
2.
Contested Therapies
P6
lasma exchangeStudies in which plasma exchange was combined
w# ith I.M., ACTH or I.V. methylprednisolone and cy-c� lophosphamide showed that remission after an exa-c� erbation was more rapid and longer lasting if plasmae� xchange was added to therapy9
&, 7
�2, 9
&9, 105, 109, 110. How-
e� ver, in this setting it is difficult to evaluate the effecto� f plasma exchange alone and moreover the resultsw# ere dependent on the used statistical method. TheC
4anadian Cooperative Trial showed no significant ef-
10 B. Dubois and G. Opdenakker: Multiple Sclerosis Therapy
f ect of plasma exchange on disability in chronic pro-
g ressive MS7�
2.
A7
zathioprineThe purine antagonist azathioprine9
&, 4
,6, 105, 110 e� xerts
its effect on rapidly dividing cells such as lymphocytes.A
( meta-analysis116 o� f some controlled studies16, 3
%4, 5
�4, 7
�9
d�emonstrated a small effect of azathioprine. This fa-
v8 ourable effect was primarily a reduction in relapser2 ate. After 2 to 3 years there is also a minimal benefi-c� ial effect on disability. The question remains whethert
�his counterbalances the side-effects.
CyclophosphamideT
�his alkylating drug9
&, 41, 46, 105, 110, 112 influences
e� ssentially proliferating cells. T cells produce less IL-2a nd this has again a negative feedback on their pro-liferation. The effect of cyclophosphamide has beene� valuated in several studies4
,1, 4
,4, 4
,5, 6
�0, 7
�7 b
�ut remains
q� uestionable. The drug can cause serious adversee� ffects44.9
CyclosporineC
4yclosporine is a potent immunosuppressant by in-
h)ibition of T helper cells (via inhibition of cytokine
synthesis) 9, 5�4, 87, 110. In a large American study87 cy-
c� losporine postponed wheelchair dependency andu5 pper extremity impairment but this had no influenceo� n long term progression nor on MRI.
Total body irradiationThe toxic effect of total body irradiation on DNA
r2 eplication is responsible for its potent immunosup-p� ressive effect9
&, 17, 2
04, 2
05, 9
&9, 110, 114. In combination with
low doses prednisone204, total body irradiation resulted
in delayed disease progression. Despite of the absenceo� f significant clinical effects of total body irradiationa lone17, 110, there was a reduced accumulation of lesionso� n MRI110. This does not counterbalance the seriousrisks of this therapy.
E:
ffective Therapies Requiring Further Study
I;ntravenous immunoglobulins
The exact action mechanism of immunoglobulins isnot yet known. Possible explanations are interactionsw# ith T cells, downregulation of cytokine production(TNF-α)
*, neutralization of cytokines, modulation of
Fc-receptors on macrophages and of anti-idiotypic net-w# orks1, 2, 9
&, 46, 5
�6, 7
�3, 9
&2, 9
&9, 103. Furthermore, immuno-
g lobulins might serve as receptor for activated comple-
m� ent. This prevents the adhesion of complement to oli-g odendrocytes and myelin proteins. Finally, they area ble to promote remyelination.
I.n relapsing-remitting MS, the relapse rate and the
number of gadolinium-enhancing lesions is reduced20
, 9&
3.The neurological disability is influenced in a beneficialw# ay3
%6.
MitoxanthroneT
�his anthracycline inhibits the relaxation of super-
c� oiled DNA by electrostatic cross-binding, leading toa block of the cell cycle. It is an immunomodulator thatr2 educes the number of T cells, suppresses humoral im-munity and inhibits T cell function9
&, 28, 46, 9
&9, 105. It has
a therapeutic effect in very active MS both on relapser2 ate and MRI40, 5
�3 and is currently being investigated in
secondary progressive MS. Its use is limited by its car-d
�iotoxicity.
Oral toleranceW
"hen intact peptides pass through the gastrointesti-
n� al mucosa a functional T cell tolerance arises againstt
�hese proteins6
�, 9
&, 9
&4, 9
&9, 106, 111. Antigen specific regula-
t�ory cells start looking for a protein that is similar to
t�he perorally ingested one and then exhibit a suppressor
e� ffect by secreting antiinflammatory cytokines e.g.T
�GF-β. There is also a decrease of the number of myelin
b�asic protein (MBP) reactive T cells.
Thirty relapsing remitting MS patients were admin-istrated 300 mg bovine myelin perorally110. There wasa reduction of 50% in the exacerbations in patients whow# ere not HLA-DR2-positive. Statistic significance wasn� ot reached and, moreover, the HLA-DR2-genotype isw# ell represented in MS. A recent trial in the UnitedStates showed no influence on the exacerbation fre-q� uency nor the disease progression.
CladribineT
�he purine-analogue 2-chloro-deoxyadenosine mi-
micks the accumulation of deoxynucleotides in adeno-sine-deaminase deficiency6
�, 9
&, 4
,6, 81, 9
&0, 9
&9, 108. It is fre-
q� uently used in the treatment of hairy cell leukemia andl
�ymphomas. The consequent effect on DNA synthesis
a nd cellular metabolism influences resting as well asd
�ividing cells.
A small trial9&0 in chronic progressive MS de-
monstrated clinical stability in patients treated withc� ladribine, whereas the others deteriorated signifi-c� antly. Unfortunately, these clinical findings could notb
�e reproduced in a larger placebo-controlled trial
a lthough MRI data from this trial show a favourablee� ffect.
B. Dubois and G. Opdenakker: Multiple Sclerosis Therapy 11
L<
inomideLinomide5
�, 5
�5, 9
&9 is a synthetic immunomodulator with
e� ffects on antigen presentation and cytokine secretion.L
3inomide showed encouraging effects in relapsing
remitting as well as in chronic progressive MS. Unfor-t
�unately, a larger trial had to be interrupted because ofsevere side-effects, particularly an increased risk ofmyocardial infarction.
M=
ethotrexateThis drug stimulates suppressor activity, production
o� f inhibitory cytokines and downregulation of pro-inflam-m� atory cytokines and proteolytic enzymes2
07, 4
,2, 4
,3, 4
,6.
In chronic progressive MS there is less progressioni
!n upper extremity impairment, but this is not reflected
i!n a favourable change in EDSS. The changes in lesionload on MRI are favourable.
In relapsing remitting MS methotrexate induceda decrease of the number of exacerbations but the side--effects of cytostatic drugs are not negligible.
Experimental Treatments
T cell vaccinationSubcutaneous vaccination of MS patients with ir-
radiated autologous MBP reactive T cells leads to a de-c� rease of MBP reactive cells in the circulation6
�, 9
&, 46, 6
�6,
102, 117, 118. In 5 out of 8 patients this correlated clini-c� ally with less exacerbations and radiologically witha smaller increase in lesion load on MRI.
A(
disadvantage of this therapy is the reappearancea fter 1 year of specific T cells against other epitopes(of MBP). These cells are then resistant to the vaccinea nd exacerbations reappear. Moreover, this strategy as-sumes the crucial role of MBP as responsible antigenin the immunopathogenesis of MS.
AntibodiesM
�onoclonal anti-CD4Demyelination may result from an inflammatory
p� rocess mediated by CD4+> T cells. Blocking of thisa ctivity was attempted by monoclonal antibodies6
�, 9
&, 46,
6�
1, 86, 9&
6, 9&9, 105, 110. Large studies still need to be done.
M�
onoclonal anti-TNF-αTNF-α e� xerts its disease-promoting influence by
stimulation of several cytokines and metabolites of ara-c� hidonic acid and by induction or enhancement of thee� xpression of adhesion molecules on endothelial cells6
�, 4
,6.
In a recent study104 two rapidly progressing MS pa-t
�ients were treated with such an inhibitory monoclonal
a ntibody. There was an increase of gadolinium enhanc-
i!ng lesions on the MRI and also of cytosis and IgG
index in the cerebrospinal fluid. These signs of immunea ctivation were not reflected in a clinical deteriorationb
�ut the study was interrupted.
C4
ampath-1HT
�his monoclonal and humanized antibody recog-
nizes the CDw-52-antigen on lymphocytes and mono-c� ytes, resulting in a lymphocytic depletion21, 46. In-t
�ravenous administration in 7 patients resulted ina reduction of disease activity on MRI.
A(
nti-α4?
β1 integrinAntibodies against this adhesion molecule impair
t�he adhesion of leukocytes to endothelial cells. This
p� revents inflammatory cells to infiltrate perivascular-ly5
�7. In the guinea pig this treatment resulted in a re-
d�uction of clinical and pathological hallmarks of EAE.
F@
urther studies are warranted.
RA
olipramT
�he antidepressant (±
B)
* -4-(3-cyclopentyloxy-4-meth-
o� xyphenyl)-2-pyrolidon increases the intracellularc� AMP by inhibition of the type IV phosphodiesterase3
%7,
4,
6, 9&
1. This leads to an inhibition of the transcription oft
�he TNF-α g ene. There is also a decrease of lym-
p� hotoxin-α a nd INF-γ - b�ioactivity. Rolipram protects
a nimals against EAE. This therapy has not yet beena pplied in humans.
M=
ofetilMofetil46 inhibits the de novo pathway of the
p� urine synthesis. There is a suppression of T and B cellfunction with a consequent inhibition of antibody pro-d
�uction.
FC
uture Perspectives
BD
ased on the role of cytokines and proteases in auto-immune diseases7
�5 and in the control of inflammatory
c� ell infiltrations7�
4, it has been suggested to use thisknowledge in the treatment of MS.
Suppresion of inflammatory activity by using anti-inflammatory cytokines (IL-4, IL-10, TGF-β)
* and in-
h)ibition of pro-inflammatory cytokines (IL-1, IL-2,
TNF-α, TNF-β, IFN-γ- , IL-12) will remain an importantg oal in future research84, 88.
Similarly, inhibition of metalloproteinases mayb
�ecome a novel target. Unspecific inhibitors of gelati-
nase B, such as hydroxamate3%
8, D-penicillamine and te-t
�racyclines3
%9, 7
�1, have shown antiinflammatory proper-
t�ies in animal models. The only clinical study2
09 in MS
12 B. Dubois and G. Opdenakker: Multiple Sclerosis Therapy
p� atients with a combination of D-penicillamine andmetacycline showed, however, toxicity. There is an ur-g ent need for more selective and efficaceous metallo-p� roteinase inhibitors. Further improvements are alsoe� xpected by optimized timing and dosing of the curren-t
�ly available agents and by combination of partially
e� ffective drugs. Finally, promotion of remyelination byg rowth factors and by transplantation of myelin produc-ing oligodendrocytes21 is under investigation as an al-t
�ernative route to treat demyelinating diseases.
In conclusion, it is clear that the therapy of MSn� eeds to be improved, although much progress has beenmade during the last years. Mainly IFN-β appears cur-r2 ently to give hope for many patients and their physi-c� ians. However, it must be stressed that this therapy isfar from ideal, with side-effects and an influence ond
�isease progression that still needs to be confirmed.
I.ndeed, for MS patients it is certainly important to have
less exacerbations, but their global functional state withd
�isease progression must not be overlooked.
T�
here exists an urgent need for less toxic and moree� ffective (immune) therapies that can be administerede� arly in the diseae progress and without limitation int
�ime. The complexity and interconnection of immuno-
logical processes, the heterogeneity of contributoryg enetic factors and the interactions with partially un-known exogenous risks make rapid scientific advancesd
�ifficult in the treatment of this mutilating disease.
AE
cknowledgment. TF
his work is supported by the National Fundfor Scientific Research (FWO-Vlaanderen), the Multiple SclerosisResearch Foundation (WOMS) and the General Savings and Retire-ment Fund (ASLK). The authors thank Mr. R. Conings for makingt�he illustration. Dr. B. Dubois is a research assistant of the FWO-VG
laanderen.
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Received in June 1998Accepted in July 1998
N}
ote added in proof. Meanwhile it has been established that treat-ment with interferon β
d-1b delays sustained neurological deteriora-
tion in patients with secondary progressive MS (Lancet 1998, 352,1491–1497).
16 B. Dubois and G. Opdenakker: Multiple Sclerosis Therapy