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Immunotherapy of multiple sclerosis.

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NEUROLOGICAL PROGRESS
Immunotherapy of Multiple Sclerosis
Howard L. Weiner, MD, and David A. Hafler, MD
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Based on the assumption that multiple sclerosis is an autoimmune disease, a number of clinical trials designed to
suppress the immune system or to restore immune balance in multiple sclerosis have been attempted. Depending on
the disease category, the clinical goals of immunotherapy differ. Therapeutic goals include improving recovery from
acute attacks, preventing or decreasing the number of relapses, and halting the disease in its progressive stage. The
ultimate goal of multiple sclerosis therapy is the early treatment of patients in an attempt to halt the onset of
progression. Specific strategies of immunotherapy include generation of a suppressor influence, removal of helper/
inducer cells, manipulation of activated T cells, manipulation of class I1 major histocompatibility complex-bearing
cells, alteration of lymphocyte traffic, extracorporeal removal of serum factors or cells, and manipulation of antigenspecific cells. Present treatment modalities are beginning to show some efficacy of nonspecific immunosuppression,but
these treatments are limited by their toxicities. As the immunotherapy of multiple sclerosis moves to the next stage in
the coming years, patients at an earlier stage of their disease will have to be treated, nontoxic forms of therapy
developed, clinical trials lengthened, and a laboratory monitor of the disease developed. Given the positive effects of
immunotherapy seen thus far in the disease, it is possible that appropriate immunotherapeutic intervention may
provide effective treatment for the disease in the future.
Weiner HL, H d e r DA. Immunotherapy of multiple sclerosis. Ann Neurol 1988;23:211-222
Although the cause and pathogenesis of multiple sclerosis (MS)are unknown, the most commonly held
view is that it is an autoimmune disease related in some
way to a viral infection {70, 110, 1171. Pathologically,
there is an inflammatory response in the central nervous system (CNS) consisting predominantly of activated T lymphocytes and macrophages 1953 accompanied by a local immune reaction with the secretion
of interleukins, which results in the synthesis of oligoclonal immunoglobulin ( 1 6 ) by plasma cells 1397. Immune abnormalities have been described in the peripheral blood of MS patients, including loss of suppressor
function 131, the presence of activated T cells E42, 49,
501, and alterations in T-cell populations E6, 58, 64,
93, 96, 1181. It has been hypothesized that the loss
of suppression or “imbalance” in the immune system
may play a crucial role in the disease pathophysiology Ello}. The most widely studied animal model of
MS,experimental allergic encephalomyelitis (EM), is
known to be a T cell-mediated autoimmune disease in
which there is inflammation and, in chronic models,
demyelination {4, 9 11. Immune suppressor mechanisms play an important role in modulating the disease
process: EAE can be treated with a variety of immunoregulatory agents, and the application of immunotherapeutic strategies to MS has often stemmed from their
success in EAE, even though EAE may or may not be
From the Multiple Sclerosis Unit of the Center for Neurologic Diseases, Division of Neurology, Department of Medicine, Brigham
and Women’s Hospital and Hamud
Boston, MA
02115.
a true model for the disease 12, 15, 16, 18, 25, 55, 61,
92, 102, 104, 105, 111).
Given the potentially debikitating course of MS,
physicians have attempted a variety of treatments to
ameliorate or prevent the nervous system dysfunction
that may occur. Many of these treatments are designed
to alter or suppress the immune response. In the past
five years, there have been increasing numbers of new
and planned trials of immunotherapy, some of which
are beginning to claim efficacy in the disease 119, 54,
84, 1071. These trials not only hold promise for developing an effective treatment for MS, but are raising
important questions concerning pathogenic mechanisms in the disease. The present overview will (1)
analyze the different clinical categories of the disease,
the different goals of immunotherapy depending on
the category being treated, and the unique problems
associated with treatment of each of the categories; (2)
describe current and planned strategies of immunotherapy; and (3) review current treatment programs in
terms of how they specifically or nonspecifically affect
the immune system and what information they provide
Concerning the pathogenesis of MS. This review assumes, as do the investigators treating patients with
immunomodulatory agents, that MS is an immunemediated disease, and focuses on cellular immune
mechanisms in the disease and attempts to modify them.
Received Oct 21, 1986, and in revised form Oct 12, 1987. Accepted
for publication Oct 23, 1987.
Address correspondence to Dr Weiner, Center for Neurologic Diseases, Brigham and Women’s Hospital, Boston, MA 02115.
Copyright 0 1988 by the American Neurological Association 211
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Fig 1. Clinical course and treatment of multiple rclerosis. The
horizontal axis represents time, and the vertical axis level of disability. The vertical dotted line represents the onset of the progressive disease phase. The progressive phase may evolve after a
number of relapses or, in a subcategory of patients, may be the
clinical course of the diseasefrom the onset.
Clinical Course and Treatment
of Multiple Sclerosis
The clinical course and treatment of MS are outlined
in Figure 1. Although the clinical course of MS is often
unpredictable, studies of large numbers of patients
suggest that clear disease patterns emerge over time
and that these patterns are important in designing therapy [29, 671. There are four clinical categories of MS,
although at times they overlap. Different immune
mechanisms may be operating during various stages of
the disease, and different strategies of immunotherapy
have been attempted, depending on the clinical stage.
Treatment of Acute Attacks
It would seem logical that some form of therapy
should be administered at the time of an acute attack,
that is, when the disease is active. The goal of such
therapy would be to shorten the attack and/or improve
the degree of recovery from the attack. Two difficulties with measuring the effect of treatment on an acute
attack are that many patients recover from an attack
with no treatment at all and an attack may represent
not a new immunological event, but temporary worsening of an old symptom related to changes in physiology of conduction along a demyelinated axon, such as
occurs with elevated body temperature. Nonetheless,
careful neurological examination and history can identify most attacks. In addition, magnetic resonance imaging (MRI) may help define when new lesions occur
[40, 651, and pleocytosis in the cerebrospinal fluid
(CSF) may also indicate the presence of active inflammation, although acute attacks may occur without CSF
pleocytosis. The most commonly used treatment for
acute attacks is some form of corticosteroid preparation. There have been few clinical trials measuring the
effect of treatment on acute attacks. The major study is
a double-blind trial of adrenocorticotropic hormone
212
Annals of Neurology Vol 23 No 3 March 1988
(ACTH) versus placebo carried out almost twenty
years ago @9}. Although ACTH was found to shorten
the time to recovery, it did not affect the level of
recovery. One fault of the study is that the follow-up
period was only six weeks. A double-blind study of
plasma exchange in conjunction with ACTH and oral
cyclophosphamide for the treatment of acute attacks is
currently in progress I1 141.
It is postulated that an acute attack represents the
movement of cells into the brain, leading to an inflammatory response with subsequent edema and demyelination. If this is true, a major immunological question
is, why does the attack stop? There is suggestive evidence that acute attacks are associated with changes in
peripheral blood T-cell populations and function [b,
58, 1181. For example, in one study, acute attacks
were associated with a decrease in T-cell suppressor
function, whereas during recovery, increased functional immune suppression was found [58}. Because
the brain and spinal cord do not normally have the
large number of lymphocytes and macrophages present in the CNS of MS patients, these cells must initially migrate from the blood into the brain and spinal
cord. Some of the more important questions regarding
immunotherapy of MS are the following. In which, if
any, compartment(s) outside the CNS does disease activity occur? Is this activity related to the stage of the
disease? To what extent is inflammation in the CNS
dependent on or independent of the peripheral immune compartment? The answers to these questions
are crucial in devising effective immunotherapy. Furthermore, a monitor of disease activity within both the
CNS and the peripheral immune compartment may
ultimately be needed to monitor response to therapy.
Treatments Designed to Prevent or Decrease
the Number of Relapses
Another goal of therapy is to prevent or decrease the
number of relapses. Such trials generally involve continuous treatment on a daily basis, with the presumption that whatever initiates a relapse can be prevented.
However, certain difficulties exist in trials that use re-
lapses as an endpoint: (1) the natural history of MS at
this stage of the disease is variable, and with time, the
incidence of relapses usually decreases and the disease
may enter the progressive phase (29, 67); (2) the clinical definition of a relapse can sometimes be difficult;
and (3) all relapses are not clinically the same, with
some causing greater disability than others. Furthermore, repeated MRI imaging of the CNS in relapsingremitting MS indicates that new lesions can appear
without clinical sequelae, suggesting that whether a
clinical attack occurs depends on the location of the
lesion in the CNS. A number of drugs have been tried
and are currently being studied in relapsing MS. The
chronic toxicities of globally immunosuppressive
agents such as azathioprine and cyclophosphamide prevent the long-term prophylactic use of these agents for
early, mild cases of relapsing-remitting MS.
Treatments Designed to Prevent Onset
of the Progressive Phase
A number of clinical studies have demonstrated that
the most debilitating and clinically predictable form of
the disease is the progressive stage {29, 831. Although
some patients have progressive MS from the onset, the
majority enter the progressive phase after a number of
relapses. A common pattern is less and less recovery
from successive relapses. In addition, increasing frequency of relapses and short intervals between relapses often herald progression (291.
What happens immunologically when the disease
moves from the relapsing to the progressive stage?
One possibility is that a self-perpetuating immune
reaction is established within the CNS. If this were
true, it would have important implications for therapy,
as it would suggest that once the progressive phase
began, treatment would have to be directed at the
CNS compartment. However, results from clinical
trials and immunological studies suggest that the peripheral immune system plays an important role in the
progressive phase of the disease. Specifically, treatment of progressive MS patients with total lymphoid
irradiation, a treatment directed only at peripheral immune organs, which spares the neuroaxis, has been
found in a double-blind trial to affect the course of the
disease favorably 1301. In addition, as mentioned previously, a large number of immunological abnormalities are found in the peripheral blood of MS patients, including the presence of activated T cells and
the loss of both phenotypic and functional measures of
suppression. These abnormalities are most consistently
found in patients with progressive disease. Although
these immunological abnormalities could be secondary
to the disease process, they add to the weight of evidence that the peripheral immune compartment plays
an essential role in chronic progressive MS.
There have been no studies designed with the express purpose of administering treatment to patients in
the relapsing-remitting stage of the disease to prevent
the onset of the progressive phase. Ultimately, it
seems logical that this must be one of the major goals
of MS immunotherapy. The difficulties in carrying out
such a trial are twofold: (1) finding an agent that can be
administered over the length of time needed to perform such a study which does not have long-term foxicity, and (2) embarking on a large controlled trial in
which a minimum of five years would be needed to
reach the defined outcome.
Treatment Designed to Halt the Progressive Phase
Although most patients enter the progressive phase
following a number of relapses, there is a subcategory
of patients whose disease is progressive from the onset
[29, 671. It is not known whether these patients represent a subcategory of disease related to different immunological or other mechanisms or whether they
might, in fact, have had subclinical attacks. The following immune mechanisms could be operating: (1) the
relapsing-remitting form could involve an autoimmune
response against one white-matter antigen, whereas in
the progressive phase, a different autoantigen could
become the target; (2) with time, a localized immune
response in the CNS could be created that might not
be antigen specific, that is, it could involve nonspecific
activation of immunocompetent cells in the CNS by
interleukins; ( 3 ) with time, a more consistent defect in
immunoregulation could occur in the peripheral immune system; and (4) it is theoretically possible that
changes within the nervous system itself could affect
immune regulation.
Because of the disabling nature of the progressive
disease, several trials have been undertaken and are
currently in progress in patients with progressive MS.
Although some benefit has been reported with certain
agents, the long-term effects of treatment and the potential toxicities associated with these agents should
engender caution in their use. Two treatment regimens
that have been reported to be of benefit, cyclophosphamide [22, 43, 52, 56, 1191 and total lymphoid irradiation 1301, illustrate a feature important in designing treatment programs for progressive MS. In both
trials, although positive results have been reported,
reprogression began within one to three years following initial treatments. These results suggest that once
the patient enters the progressive phase, retreatment
or some form of maintenance must be added to original induction regimens to maintain clinical effects.
These treatments demonstrate that immunosuppression can indeed affect the course of progressive MS
and that patients’ conditions are not made worse. This
helps support the role of immunopathogenic mechanisms in the disease and provides a rationale for attempting to find an immunospecific, relatively nontoxic form of therapy that can be administered over
longer periods of time.
Neurological Progress: Weiner and Hafler: Immunotherapy of Multiple Sclerosis
2 13
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F i g 2. The immune response is initiated in the peripheral immune compartment when antigen is processed and presented to an
inducer cell /ga macrophage or antigen-presenting cell. The inducer cell becomes activated and releases a number of soluble factors, including interleukins and interferons, which act on both B
cells and T cells t o augment the immune response. T suppressor
cells act to hmpen the immune response. Activated T cells trafFc
into the central newous system (CNS),where t h g again release
factors, presumably after having antigen presented t o them. In
thij regurd, ustrocytes are capable of presenting antigem to T
cellr. Other cellular elements also enter the CNS (macrophages,B
cellr), where the potentialfar a local immune response occurs. B
cells are known to produce immunoglobulin locally within the
CNS,and mamphages function within the CNS to phagocytose
myelin, in addition to their antigen-Presentationproperties.
Treatment of Stable Mult*le SclerosiJ
The term stable MS raises the question of the ability to
define when the disease is indeed immunologically
quiescent, an ability that we do not currently have. In
many instances, it is probable that subclinical disease
activity occurs, especially as demonstrated on MRI
studies. Patients with stable MS would be candidates
for treatment with immunotherapy that could affect
the disease process prophylactically, perhaps by adding
a specific or nonspecific suppressive influence. More
important, a central goal of devising immunotherapy
for MS is the ability to identify immunological stability,
which first requires an understanding of immune alterations in the disease.
The Normal Immune Response
and Strategies of Immunotherapy
The normal immune response [reviewed in 851 consists of a cascade of events, and strategies of immu214 Annals of Neurology Vol 23
No 3 March 1988
notherapy are designed to intervene at a number of
places in the circuit (Fig 2). The immune response is
generated when an antigen is presented to a T cell, or
thymus-derived lymphocyte, by an antigen-presenting
cell, or macrophage. T cells can only recognize antigen
when the antigen is presented to the T cell in the
context of particular self proteins that are part of the
major histocompatibility complex (MHC) on antigenpresenting cells. T inducer cells (T4+ or CD4+ T
cells) recognize antigen only in the context of class I1
MHC molecules, whereas other T cells (T8+ or
CD8+ T cells) are class I restricted. Substances that
augment class 11 MHC expression (such as gamma
interferon) augment the immune response. T cells
mediate cell-mediated immune responses such as graft
rejection and delayed-type hypersensitivity reactions
(e.g., sensitivity to poison ivy, tuberculin reactions). In
addition, they are the major immunoregulatory cells of
the immune system. T inducer (CD4 + ) cells induce B
lymphocytes to produce antibody, as well as inducing
other T cells to perform their function. T suppressor
cells (CD8 + ) down-regulate the immune system by
suppressing other T cells, although their mechanism(s)
of action is unknown. It has recently been shown that
the T inducer (CD4+) cells can be separated into
inducers of help (CD4+4B4+) and inducers of
suppression (CD4 + 2H4 + >. The suppressor-inducer
(CD4 + 2H4 + ) T cell then induces the suppressor
CD8 + cell to carry out suppressor function, and it has
been reported that the suppressor-inducer cell is reduced in MS 124, 77, 1003. T cytotoxic cells have the
ability to lyse other cells. In addition to cellular ele-
ments, there are soluble factors that play a role in the
generation of the immune response. These include interleukins, such as IL-1 and IL-2, interferons, and B
cell-stimulating factors, which are important in activating cells of the immune system.
In MS, it is assumed that an activated inducer or
effector T cell migrates into the nervous system to
initiate the disease process. Why this occurs is unknown. Nonetheless, experimental data suggest that
for a T cell to migrate into the nervous system it must
be activated 1121). The capacity for a localized immune response exists within the nervous system compartment of MS patients, where there are T cells
infiltrating lesions and macrophages mediating demyelination, and astrocytes may express class I1 MHC,
thus having the capacity to function as antigenpresenting cells l371. In addition, it has been known
for many years that there is local production of immunoglobulin within the CNS by B cells (39). Given
this cascade of immune reactivity, the following strategies of immunotherapy have been attempted in MS
patients or are being planned.
Nonspecific Immunosuppression
Most of the immunosuppressive agents that have been
tried in MS patients nonspecificdy suppress the immune response 133, 71, 72, 84, 971. These include
drugs such as cyclophosphamide, azathioprine, antilymphocyte globulin, and treatments such as plasma
exchange, lymphocytapheresis, thoracic duct drainage,
and total lymphoid irradiation. Although these drugs
and treatments may affect one limb of the immune
response over another, they remain relatively nonspecific in their actions.
Generation of a Suppressor InfEience
Many investigators feel that the immune system functions on a delicate balance of suppression and help. In
MS, there is evidence that there are losses of suppressor influences, both functionally and phenotypically 13,
77, 1lo}. Thus, the generation of increased functional
suppression is an attractive approach for treatment of
the disease, although at the present time there are no
specific suppressor factors or cellular elements that can
be administered to patients. The immunological effects
of total lymphoid irradiation result in an increase in
functional suppression both by decreasing the number
and function of helper T cells and by stimulating the
appearance of antigen-nonspecific suppressor cells
(l06}. Suppressor cells have been shown to play a
crucial role in down-regulating EAE f4, 91).
Removing Helperllnducer Cells
Inducer T cells trigger the immune response and they
can be specifically down-regulated using monoclonal
antibodies. Monoclonal antibodies against inducer
(CD4+) T cells have proven effective in both acute
and chronic animal models of EAE 118, 104, 111).
Monoclonal antibodies directed against inducer cells
have also been administered in phase one clinical trials
in MS patients and have shown suppressive effects
11161. Further trials with anti-CD4 monoclonal antibodies in MS patients are planned.
Manipulation of Activated T Cells
Experimental data suggest that activated T cells traffic
to the CNS more efficiently than nonactivated T cells
11211, and rapid traffic of T cells to the CNS has been
observed in progressive MS 151). Furthermore, increased numbers of activated cells have been described
both in the periphery and in the CNS of MS patients
142, 49, 50, 82}. One strategy of immunotherapy in
MS is the elimination of activated T cells. Such therapy
would not require knowledge of the specific antigen in
MS, if indeed there is one antigen, but would allow the
relatively specific removal of activated T cells. Treatment of EAE with monoclonal antibodies directed
against activated T cells has been successful 1102).
Manipulation of Cells Bearing Class II MHC Molecules
As discussed previously, class I1 MHC molecules play
a crucial role in the generation of immune responses,
since antigen is presented to T cells in the context of
class I1 MHC antigens. Increased class I1 MHC expression results in increased immune responsiveness,
with the converse also being true. In fact, a recent trial
of gamma interferon, which is known to increase class
I1 MHC expression, resulted in clinical worsening of
MS patients 1901. Thus, it would appear that treatments to decrease class I1 MHC expression might be
beneficial in MS. Of note is that corticosteroids, which
have been used extensively in the treatment of MS,
cause a down-regulation of class I1 MHC expression
1101. Another experimental approach that has been
used successfully in animal models of autoimmunity is
the administration of monoclonal antibodies directed
against class I1 MHC antigens, which may have a positive effect by increasing immune suppression [lOS).
Altering Lymphocyte Trafic
If the progression of MS is linked to the continued
trafficking or movement of cells into the CNS, treatments that prevent such traffic might be effective in
altering disease progression. Molecules on the surface
of immunocompetent cells that are specific for the
traffic of cells have been described [GO, 801. Whether
unique recognition structures and pathways of traffic
into the nervous system exist is not known. However,
such an approach could protect the CNS from the
influx of the immunocompetent cells without requiring
identification of the antigen specificity of the cells.
Prazosin, an al-adrenergic receptor antagonist, may
suppress EAE by altering permeability of CNS vasculature to cells 1161. Heparin has been shown to alter
Neurological Progress: Weiner and H d e r : Immunotherapy of Multiple Sclerosis 2 15
lymphocyte traffic in animals by affecting enzymes required for lymphocyte movement across the endothelial cell surface and has been used to treat EAE (23,
26, 81, 122). In some animal models, extremely low
doses (equivalent to 400 unitdday in humans) were
found effective (261, and we have initiated pilot trials
using such doses in MS patients 165al.
Extracorporeal Removal of Serum Factors or Cells
Myasthenia gravis, one of the best characterized autoimmune diseases, is associated with autoantibodies directed against the acetylcholine receptor, and treatment with plasma exchange has been of benefit in a
certain number of patients 1311. A number of studies
of plasma exchange in MS have been undertaken even
though a specific autoantibody has not been identified
in the disease, and there is a suggestion that plasma
exchange may benefit MS patients [32, 62, 108, 112,
1IS}. Plasma exchange could benefit patients in a number of ways, including by removing serum factors
other than immunoglobulins (e.g., interleukins), by affecting cellular immune responses, or by improving
conduction along demyelinated axons. Of note is that
plasma exchange can be beneficial in patients with
Guillain-Barrk syndrome (471. Investigators have also
attempted to treat MS by using leukocytapheresis,
which nonspecifically removes cells (531. If serum factors, antibodies, or cells responsible for the disease can
be identified, it is theoretically possible to remove
them specifically on affinity columns. The advantages
of such treatment are that it would be specific and all
manipulations would be carried out extracorporeally.
Manipulation of AntigenSpecific Cells
The ultimate goal of immunotherapy in MS is to identify those antigen-specific autoreactive cells responsible for the disease and either to eliminate or suppress
them. Attempts at antigen-specific therapy have been
tried using myelin basic protein (MBP), the primary
antigen that causes EAE in animals. Investigators have
postulated that MBP might be the autoantigen in MS
and have treated MS patients with MBP using regimens designed to desensitize against MBP and thus to
administer antigen-specific immunotherapy (2 1, 44,
981. These treatments, however, were not of benefit.
Another treatment initially designed as antigen-specific
immunotherapy was copolymer 1 (Copl), a synthetic
polymer that can protect against EAE [61) and that is
discussed later in this review.
Combination Immunotherapy
Although investigators have focused on individual immunotherapeutic approaches, therapy directed against
one limb of the immune response may not be as effective as combination therapy, and multiple drug or
treatment regimens may be more effective than treatment with a single drug. The use of more than one
216 Annals of Neurology Vol 23
No 3 March 1988
drug, however, complicates the interpretation of clinical trials. Furthermore, a long-term treatment plan that
employs a number of strategies is probably needed.
For example, in early stages of the disease, treatment
designed to suppress antigen-specific reactivity might
be of benefit, whereas in later stages, nonspecific irnmunotherapy or treatment directed against lymphocyte traffic or activated T cells may be required for
positive clinical effects. Also, certain forms of immunotherapy might be applied on a continuous basis,
with others used during flare-ups or periodically.
Review of Treatment Modalities
in Multiple Sclerosis and Their Relationship
to Strategies of Immunotherapy
Corticosteroids
Corticosteroids andor ACTH are probably the most
widely used forms of therapy for MS. A double-blind
study of ACTH has shown improved short-term recovery from acute attacks, but no long-term effect
[99}. Long-term treatment of MS with conicotropin or
corticosteroids has also not shown significant positive
effects (35, 751. Intrathecal steroids have been administered to MS patients without proven benefit and,
in fact, may cause local complications. Given the evidence of systemic immune abnormalities in MS, it
would seem unlikely that local treatment with antiinflammatory agents would have significant benefit.
There has been recent interest in the use of high-dose
intravenous methylprednisolone [reviewed in 1091,
which has been reported to improve recovery from
acute attacks better than ACTH does [9} and to hasten
recovery from attacks, decreasing morbidity and length
of hospitalization 128, 761. Positive effects from corticosteroids could relate to the antiedema effects or temporary physiological effects of the drug on nerve conduction. Furthermore, it is a well-recognized clinical
observation that patients may respond initially to
ACTH or prednisone, but with repeat treatments the
effect is lost. The basis for this observation probably
relates to the accumulation of fixed white-matter lesions. Use of corticosteroids for longer periods of time
(> one month) may induce steroid dependency in
which treatment is no longer efficacious and removal
of therapy causes clinical worsening. In summary,
short, intensive courses of steroids hasten recovery
from attacks but have minimal effect on progressive
MS or the ultimate course of the disease.
Azathioprine
A large number of clinical trials have been carried out
using azathioprine, either alone or in combination with
other agents [I, 38, 87,94, l o l l . It is a purine antagonist and its primary lymphocytic effects are directed
against actively replicating cells. Although there is
some suggestion that azathioprine may be of benefit to
MS patients, the effect is not dramatic and is primarily
seen in those patients with a component of relapsing
disease. Patzold and colleagues found azathioprine to
slow progression of the disease in patients with an
intermittent-progressive course, but not in those with
chronic progressive disease or intermittent disease
(941. Ellison studied chronic progressive patients for a
three-year period in which azathioprine therapy to
maintain a white blood cell count from 3,000 to 4,000/
mm3 with or without alternate-day methylprednisolone was compared with a placebo control (341. Although the rate of progression was similar in the three
groups when compared as a whole, subcategory analysis favored patients who received azathioprine plus
methylprednisolone, as did outcome as measured by
changes in visual evoked responses. A study of immune function in patients treated with azathioprine
showed a decrease in IgG secretion by B cells, but no
effect on suppressor function (861. In summary, azathioprine may offer some benefit to patients and is
used by some physicians who wish to treat patients
with immunosuppressive medication.
Cyclophosphamide
A number of studies suggest that cyclophosphamide
is beneficial in MS 122, 43, 46, 52, 56, 62a, 1191.
Cyclophosphamide is an alkylating agent that acts on
resting and proliferating cells, with more of an effect
on proliferating cells. A regimen of particular interest
has been the use of two to three weeks of intensive
treatment (5-7 gm) designed to produce a significant
leukopenia (< 2,000 WBC/mm3). Although there
have been some studies in relapsing-remitting disease
[43,62a], most of the studies are in progressive MS. In
one study, those who responded to cyclophosphamide
tended to be younger patients with a relatively short
disease duration who had a rapidly progressive course
before treatment (5 7). Cyclophosphamide could be
acting both peripherally by killing autoreactive cells
and locally, as cyclophosphamide is found in the CSF
of treated patients (71. In the doses given, it affects
both cellular and humoral immunity. In a preliminary
trial, increasing pulses of cyclophosphamide appeared
to ameliorate the disease course of patients but were
not well tolerated 173, 791. It is a drug with the potential for both short- and long-term toxicity, and recent
reports emphasize that although there might be benefit
from a short, intensive course of treatment with cyclophosphamide, patients usually begin progressing again
and retreatment or some form of maintenance therapy
is required (221. Treatment programs are currently
under way using a two-or three-week induction period
followed by maintenance intravenous boluses of cyclophosphamide (1191, a regimen that has been successfully applied to lupus nephritis (51. Future studies may
involve short-term use of a drug such as cyclophosphamide to induce a remission, followed by maintenance
therapy with other drugs. In summary, cyclophospha-
mide appears to be the most efficacious drug for the
treatment of progressive MS, but long-term toxicities
are unknown, and at the present time its positive effects are not long lasting. A recent double blind study
of monthly pulses of intravenous cyclophosphamide in
relapsing-remitting disease demonstrated a reduction
in exacerbation rate in those receiving cyclophosphamide (62al.
Plasma Exchange
A number of studies of plasma exchange have been
carried out in MS 132, 62, 108, 112, 115). A recent
double-blind study suggests that there may be beneficial effects in patients given five months of weekly
plasma exchange in conjunction with oral cyclophosphamide and prednisone 162). Less prolonged regimens or regimens that do not include immunosuppression do not appear to be of benefit. Two additional
double-blind studies of plasma exchange plus immunosuppression are in progress: a Canadian study in progressive MS and an American study in acute MS
{114}. The results of these trials will help define what
role plasma exchange has in treatment of this disease.
Lymp hog tapheresis
Lymphocytapheresis is analogous conceptually to treatment of MS via thoracic duct drainage. To date, there
is no clear evidence that the global removal of cellular
elements benefits MS patients {41, 53, 691. One
difficulty with this form of therapy is that there are
more than 10” lymphocytes in the human immune
system and only a small fraction of these cells can be
removed by extracorporeal lymphocytapheresis.
Znterjimn
The rationale for the use of interferon rests primarily
on its antiviral effects, although it has immunological
effects primarily related to natural killer cell activity.
Three forms of interferon have been used in MS:
alpha, beta, and gamma. In a double-blind study, beta
interferon administered intrathecally was reported to
reduce the number of relapses (591, although it had no
effect on the level of disability. Pleocytosis and raised
CSF protein occurred during treatment. Alpha interferon administered systemically provided slight benefit
in patients with relapsing disease, although some patients entered the progressive stage, making data interpretation difficult (63). Long-term followup of twelve
systemic alpha interferon-treated patients suggested
that there may have been subsequent benefit following
cessation of therapy, using a route potentially less
hazardous than inuathecal interferon (89}. One of the
more provocative studies of interferon was treatment
of MS patients with gamma interferon, an immune
enhancer that increases the expression of class I1 MHC
molecules on macrophages 1901. Patients treated with
gamma interferon experienced exacerbations of their
Neurological Progress: Weiner and Hafler: Immunotherapy of Multiple Sclerosis 2 17
disease, one of the few instances in which a treatment
clearly made the disease worse. These results strongly
support the concept of MS as an autoimmune disease.
Since gamma interferon probably does not cross the
blood-brain barrier, the exacerbations associated with
treatment are further evidence of the importance of
the peripheral immune system in the disease's pathogenesis, although gamma interferon could also have
been exerting its effect by inducing class I1 MHC expression on cerebral endothelial cells [68]. There have
been trials with agents to enhance immune responsiveness (levamisole) or restore defective immunity
(transfer factor) which have not been successful in MS
f27, 36, 45, 78}. In summary, for MS, treatment with
the interferons remains experimental, with further
trials being planned.
Total Lymphoid lwadiation
Total lymphoid irradiation (TLI) has potent immunosuppressive effects, and a double-blind study of lymphoid irradiation has reported benefit in patients with
chronic progressive MS [30]. As discussed previously,
these results provide the important conceptual information that treatment of the peripheral immune system can indeed affect disease of the CNS. Similar results have been reported for rheumatoid arthritis
[l06]. Of note is that in MS patients, the absolute
lymphocyte count appeared to be a crude indication of
therapeutic efficacy, with greater efficacy in patients
with lower counts. Approximately half of MS patients
treated with TLI began progressing at 36 months. The
major limitations of the use of TL.1 are whether it can
be administered more than once and whether its use
precludes the use of other immunosuppressive drugs.
It is an experimental treatment undergoing trials.
tial difficulty with a drug such as cyclosporine in terms
of immune hyperactivity and subsequent disease relapse that could occur when the medication is stopped.
Assessment of the role of cyclosporine in the tredtment of MS awaits the results of the current multicenter trial in the United States.
Copolymer 1
Copl is a synthetic peptide developed by scientists at
the Weizmann Institute in the early 1970s which was
nonencephalitogenic and was effective in the treatment
of EAE [61]. It was originally designed as an MBP
analog. Preliminary clinical trials did not show clear
positive effects in MS 1131, but a recent double-blind
pilot trial in MS patients with early relapsing-remitting
disease demonstrated a decrease in the number of relapses and an effect on disability in patients with
Kurtzke disability scores of 0 to 2, that is, those with
virtually normal neurological examinations 112, 1131.
The drug did not affect disability in more severely
affected patients. The mechanism of Copl action in
MS is unknown, and there is no evidence at the
present time that in humans it works by affecting
MBP-reactive cells C201, although Copl does have
nonspecific immunological effects on human lymphocytes [17). A larger trial to establish efficacy in early
relapsing-remitting patients is planned, and a pilot trial
in progressive MS is in progress. Copl is currently not
available outside of ongoing clinical trials. One of the
most important conceptual points to emerge from the
Copl study is that it represents a nontoxic form of
therapy that can be administered early in the course of
the disease and was conceptualized as an antigenspecific form of therapy. This is clearly the direction in
which investigators would like to proceed as new
forms of immunotherapy are developed.
Cyclosporine
Cyclosporine is a fungal metabolite that has been
found clinically useful in organ transplantation I l l , 141
and is currently being tested in MS in three clinical
trials: two in Europe and one in the United States
{boa]. Cyclosporine has a specific, reversible effect on
T cells, acting primarily to prevent the production of
interleukin-2 (IG2), which is necessary for T-cell proliferation. It does not affect hematopoietic or phagocytic cells, although it has renal and hepatic toxicity
and may cause blood pressure elevation. A German
multicenter study comparing cyclosporine and azathioprine in both progressive and relapsing-remitting
patients found no difference between the two groups
with increased side effects in cyclosporine-treated patients [boa]. The United States trial is a twelve-center
double-blind study of patients with progressive MS
supported by Sandoz. The specificity of cyclosporine
for T cells makes it a more specific treatment than
akylating agents. It is given on a continuous basis and
its effects are rapidly reversible. Thus, there is a poten218 Annals of Neurology Vol 23 No 3 March 198,
'8
Colcbicine
Macrophages play an important role in the pathogenesis of MS as effector cells involved in the CNS demyelinative process. In the EAE experimental model,
substances that interfere with macrophage function can
have a palliative effect IlS}. Colchicine can affect various metabolites that may be important in macrophage
function, and clinical trails using colchicine are in progress f 1201. Colchicine represents an experimental approach that has not been studied extensively in MS.
Monoclonal Antibodies
Monoclonal antibodies are synthesized by clones of
immunoglobulin-secreting hybrids of B cells and
tumor lines. The hybrids are selected on the basis of
specific reactivity to a target of interest, and once a
successful clone or hybridoma is made, it can be used
to synthesize large quantities of the desired antibody
indefinitely. This technology has been used to make a
series of reagents that recognize specific determinants
on T lymphocytes, and monoclonal antibodies have
been used successfully for the in vivo treatment of
EAE {18, 102, 104, 105, 1111, and in humans for
treatment of renal allograft rejection [88], Monoclonal
antibodies offer the opportunity for specific targeting
of T cells, and EAE has successfully been treated by
targeting inducer cells, activated T cells, and class I1
MHC products. In the past, global targeting of T cells
with anti-lymphocyte globulin was attempted in MS
166, 1031. Phase one trials using anti-T cell monoclonal antibodies have been initiated in MS using pan
T cell monoclonal antibodies, anti-T11 and anti-T12,
and anti-T4, which targets inducer cells 148, 1161.
Anti-T1 1 is directed against the T11 (CD2) cell surface structure, which is the receptor for LFA-3, which
appears to be an important accessory molecule for cellto-cell adhesion. Anti-Td (CD4) can inhibit triggering
of T cells in vitro by anti-T3 bound to sepharose beads
(81. Complete inhibition of the pokeweed mitogeninduced immunoglobulin response in vitro after infusions of anti-T4 monoclonal antibodies in MS patients
has been observed El 161.
The number and specificity of monoclonal antibodies that can be used to immunosuppress specifically
are very large. As more is learned about the immune
system, it may be possible to infuse antibodies that
specifically target certain immunoreactive cells or that
can change the inducer-suppressor balance of the immune system, which appears altered in MS. The major
drawback of monoclonal antibody therapy at the present time relates to the human response against the
murine monoclonal antibodies {48}. Immune response
can occur to both the Fc (common region) portion of
immunoglobulin and to the antigen binding site (Fab
portion). Antibodies to the Fab portion could even
limit the usefulness of the infusion of human monoclonal antibodies. Nonetheless, strategies to develop
immunological tolerance to the antibodies are being
investigated, and these antibodies may also be administered in the future with toxins attached in an attempt
to delete specific populations of lymphocytes. At present, although monoclonal antibody therapy of MS has
affected immunological function, only small numbers
of patients have been treated in open pilot trials and
clinical effects cannot be assessed.
Design of Clinical Trials and Future Directions
As the immunotherapy of MS moves to the next stages
in the coming years, the following four prerequisites
will be needed to demonstrate a positive effect of a
treatment in MS. (1) Patients at an early stage of the
disease will have to be treated. It has become clear that
as the illness progresses, increased scarring and fixed
disabilities make the effectiveness of immunotherapy
more and more difficult to detect. Thus, the demonstration of the effectiveness of immunotherapy in MS
will require treatment of patients at earlier stages of
the disease. (2) Given the potential toxicities of many
of the current treatments, relatively nontoxic forms of
therapy will have to be developed to treat patients
at earlier stages. (3) Clinical trials will have to be
lengthened. MS is a chronic disease, and to demonstrate clinical effects, trials of five and even ten years’
duration will ultimately be required. Although physicians and patients may not be able to assess disease
activity and progression over a period of six to twelve
months, when the disease is viewed over a five-year
period the course of the disease is usually apparent.
With long trials, the issue of placebo effects becomes
less relevant. However, five-year trials will require the
commitment of investigators and patients over long
periods, cooperation among investigators, and longterm, stable funding. Furthermore, the number of patients with MS and their ability to participate in clinical
trials is finite. As more agents become available for
trial, cooperation among investigators will be needed
to determine which agents should be tried, when they
should be tried, and by whom. (4) A vahd laboratory
monitor of disease is crucial to developing an effective
therapy. Current clinical scales have many imperfections as a means of measuring disease progression.
Two areas that may prove of benefit are immunological
monitoring and the use of MRI. With increased
sophistication of immunological techniques, it may be
possible to monitor disease activity in the peripheral
blood by measuring such indexes as numbers of activated T cells or the presence of suppression. MRI
offers the potential to monitor MS lesions in the way
that chest x-rays monitor the growth of lung tumors.
Finally, it must be emphasized that statistical analysis is
a crucial aspect of clinical trials, and all trials must be
planned by determining what effect of treatment is
being tested, how many patients are needed to demonstrate that effect, and how the data will be analyzed.
In summary, if MS is indeed an autoimmune disease
and the current treatments that have shown effectiveness lead to treatments that have immunological
specificity and less toxicity, effective immunotherapy
for the disease will be possible. New areas of immunotherapy include T-cell vaccines [25}, which we
are currently developing for administration to MS patients; drugs to alter lymphocyte traffic; orally induced
immunological tolerance [ 5 5 } ; and drugs targeted to
activated cells. Finally, other major autoimmune diseases, such as diabetes and rheumatoid arthritis, may
involve autoimmune mechanisms similar to those that
occur in MS, and treatment approaches developed for
patients with these disorders could ultimately find
usefulness in MS patients as well.
Supported by N I H grant NS17182 and grants from the National
Multiple Sclerosis Society. Dr Hafler is the recipient of an NIH
Clinical Investigator Award and is a Harry Weaver Scholar of the
National Multiple Sclerosis Society.
Neurological Progress: Weiner and Hafler: Immunotherapy of Multiple Sclerosis 2 19
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