NEUROLOGICAL PROGRESS
`
`Immunotherapy of Multiple Sclerosis
`
`Howard L. Weiner, MD, and David A. Hafler, MD
`
`
`
`Based on the assumption that multiple sclerosis is an autoimmune disease, a numberof clinical trials designed to
`suppress the immunesystem 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 numberof 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 If major histocompatibility complex—bearing
`cells, alteration of lymphocyte traffic, extracorporeal removal of serum factors or cells, and manipulation of antigen-
`specific cells. Present treatment modalities are beginning to show someefficacy 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. Giventhe 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, Hafler DA. Immunotherapy of multiple sclerosis. Ann Neurol 1988;23:211—222
`
`
`Although the cause and pathogenesis of multiple scle-
`rosis (MS) are unknown,
`the most commonly held
`view is that it is an autoimmunedisease related in some
`way to a viral infection {70, 110, 117]. Pathologically,
`there is an inflammatory response in the central ner-
`vous system (CNS) consisting predominantly of ac-
`tivated T lymphocytes and macrophages [95] accom-
`panied by a local immunereaction with the secretion
`of interleukins, which results in the synthesis of oligo-
`clonal immunoglobulin (IgG) by plasmacells {39}. Im-
`mune abnormalities have been described in the periph-
`eral blood of MSpatients, including loss of suppressor
`function [3], the presence ofactivated T cells [42, 49,
`50], and alterations in T-cell populations [6, 58, 64,
`93, 96, 118}. It has been hypothesized that the loss
`of suppression or “imbalance” in the immune system
`may play a crucial role in the disease pathophysiol-
`ogy {110}. The most widely studied animal model of
`MS,experimental allergic encephalomyelitis (EAE), is
`known to be a T cell—mediated autoimmunedisease in
`which there is inflammation and, in chronic models,
`demyelination [4, 91].
`Immune suppressor mecha-
`nisms play an important role in modulating the disease
`process: EAE can be treated with a variety of immuno-
`regulatory agents, and the application of immunothera-
`peutic strategies to MS has often stemmed from their
`success in EAE, even though EAE may or may not be
`
`a true modelfor the disease [2, 15, 16, 18, 25, 55, 61,
`92, 102, 104, 105, 111}.
`Given the potentially debilitating course of MS,
`physicians have attempted a variety of treatments to
`ameliorate or prevent the nervous system dysfunction
`that may occur. Manyof 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 [19, 54,
`84, 107]. These trials not only hold promise for devel-
`oping an effective treatment for MS, butare raising
`important questions concerning pathogenic mecha-
`nisms in the disease. The present overview will (1)
`analyze the differentclinical categories of the disease,
`the different goals of immunotherapy depending on
`the category being treated, and the unique problems
`associated with treatment of each ofthe categories; (2)
`describe current and planned strategies of immuno-
`therapy; and (3) review current treatment programsin
`terms of how they specifically or nonspecifically affect
`the immune system and what information they provide
`concerning the pathogenesis of MS. This review as-
`sumes, as do the investigators treating patients with
`immunomodulatory agents,
`that MS is an immune-
`mediated disease, and focuses on cellular immune
`mechanisms in the disease and attempts to modify them.
`
`
`
`From the Multiple Sclerosis Unit of the Center for Neurologic Dis-
`eases, Division of Neurology, Department of Medicine, Brigham
`and Women’s Hospital and Harvard Medical School, Boston, MA
`02115.
`
`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 Dis-
`eases, Brigham and Women’s Hospital, Boston, MA 02115.
`
`211
`Copyright © 1988 by the American Neurological Association
`1
`Hopewell EX1008
`
`Hopewell EX1008
`
`1
`
`

`

`CLINICAL COURSE AND TREATMENT OF MULTIPLE SCLEROSIS
`
`PREVENT ONSET OF PROGRESSIVE PHASE
`
`IMPROVE RECOVERY
`FROM AN ATTACK
`
`PREVENT RELAPSES
`
`
`
`Fig 1. Clinical course and treatment ofmultiple sclerosis. The
`horizontal axis represents time, and the vertical axis level ofdis-
`ability. The vertical dotted line represents the onset ofthe pro-
`gressive disease phase. The progressive phase may evolve after a
`number ofrelapses or, in a subcategory ofpatients, may be the
`clinical course ofthe diseasefrom the onset.
`
`Clinical Course and Treatment
`of Multiple Sclerosis
`Theclinical course and treatment of MSare outlined
`in Figure 1. Althoughtheclinical course of MSis often
`unpredictable, studies of large numbers of patients
`suggest that clear disease patterns emerge over time
`and that these patterns are importantin designing ther-
`apy {29, 67]. 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 onthe 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 theattack and/or improve
`the degree of recovery from the attack. Two difficul-
`ties 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 wors-
`ening of an old symptom related to changesin physiol-
`ogy of conduction along a demyelinated axon, such as
`occurs with elevated body temperature. Nonetheless,
`careful neurological examination and history can iden-
`tify most-attacks. In addition, magnetic resonance im-
`aging (MRI) may help define when new lesions occur
`{40, 65], and pleocytosis in the cerebrospinal fluid
`(CSF) mayalso indicate the presence of active inflam-
`mation, although acute attacks may occur without CSF
`pleocytosis. The most commonly used treatment for
`acute attacks is some form of corticosteroid prepara-
`tion. There have been fewclinical 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
`
`2
`
`twenty
`(ACTH) versus placebo carried out almost
`years ago [99]. Although ACTH was found to shorten
`the time to recovery, it did not affect the level of
`recovery. Onefault 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 attacksis
`currently in progress [114].
`It is postulated that an acute attack represents the
`movementofcells into the brain, leading to an inflam-
`matory response with subsequent edema and demye-
`lination. If this is true, a major immunological question
`is, why does the attack stop? There is suggestive evi-
`dence that acute attacks are associated with changes in
`peripheral blood T-cell populations and function [6,
`58, 118]. For example,
`in one study, acute attacks
`were associated with a decrease in T-cell suppressor
`function, whereas during recovery,
`increased func-
`tional immune suppression was found [58]. Because
`the brain and spinal cord do not normally have the
`large number of lymphocytes and macrophages pres-
`ent in the CNS of MSpatients, these cells must ini-
`tially 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 ac-
`tivity 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
`im-
`mune compartment? The answers to these questions
`are crucial in devising effective immunotherapy. Fur-
`thermore, a monitorof disease activity within both the
`CNSand 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
`numberofrelapses. Such trials generally involve con-
`tinuous treatment on a daily basis, with the presump-
`tion that whateverinitiates a relapse can be prevented.
`However, certain difficulties exist in trials that use re-
`
`2
`
`

`

`lapses as an endpoint: (1) the natural history of MS at
`the relapsing-remitting stage of the disease to prevent
`this stage of the disease is variable, and with time, the
`the onset of the progressive phase. Ultimately,
`it
`incidence of relapses usually decreases and the disease
`seems logical that this must be one of the major goals
`may enter the progressive phase [29, 67]; (2) the clini-
`of MS immunotherapy. Thedifficulties in carrying out
`cal definition of a relapse can sometimes be difficult;
`suchatrial are twofold: (1) finding an agent that can be
`and (3) all relapses are not clinically the same, with
`administered over the length of time needed to per-
`some causing greater disability than others. Further-
`form such a study which does not have long-term tox-
`more, repeated MRI imaging of the CNSin relapsing-
`icity, and (2) embarking on a large controlled trial in
`remitting MS indicates that new lesions can appear
`which a minimum of five years would be needed to
`without clinical sequelae, suggesting that whether a
`reach the defined outcome.
`clinical attack occurs depends on the location of the
`lesion in the CNS. A numberof drugs have been tried
`and are currently being studied in relapsing MS. The
`chronic
`toxicities of globally immunosuppressive
`agents such as azathioprine and cyclophosphamide pre-
`vent the long-term prophylactic use of these agents for
`early, mild cases of relapsing-remitting MS.
`
`Treatment Designed to Halt the Progressive Phase
`Although most patients enter the progressive phase
`following a numberofrelapses, there is a subcategory
`of patients whose disease is progressive from the onset
`{29, 67}. It is not known whetherthese patients repre-
`sent a subcategory of disease related to different im-
`munological or other mechanisms or whether they
`might, in fact, have had subclinical attacks. The follow-
`ing 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
`becomethetarget; (2) with time, a localized immune
`response in the CNScould be created that might not
`be antigen specific, that is, it could involve nonspecific
`activation of immunocompetentcells in the CNS by
`interleukins; (3) with time, a more consistent defect in
`immunoregulation could occur in the peripheral im-
`mune system; and (4) it is theoretically possible that
`changes within the nervous system itself could affect
`immuneregulation.
`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 po-
`tential toxicities associated with these agents should
`engendercautionin their use. Two treatment regimens
`that have been reported to be of benefit, cyclophos-
`phamide [{22, 43, 52, 56, 119} and total lymphoid ir-
`radiation [30], illustrate a feature important in design-
`ing treatment programs for progressive MS. In both
`trials, although positive results have been reported,
`reprogression began within one to three years follow-
`ing initial treatments. These results suggest that once
`the patient enters the progressive phase, retreatment
`or some form of maintenance must be addedtoorigi-
`nal induction regimens to maintain clinical effects.
`These treatments demonstrate that immunosuppres-
`sion can indeed affect the course of progressive MS
`and thatpatients’ conditions are not made worse. This
`helps support the role of immunopathogenic mecha-
`nisms in the disease and provides a rationale for at-
`tempting to find an immunospecific, relatively non-
`toxic form of therapy that can be administered over
`longer periods of time.
`
`Treatments Designed to Prevent Onset
`of the Progressive Phase
`A numberofclinical studies have demonstrated that
`the most debilitating and clinically predictable form of
`the disease is the progressive stage [29, 83}. 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 fre-
`quency of relapses and short intervals between re-
`lapses often herald progression [29].
`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 pe-
`ripheral immune system plays an importantrole in the
`progressive phase of the disease. Specifically,
`treat-
`ment of progressive MSpatients with total lymphoid
`irradiation, a treatment directed only at peripheral im-
`mune organs, which spares the neuroaxis, has been
`found in a double-blindtrial to affect the course of the
`disease favorably [30]. In addition, as mentioned pre-
`viously, a large number of immunological abnor-
`malities are found in the peripheral blood of MS pa-
`tients, 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 evi-
`dence that the peripheral immune compartmentplays
`an essential role in chronic progressive MS.
`There have been no studies designed with the ex-
`press purpose of administering treatmentto patients in
`
`Neurological Progress: Weiner and Hafler: Immunotherapy of Multiple Sclerosis
`
`213
`
`3
`
`

`

`
`
`PERIPHERAL IMMUNE SYSTEM
`
`T suppressorcell
`
`UMMM
`
`»
`Blood Brain Barrier
`
`CENTRAL NERVOUS SYSTEM
`
`effector macrophage
`
`Traffic into
`——
`
`o°
`
`) MB
`_
`
`activated T cell
`
`
`
`
`myelin
`
`:
`activated
`astrocyte
`
`Cc
`E
`L
`L
`F
`
`Macrophage
`
`
`activated T cell
`j
`BS is,
`
`inducerT cell
`a
`;
`interleukins
`ie
`
`F
`a
`
`Interferons
`
`2
`.
`F
`U
`if
`E
`B cell
`CcT
`an
`oe
`Immunoglobulins
`.
`Ss
`Immunoglobulins
`
`antigen
`uf
`Interleukins
`\
`
`A
`
`B cell
`
`@
`
`Fig 2. The immuneresponse ts initiated in the peripheral im-
`mune compartment when antigen is processed and presented to an
`notherapy are designed to intervene at a number of
`inducer cell by a macrophage or antigen-presenting cell. The in-
`places in the circuit (Fig 2). The immuneresponse is
`ducer cell becomes activated and releases a number ofsolublefac-
`generated when an antigen is presented to aTcell, or
`tors, including interleukins and interferons, which act on both B
`thymus-derived lymphocyte, by an antigen-presenting
`cells and T cells to augment the immuneresponse. T suppressor
`cell, or macrophage. T cells can only recognize antigen
`cells act to dampen the immuneresponse. Activated T cells traffic
`when the antigen is presented to the T cell in the
`into the central nervous system (CNS), where they again release
`context of particular self proteins that are part of the
`factors, presumably after having antigen presented to them. In
`this regard, astrocytes are capable ofpresenting antigens to T
`major histocompatibility complex (MHC) onantigen-
`cells. Other cellular elements also enter the CNS (macrophages, B
`presenting cells. T inducer cells (T4+ or CD4+ T
`cells), where the potentialfor a local immune response occurs. B
`cells) recognize antigen only in the context ofclass II
`cells are known to produce immunoglobulin locally within the
`MHC molecules, whereas other T cells (T8+ or
`CNS, and macrophages function within the CNS to phagocytose
`CD8-+ T cells) are class I restricted. Substances that
`myelin, in addition to their antigen-presentation properties.
`augment class II MHC expression (such as gamma
`interferon) augment
`the immune response. T cells
`mediate cell-mediated immune responses suchas 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 shownthat
`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 re-
`duced in MS [24, 77, 100}. T cytotoxic cells have the
`ability to lyse other cells. In addition to cellular ele-
`
`Treatment ofStable Multiple Sclerosis
`The term stable MS raises the question ofthe ability to
`define when the disease is indeed immunologically
`quiescent, an ability that we do notcurrently 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 MSis the ability to identify immunological stability,
`which first requires an understanding of immunealter-
`ations in the disease.
`
`The Normal Immune Response
`and Strategies of Immunotherapy
`The normal immune response [reviewed in 85} con-
`sists of a cascade of events, and strategies of immu-
`
`214 Annals of Neurology Vol 23 No 3 March 1988
`
`4
`
`

`

`and chronic animal models of EAE [18, 104, 111].
`Monoclonal antibodies directed against inducer cells
`have also been administered in phase oneclinical trials
`in MS patients and have shown suppressive effects
`{116}. Further trials with anti-CD4 monoclonal anti-
`bodies in MSpatients are planned.
`
`ments, there are soluble factors that play a role in the
`generation of the immune response. These include in-
`terleukins, such as IL-1 and IL-2, interferons, and B
`cell—stimulating factors, which are important in activat-
`ing cells of the immunesystem.
`In MS,it is assumed that an activated inducer or
`effector T cell migrates into the nervous system to
`Manipulation of Activated T Cells
`initiate the disease process. Why this occurs is un-
`known. Nonetheless, experimental data suggest that
`Experimental data suggest that activated T cells traffic
`for a T cell to migrate into the nervous system it must
`to the CNS moreefficiently than nonactivated T cells
`be activated [121]. The capacity for a localized im-
`{121}, and rapid traffic of T cells to the CNS has been
`observed in progressive MS {51}. Furthermore,
`in-
`mune response exists within the nervous system com-
`partment of MS patients, where there are T cells
`creased numbers ofactivated cells have been described
`both in the periphery and in the CNS of MSpatients
`infiltrating lesions and macrophages mediating demye-
`{42, 49, 50, 82}. One strategy of immunotherapy in
`lination, and astrocytes may express class If MHC,
`thus having the capacity to function as antigen-
`MSis the elimination of activated T cells. Such therapy
`would not require knowledge of the specific antigen in
`presenting cells [37]. In addition, it has been known
`for many years that there is local production of im-
`MS,if indeed there is one antigen, but would allow the
`munoglobulin within the CNSbyBcells [39]. Given
`relatively specific removal of activated T cells. Treat-
`this cascade of immunereactivity, the following strate-
`ment of EAE with monoclonal antibodies directed
`gies of immunotherapy have been attempted in MS
`against activated T cells has been successful [102].
`patients or are being planned.
`
`Manipulation of Cells Bearing Class II MHC Molecules
`Asdiscussed previously, class II MHC molecules play
`a crucial role in the generation of immune responses,
`since antigen is presented to T cells in the context of
`class If MHC antigens. Increased class If MHC ex-
`pression results in increased immune responsiveness,
`with the converse also being true. In fact, a recenttrial
`of gamma interferon, which is knownto increaseclass
`II MHC expression, resulted in clinical worsening of
`MSpatients [90]. Thus,
`it would appear that treat-
`ments to decrease class II MHC expression might be
`beneficial in MS. Ofnote is that corticosteroids, which
`have been used extensively in the treatment of MS,
`cause a down-regulation of class IJ MHC expression
`{10}. Another experimental approach that has been
`used successfully in animal models of autoimmunity is
`the administration of monoclonal antibodies directed
`against class II MHCantigens, which may havea posi-
`tive effect by increasing immune suppression [105].
`
`Altering Lymphocyte Traffic
`If the progression of MS is linked to the continued
`trafficking or movementofcells into the CNS, treat-
`ments 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 [60, 80}. Whether
`unique recognition structures and pathwaysoftraffic
`into the nervous system exist is not known. However,
`such an approach could protect the CNS from the
`influx of the immunocompetentcells without requiring
`identification of the antigen specificity of the cells.
`Prazosin, an a j-adrenergic receptor antagonist, may
`suppress EAE byaltering permeability of CNS vascu-
`lature to cells {16}. Heparin has been shown to alter
`
`Nonspecific Immunosuppression
`Most of the immunosuppressive agents that have been
`tried in MS patients nonspecifically suppress the im-
`mune response [33, 71, 72, 84, 97}. These include
`drugs such as cyclophosphamide, azathioprine, anti—
`lymphocyte 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 nonspe-
`cific in their actions.
`
`Generation of a Suppressor Influence
`Manyinvestigators feel that the immune system func-
`tions on a delicate balance of suppression and help. In
`MS,there is evidence that there are losses of suppres-
`sor influences, both functionally and phenotypically [3,
`77, 110}. 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 orcellular 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
`{106}. Suppressor cells have been shown to play a
`crucial role in down-regulating EAE [4, 91}.
`
`Removing HelperlInducer 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
`
`Neurological Progress: Weiner and Hafler: Immunotherapy of Multiple Sclerosis
`
`215
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`

`lymphocyte traffic in animals by affecting enzymes re-
`quired for lymphocyte movementacross the endothe-
`lial cell surface and has been used to treat EAE [23,
`26, 81, 122}. In some animal models, extremely low
`doses (equivalent to 400 units/day in humans) were
`found effective [26], and we haveinitiated pilot trials
`using such doses in MS patients [65a].
`
`Extracorporeal Removal of Serum Factors or Cells
`Myasthenia gravis, one of the best characterized auto-
`immunediseases, is associated with autoantibodies di-
`rected against
`the acetylcholine receptor, and treat-
`ment with plasma exchange has been of benefit in a
`certain number of patients [31]. A number ofstudies
`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 MSpatients [32, 62, 108, 112,
`115]. Plasma exchange could benefit patients in a num-
`ber of ways,
`including by removing serum factors
`other than immunoglobulins(e.g., interleukins), by af-
`fecting cellular immune responses, or by improving
`conduction along demyelinated axons. Of note is that
`plasma exchange can be beneficial
`in patients with
`Guillain-Barré syndrome [47]. Investigators have also
`attempted to treat MS by using leukocytapheresis,
`which nonspecifically removescells [53]. If serum fac-
`tors, 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 andall
`manipulations would be carried out extracorporeally.
`
`Manipulation ofAntigen-Specific Cells
`The ultimate goal of immunotherapy in MSis to iden-
`tify those antigen-specific autoreactive cells responsi-
`ble 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 mightbe the autoantigen in MS
`and have treated MS patients with MBP using regi-
`mensdesigned to desensitize against MBP and thus to
`administer antigen-specific immunotherapy [21, 44,
`98}. These treatments, however, were not of benefit.
`Anothertreatmentinitially designed as antigen-specific
`immunotherapy was copolymer 1 (Cop1), a synthetic
`polymer that can protect against EAE [61] and thatis
`discussed later in this review.
`
`Combination Immunotherapy
`Although investigators have focused on individual im-
`munotherapeutic approaches, therapy directed against
`one limb of the immune response may notbe as effec-
`tive as combination therapy, and multiple drug or
`treatment regimens may be moreeffective than treat-
`ment 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 clini-
`cal trials. Furthermore, a long-term treatment plan that
`employs a numberofstrategies 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 im-
`munotherapy or treatment directed against lympho-
`cyte traffic or activated T cells may be required for
`positive clinical effects. Also, certain forms of im-
`munotherapy 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 and/or ACTH are probably the most
`widely used forms of therapy for MS. A double-blind
`study of ACTH has shown improved short-term re-
`covery from acute attacks, but no long-term effect
`{99}. Long-term treatment of MS with corticotropin or
`corticosteroids has also not shown significant positive
`effects [35, 75}. Intrathecal steroids have been ad-
`ministered to MSpatients without proven benefit and,
`in fact, may cause local complications. Given the evi-
`dence of systemic immune abnormalities in MS,
`it
`would seem unlikely that local treatment with anti-
`inflammatory agents would have significant benefit.
`There has been recentinterest in the use of high-dose
`intravenous methylprednisolone {reviewed in 109],
`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 [28, 76}. Positive effects from corti-
`costeroids could relate to the antiedema effects or tem-
`porary physiological effects of the drug on nerve con-
`duction. Furthermore, it is a well-recognized clinical
`observation that patients may respond initially to
`ACTH orprednisone, but with repeat treatments the
`effect is lost. The basis for this observation probably
`relates to the accumulation of fixed white-matter le-
`sions. 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
`MSorthe ultimate course of the disease.
`
`Azathioprine
`A large numberofclinical trials have been carried out
`using azathioprine, either alone or in combination with
`other agents {1, 38, 87, 94, 101}. It is a purine antago-
`nist and its primary lymphocytic effects are directed
`against actively replicating cells. Although there is
`some suggestion that azathioprine may be of benefit to
`MSpatients, the effect is not dramatic and is primarily
`
`6
`
`

`

`seen in those patients with a componentof 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
`{94}. 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/
`mm? with or without alternate-day methylpredniso-
`lone was compared with a placebo control [34]. Al-
`though the rate of progression was similar in the three
`groups when compared as a whole, subcategory analy-
`sis favored patients who received azathioprine plus
`methylprednisolone, as did outcome as measured by
`changes in visual evoked responses. A study of im-
`mune function in patients treated with azathioprine
`showed a decrease in IgG secretion by B cells, but no
`effect on suppressor function {86}. In summary, aza-
`thioprine may offer some benefit to patients and is
`used by some physicians who wish to treat patients
`with immunosuppressive medication.
`
`Cyclophosphamide
`A numberof studies suggest that cyclophosphamide
`is beneficial
`in MS [22, 43, 46, 52, 56, 62a, 119}.
`Cyclophosphamideis 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 (5S—7 gm) designed to produce a significant
`leukopenia (< 2,000 WBC/mm?). Although there
`have been somestudies in relapsing-remitting disease
`{43, 62a}, mostofthe 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 [57]. Cyclophosphamide could be
`acting both peripherally by killing autoreactive cells
`and locally, as cyclophosphamide is found in the CSF
`of treated patients [7]. In the doses given, it affects
`both cellular and humoral immunity. In a preliminary
`tria