TREATMENT STRATEGIES
`
`Rationale for Immunotherapy
`in Multiple Sclerosis
`
`John N. Whitaker, MD
`
`
`The presumed but unspecified immune-mediated basis for the pathogenesis of multiple sclerosis (MS) has led to
`therapeutic attempts to modify the immunesystem in general and in selective ways in patients with MS. In general,
`antiviral, anti-inflammatory, immunosuppressant, and immunomodulatory therapies have been considered. More spe-
`cifically, these treatments have involved the use of glucocorticoids; immunosuppressant drugs and physical agents
`such as irradiation; modifications of the immune environment with therapeutic plasma exchange and intravenous
`immunoglobulin; and more recently, alteration of events surrounding antigen presentation and stages of the immune
`response of cellular proliferation, recruitment, and infiltration of the central nervous system. The moreselective
`approaches have dealt with attempts to interfere with elements of the trimolecular complex through blocking MHC
`class II, modifying T-cell receptor functions, interfering with co-stimulatory recognition steps, and altering cytokine
`effects or lymphocyte adhesion. The rationale for the current therapeutic trials of antigen-driven peripheral tolerance,
`MHCclass II blockade, and immunomodulation, especially with interferon-B, illustrate the progression from broad
`immunosuppressive treatmentto targeting specific activities of the immune system. The combination of new strategies
`in immunotherapy and sensitive disease monitoring of their effects should allow for more rapid identification of
`beneficial and tolerated treatment for MS.
`
`Whitaker JN. Rationale for immunotherapy in multiple sclerosis. Ann Neurol 1994;36:$103—S107
`
`
`To quote from Waldmann and Cobbold [1}:
`
`The ideal form of therapeutic immunosuppression would be
`one that could be given over a short-term period to achieve
`long-term unresponsiveness to the desired antigen, without
`impairing the response to infectious agents.
`
`plex (MHC)and the T-cell receptor (TCR). Through
`molecular mimicry and a recurrent or fixed dysregu-
`lated immune system, an autoimmune response to an
`endogenous myelin component such as myelin basic
`protein, proteolipid protein, or myelin oligodendro-
`cyte glycoprotein, ensues and is perpetuated by a com-
`bination of cellular and humoral mechanisms.
`Neuropathological and immunopathological obser-
`It is sometimes useful to examine what events and
`vations underscore the principle that in MS the central
`beliefs have led us to our current position from which
`nervous system (CNS)is infiltrated by lymphoid tissue
`we attemptto devise a rational strategy for therapeuti-
`that establishes an in situ immune apparatus[4, 5]. The
`cally altering multiple sclerosis (MS). If my good friend
`most commonly postulated evolution of MS lesions
`Dale McFarlin were present, he would likely be urging
`(Fig 1) begins with an initial systemic event, mostlikely
`such an examination. Information continues to accu-
`a viral infection, that leads to organ-specific CNSperi-
`mulate on the immunologic basis and etiologic mecha-
`venular inflammation. Directed against an endogenous
`nisms of MS{2, 3], leading to different opinions about
`Of cross-reactive exogenous antigen, sensitized and ac-
`the available evidence. On the one hand, there is the
`tivated T cells circulate and adhere to endothelial cells
`restrained position that acknowledges that something
`in the CNS. Theinitial wave of lymphocytes mediating
`is awry with immunefunction in MS. The abnormality
`these events are T-helper cells that carry CD3 and
`of immune function might be causal but could be an
`CD4 markers. The adherence and properties of these
`epiphenomenon.
`In contrast,
`there is the less re-
`cells alter the blood—brain-barrier so that they may
`strained position from which MSis viewed as devel-
`penetrate. Thereafter follows recruitment of a diverse
`oping in the genetically susceptible individual through
`population of lymphoid cells with subsequent cell-
`a viral infection that initiates a T cell—mediated im-
`mediated damage. Cytokines are secreted as are media-
`mune response during an early phase oflife. The ge-
`tors and other enzymes such as proteinases and lipases.
`netic susceptibility presumably occurs on the basis of a
`Antibodies are induced and synthesized by the re-
`polygenic influence but is mediated especially through
`genes encoded by the major histocompatibility com-
`cruited B cells, which transform into plasma cells. In-
`
`
`From the Departments of Neurology and Cell Biology and the Cen-
`ter for Neuroimmunology of the University of Alabama at Bir-
`mingham and the Neurology and Research Services of the Bir-
`mingham Veterans Medical Center, Birmingham, AL.
`
`Address correspondence to Dr Whitaker, Department of Neurol-
`ogy, University of Alabama at Birmingham, JT Room 1205, Bir-
`mingham, AL 35294-0007.
`
`Copyright © 1994 by the American Neurological Association
`$103
`Hopewell EX1012
`1
`Hopewell EX1012
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`
`
`as
`
`Broad Immunosuppression:
`Cyclophosphamide, Azathioprine, Methotrexate
`Chiorambucil, Mitoxantrone,Irradiation
`
`Lymphosuppression:
`Cyclosporine A
`
`Some (but unknown) Restriction:
`Immunomodulators (IFN-Alpha, IFN- Beta)
`Anti-Cytokine, Cytokine, Anti-Adhesion Factor
`
`Restricted — But Limited Specificity:
`Copolymer |
`Anti T Cell Antibody
`
`Restricted — But Relles on Distinguishing
`Target Antigens:
`T Cell Vaccination
`Tolerance Induction
`
`Greater Restriction:
`Immunization with TCR or MHC Biocking
`Peptides
`Anti TCR Peptide Antibody
`
`Specific idiotype Network Alteration
`(Passive, Active)
`
`v a v v v y
`
`Fig 2, Considerations for the move toward selectivity of immuno-
`suppression. IFN = interferon; TCR = T-cell receptor; MHC
`= major histocompatibility locus.
`
`attempt to alter the immune system. These may be
`generally classified into physical approaches, drugs, and
`biological materials. Treatments involving physical ap-
`proaches include surgery to remove the thymus, aphe-
`resis, such as therapeutic plasma exchange or leukaph-
`eresis, to alter the internal milieu, and total lymphoid
`irradiation. Drugs that have been used to alter the im-
`mune system include the antiinflammatory glucocorti-
`coids and the immunosuppressants. Biological agents,
`which are gaining more attention, are intravenous
`immunoglobulin, monoclonal antibodies to different
`markers or subsets of lymphocytes, therapy directed at
`the trimolecular complex (see below), and immuno-
`modulatory agents and other materials that may act on
`the crimolecular complex ordistal to it in the sequence
`of events following immuneactivation.
`In the field of immunology there is a strong determi-
`nation to become moreselective with therapy for im-
`munosuppression [3] (Fig 2). Broad immunosuppres-
`sion with a variety of drugs or physical treatment can
`be more focused by selective lymphosuppression with
`cyclosporine A and progressively more directed treat-
`ment with immunomodulators, anti~T-cell regimens,
`
`Initial Systemic Event (Infection)
`
`Organ-specific CNS Perivenular Inflammation
`Endogenous or Exogenous Antigen? (Molecular Mimicry)
`Trafficking, Adhesion
`Altered Blood-Brain Barrier
`CD4+ T Cell Mediation
`
`Recruitmentof
`Diverse Lymphoid Cells
`
`Cell-Mediated Damage;
`Secretion of Cytokines,
`Mediators, Enzymes,Antibodles
`
`CNS Demyelination
`Activation of Gila
`
`v
`Remyelination
`
`Retention or
`an—
`
`CNS Lymphoid Tissue
`
`Recurrent
`i
`DEMYELINATION
`Les
`
`
`and Incomplete (Blocked)
`
`
`Remyelination
`
`
`Fig 1. A postulated immunopathogenesis for evolution of lesions
`in multiple sclerosis. CNS = central nervous system.
`
`flammation and demyelination result. Microglia and
`astrocytes are activated. In early lesions oligodendro-
`cytes also rapidly proliferate. Remyelination may then
`occur. As a result of this process or in parallel with it,
`the cells that have been attracted to the CNSare re-
`tained so that in situ lymphoid tissue is in place for
`further activation leading to recurrent demyelination.
`At somepoint, the cumulative events, possibly through
`extensive astrocytosis or other membrane changes in
`axolemmaor oligodendrocyte, preclude or restrict re-
`myelination.
`It is on the basis of these observed tissue changes
`and postulated mechanismsthat therapy is considered.
`The general stategies for treating MS may be divided
`into three categories. First, efforts may be directed at
`limiting demyelination through systemic immuno-
`modulation with consideration given for what reagents
`and drugs will penetrate into the CNSso as to have
`an effect on the lymphoid function in situ. Most of
`the treatment administered heretofore and currently
`would fall within the category of limiting demyelin-
`ation through limiting inflammation and suppressing
`the immune response [3]. Second, efforts may be di-
`rected to enhance remyelination {6}. Although stimula-
`tory agents may be found for inducing this phenome-
`non,
`it
`is
`likely that
`limiting demyelination and
`oligodendrocyte injury may enhance remyelination.
`Third, one can attempt to improve conduction in de-
`myelinated fibers. This is the objective of the use of
`potassium channel blockers such as 4-aminopyridine
`{7}. In attempting to effect the general strategies just
`mentioned, numerous therapeutic claims have been
`made [8].
`A numberof therapeutic regimens are available co
`
`$104 Annals of Neurology Supplement to Volume 36, 1994
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`
`Cytokines
`
`(CD3*, CD4*), working in conjunction with a host of
`costimulatory factors,
`leads to activation of the T-
`helper cell so that it proliferates and secretes cytokines.
`The cytokines may then stimulate other cells within
`(CostimulatoryFactors)
`the T-cell series, stimulate B cells, and the activated T
`Trafficking
`Ag Presenting|MHCII—Peptide—TCR oe —
`
`and B cells carry out the cellular and humoral compo-
`cu ye
`Secretion
`Adhesion
`/
`Infiltration
`nents of an immune response. Othercells, especially
`the CD3*, CD8* T-suppressor cell, may suppress
`Proliferation
`oenhge
`these phenomena.
`Glucocorticoids have been used in MSsince the
`early 1950s. Glucocorticoids have many effects [11]
`and among those include inhibition of secretion by
`antigen-presenting cells and T cells of the cytokines
`tumor necrosis factor-« and interleukin-6. Glucocorti-
`coids may in turn interfere with synthesis or secretion
`of interferon-y (IFN-y) and interleukin-2 by activated
`T cells. This plethora of effects of glucocorticoids indi-
`cate that in those trials of other agents that permit
`glucocorticoid usage for treatment of exacerbations, ef-
`fects may also be noted that might be ascribed to gluco-
`corticoids themselves.
`The typical immunosuppressive agents [3] that have
`been used in MS include (1) the thiopurines, such as
`azathioprine
`and 6-mercaptopurine, which work
`through inhibiting nucleic acid synthesis; (2) metho-
`trexate, an antifolate;
`(3) alkylating drugs, such as
`cyclophosphamide and chlorambucil, which bind to
`purine bases of DNA;
`(4) mitoxanthrone, which
`cross-links DNA and binds to mRNA;and (5) cyclo-
`sporine, which interferes with cytokine secretion. Each
`has been used in MSoris currently being tried without
`clear and persuasive evidence that they work [3].
`Most of the current therapeutic strategies in MS re-
`volve around directing drugs toward some component
`of the trimolecular complex that is comprised of the
`MHCclass II of the antigen-presenting cells, digested
`peptide lying in a groove of the MHCclass II mole-
`cule, and the TCR on the CD4* T lymphocyte (see
`Fig 3; Table). Strategies may be developed for targeting
`the antigen-presenting cell to interfere with processing
`and with presentation by MHC class II. This might
`involve the use of blocking antibodies to MHCclass
`II or the use of modified epitopes such as copolymer-1
`to displace peptide and prevent
`its presentation
`through MHCclass II to TCR [3, 12]. Alternatively,
`therapy might be directed at the T cell itself through
`vaccination with T cells or passively administering anti-
`body against the markers CD3 [13] and CD4 [14]. It
`is also possible to use peptides of the TCR or todirect
`an antiidiotypic response against TCR [15, 16}.
`In addition to the trimolecular complex itself, the
`various costimulatory factors have an importantrole in
`makingit possible for the T cell to be stimulated. Rele-
`vant to a discussion of the role of the costimulatory
`factors is that of the process of tolerance and anergy
`{17]. In the usual immune response,a clone ofcells is
`
`4
`i
`Formation ot Plasma Cells
`\!
`|
`Antibody Secretion ————
`
`Fig 3. General principles of the immune response and the cells
`and their components involved. This figure should be used in
`reference to the information presented in the Table. IFN-y =
`interferon-y; MHC = major bistocompatibility complex; Ts =
`T suppressor cell; Th = T helpercell.
`
`tolerance induction and immunotherapy altering the
`TCR, MHCclass II, or components of the idiotype
`network. Concurrent with this drive on the part of the
`immunotherapist to use more selective treatmentis the
`generation of nonspecificity during an immune re-
`sponse {9}. In animals where experimental conditions
`can be rigidly controlled, specific immuneactivation is
`initiated. There soon follow amplification and recruit-
`mentofcells, much as described for MS(see Fig 1) and
`then the cascading phenomenon of cytokine secretion,
`formation of antibodies, enzymes, and mediators.
`Within the antigenic molecule having major and domi-
`nant epitopes there may be a spread of specificity to
`other portions of the same molecule to less dominant
`and sometimes cryptic (inaccessible in the intact mole-
`cule) epitopes.It is also possible for there to be spread-
`ing to other molecules besides that which produced
`the initial response. Thus, the desire to be selective
`with immunotherapy and avoid complications must be
`balanced with the need to be broad based enough to
`cover the widening immuneresponse that is likely to
`have been in place by the time MS is diagnosed and
`therapy started.
`In the sequence of steps involved in an immune
`response [10], an antigen-presenting cell, commonly a
`macrophage or a monocyte, takes up an antigen and
`degrades it and presents it on its surface in the context
`of an MHCclass II molecule (Fig 3). The antigen-
`presenting cell may elaborate cytokines
`such as
`interleukin-1, and different cytokines may up-regulate
`the MHCclass II expression on professional antigen-
`presenting cells such as the macrophage, or induce
`“nonprofessional” antigen-presenting cells such as the
`astrocyte or endothelial cell, to express MHCclassII
`and become antigen presenters.
`In the context of
`MHCclass If, the TCR on the T-helper lymphocyte
`
`Whitaker: Immunotherapy in MS
`
`$105
`
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`

`Cells and Processes as Potential Targets for Immunotherapeutic
`Reagents in Multiple Sclerosis
`
`Antigen presenting cell
`Processing
`MHCII (Presenta-
`tion)
`
`Proteinase inhibitor
`Blocking or displacement
`antibodies to MHCII;
`modified epitopes (copolymer-1)
`
`T cell
`Vaccination with T cells
`Antibody to CD3
`Antibody to CD4
`Antibody to T-cell-receptor (TCR)
`Immunization with TCR peptides
`Antibody to TCR peptides (passive)
`Generate antiidiotype (active or passive)
`Costimulatory factors
`Antiadhesion molecules
`CTLA-4
`Antiergotopes
`Peripheral tolerance
`Cytokines and cytokine receptors
`Antibodies, soluble receptors, receptor antagonists,
`interferon-e, interferon-B, transforming growth
`factor-B
`Trafficking of cells
`Antiadhesion molecules
`Blood—brain barrier
`Prazosin; glucocorticoids
`Promote remyelination
`Intravenous immunoglobulin, apheresis
`
`MHC = major histocompatibility complex; TCR = T-cell receptor.
`
`expressed and expanded through activation of CD4+
`T cells by antigen, which leads to proliferation and
`secretion of cytokines. The responsive clone may be
`deleted in the thymus so that the CD4* T cell
`is
`missing in the periphery. In clonal anergy, which ap-
`pears to result from a peripheral phenomenonoutside
`the thymus, the CD4* T cell may respond to antigen
`through proliferation but does not secrete inflamma-
`tory cytokines. The lack ofparticipation by costimula-
`tory factors or interference with their usual effect can
`lead to clonal anergy. Another mechanism for toler-
`ance is the elaboration of suppressor cells that block
`the response of CD4* T cells to antigen. One or more
`of these mechanismsis involved in induction oftoler-
`ance so that lessened immune activation may be re-
`established. Oral myelin basic protein given to animals
`{18, 19} or oral myelin given to humans [20] appears
`to result in tolerance through anergy or suppressor
`cells. Other agents that may work on costimulatory
`factors iticlude antibodies to adhesion molecules, the
`fusion product of CTLA-4 to interfere with the reac-
`tion of CD28 and B7, and reagents that react with
`ergotopes, which are markers of activation of T cells.
`Other therapeutic strategies include altering the ef-
`fects of cytokines through blocking harmful cytokines
`or inducing or administering cytokines that appear to
`
`be immunosuppressive or immunomodulatory them-
`selves. The best studied therapeutic strategies for cy-
`tokine modification deal with those for interleukin-1
`{21}. Cytokine effects may be abolished or reduced by
`blocking or inhibiting conversion and release of active
`cytokine, by neutralizing the released cytokine with
`antibodies or soluble receptors or by blocking the
`cytokine receptor with antireceptor antibodies or
`receptor antagonists. Cytokines may also be blocked
`nonspecifically with glucocorticoids,
`interleukin-4,
`interleukin-10, and transforming growth factor-B.
`Other immunotherapeutic approaches would beto in-
`terfere with the trafficking ofactivated T cells through
`the use of antiadhesion molecules or to prevent the
`penetration of cells through the blood—brain barrier
`with various drugs altering vascular permeability, such
`as prazosin {22} or glucocorticoids. Evidence to indi-
`cate that remyelination can be promoted therapeuti-
`cally in humans with MS does not yet exist, although
`it is an approach that should be considered.
`The recent success of the use of interferon-8 (IFN-
`8) for the treatment of relapsing—remitting MS [23,
`24} has led to a number of additional studies on the
`mechanism wherebythis beneficial effect of IFN-8 was
`expressed. There is evidence that IFN-8 may augment
`suppressor function [25], reduce the effects of IFN-y
`to induce MHC class IJ molecules [26], and reduce
`the production of IFN-y in MS patients [27]. IFN-6
`does not work by raising the level of glucocorticoids
`{28]. It is possible that IFN-B has even more diverse
`sites of action {29}. Even though the goal of specific
`immunotherapy will continue to motivate immuno-
`therapists, it may be morerational at this point to con-
`sider the broad-based therapy, such as with immuno-
`modulators and IFN-B, to deal with the variety of steps
`envisioned to lead to tissue injury in MS.
`
`Presented at the meeting, Multiple Sclerosis: Approaches to Man-
`agement, held as part of the Multiple Sclerosis Satellice Symposium
`in Victoria, British Columbia, Canada, September 10-13, 1993.
`
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`achieve immunological tolerance. Trends Pharmacol Sci 1993;
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`6. Rodriguez M, Lennon VA. Immunoglobulins promote remy-
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`$106 Annals of Neurology Supplement to Volume 36, 1994
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`suppresses experimental
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`Whitaker: Immunotherapy in MS $107
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