CME Differential mechanisms of action of
`interferon-␤ and glatiramer acetate in MS
`
`V. Wee Yong, PhD
`
`Views & Reviews
`
`Abstract—Interferon-␤ and glatiramer acetate (GA) are the two main groups of drugs used in the treatment of MS.
`Notably, while both ultimately decrease CNS inflammation, they do so by very different mechanisms. Interferon-␤ has
`potent activity at the blood-brain barrier and impairs the trafficking of inflammatory cells into the CNS. In contrast, GA
`has negligible effect at the blood-brain barrier, allowing GA-specific T helper 2 lymphocytes to enter the CNS to decrease
`inflammation through bystander suppression. Other differences are also emphasized. The presence of GA-reactive lym-
`phocytes within the CNS parenchyma may have the additional benefit of conferring neuroprotection through protective
`autoimmunity.
`NEUROLOGY 2002;59:802–808
`
`The introduction of interferon-␤ (Betaseron, Avonex,
`and Rebif) and glatiramer acetate (GA; Copaxone)
`into MS therapeutics has altered the natural course
`of the disease. The annualized relapse rate of drug-
`treated patients is lower compared to placebo con-
`trols, and more treated patients remain relapse free for
`several years relative to untreated cohorts. What is
`still unclear is how interferon-␤ and GA achieve their
`therapeutic benefit in MS. This review discusses the
`possible mechanisms by which interferon-␤ and GA
`may work in MS and emphasizes their different modes
`of activity. All three interferon-␤ preparations are used
`interchangeably here, given that the evidence does not
`suggest their activity to be different if utilized at simi-
`lar concentrations, at least in vitro.
`
`Mechanisms of action of drugs in the periphery.
`Antigen presentation and cytokines. A key concept in
`immunology required to discuss this section is the phe-
`nomenon of antigen presentation. Here, a foreign mol-
`ecule is first engulfed by an antigen presenting cell
`(APC), which is usually a dendritic cell, macrophage, or
`B cell. Part of that antigen is then displayed on the
`surface of the APC within the groove of a major histo-
`compatibility complex (MHC) molecule. The antigen-
`MHC complex is recognized by a specific T-cell receptor
`(TCR) of a responding T cell. Costimulatory molecules
`are also required to provide optimal activation, includ-
`ing CD40 interacting with CD40L on APC, and B7
`with CD28 on T cell. If the costimulatory molecules are
`not engaged, the responding T cell may undergo func-
`tional inactivation (anergy) or apoptosis. Upon antigen
`
`presentation, the T cell then undergoes clonal expan-
`sion and differentiation into effector cells. A subtype of
`T cells with the CD4 molecule on its surface differenti-
`ates into two subsets: T helper 1 (Th1), and T helper 2
`(Th2) cells (figure 1). The Th1 and Th2 effector arms
`have important functions, including promoting cell-
`mediated immunity (Th1) and humoral immunity
`(Th2). Th1 cells produce Th1 cytokines that include
`interleukin (IL)-2, IL-12, interferon-␥, and tumor ne-
`crosis factor (TNF)-␣; in general, these tend to be
`proinflammatory. Th2 cells produce Th2 cytokines such
`as IL-4, IL-5, and IL-10, which tend to be anti-
`inflammatory (regulatory); indeed, Th2 cytokines can
`inhibit the production of cytokines by Th1 cells or mac-
`rophages. In MS, there appears to be an elevation of
`Th1 cytokines, and a diminution of Th2 cytokines, pre-
`ceding and during relapse.1,2 Finally, a current concept
`of MS pathogenesis is that myelin-reactive CD4⫹ Th1
`cells are activated and these then traffic into the CNS
`to produce disease.1-4 Thus, some of the aims of therapy
`would be to decrease the generation/activation of auto-
`reactive Th1 cells through antigen presentation, and to
`produce “immune deviation” away from a Th1 milieu
`toward a Th2 environment (see figure 1).
`
`GA and interferon-␤ both affect antigen pre-
`sentation and cytokine levels but by different
`means. GA and interferon-␤ both affect antigen
`presentation and the cytokine milieu, but they do so
`by different mechanisms (figure 2). GA has high af-
`finity for the MHC groove and is thought to bind to,
`and to be displayed, as an antigen within this
`
`From the Departments of Oncology and Clinical Neurosciences, University of Calgary, Alberta, Canada.
`V.W.Y. has received honoraria from Teva Neurosciences, Berlex Laboratories and Serono, and was supported by research grants from Teva Neurosciences
`and Berlex Laboratories.
`Received January 15, 2002. Accepted in final form April 13, 2002.
`Address correspondence and reprint requests to Dr. V. Wee Yong, Professor, Departments of Oncology and Clinical Neurosciences, 3330 Hospital Drive,
`Calgary, Alberta T2N 4N1, Canada; e-mail: vyong@ucalgary.ca
`
`802 Copyright © 2002 by AAN Enterprises, Inc.
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`Figure 1. Naïve CD4 helper T cells dif-
`ferentiate into T helper 1 (Th1) and T
`helper 2 (Th2) cells. Th1 cells are proin-
`flammatory, whereas Th2 cells are anti-
`inflammatory or regulatory. Evidence
`suggests a preponderance of Th1 cyto-
`kines in MS relapse, and elevated Th2
`cytokines during remission. Thus, ratio-
`nal therapies include strategies to de-
`crease the generation of autoreactive
`Th1 cells, or immune deviation in favor
`of a Th2 environment.
`
`groove.5 Alternatively, GA is engulfed by APC and
`fragments are then presented. Either way, the pre-
`sentation of GA leads to the generation of GA-
`specific T cells. Through mechanisms that are still
`unclear, the GA-specific T cells are predominantly
`Th2 biased, as has been amply demonstrated in ani-
`mal studies and in leukocytes derived from individu-
`als with MS treated with GA.5,6 That the generation
`of GA-specific Th2 cells is important is indicated by
`the finding that the injection of these cells into mice
`prevented experimental autoimmune encephalitis
`(EAE) when animals were subsequently immunized
`with spinal cord homogenates.7 EAE is an inflamma-
`tory disease in animals that bears several histologic
`features of MS.
`Interferon-␤ also affects antigen presentation, but
`by decreasing the expression of molecules that are
`necessary for this process (see figure 2). Thus,
`interferon-␤ is particularly effective in preventing
`the interferon-␥-induced upregulation of MHC II on
`APC.1 Interferon-␤ also downregulates the expres-
`sion of co-stimulatory molecules, and impacts on
`other aspects of antigen presentation. As an antipro-
`liferative agent, interferon-␤ inhibits the expansion
`
`of T cell clones. Recently, interferon-␤ (and GA) was
`shown to decrease the production by dendritic cells
`of IL-12, which is required for differentiation along
`the Th1 route.8 Finally, interferon-␤ inhibits the ex-
`pression of FLIP, an anti-apoptotic protein, leading
`to an increased incidence of death of T cells.9 Overall,
`when the frequency of myelin basic protein (MBP)
`reactive T cells was analyzed in MS, this was found
`to be reduced following treatment with interferon-␤
`compared to pretreatment levels.10 In contrast, GA-
`reactive T cells may have a survival advantage.11
`Does interferon-␤ cause a Th2 shift as is the case
`for GA? The literature has been extremely confusing.
`Several studies have reported the elevation of the
`Th2 cytokine, IL-10, in the mononuclear cell fraction,
`and serum and CSF of patients with MS treated
`with interferon-␤,12,13 but this has not been con-
`firmed in other studies.14 Furthermore, while the
`Th1 cytokines, interferon-␥, IL-12 and TNF␣ were
`decreased by interferon-␤ in a majority of studies,1
`no difference, or even an increase,15,16 were noted by
`others. In other studies, the number of circulating T
`cells that express either Th1 or Th2 cytokines was
`reduced following interferon-␤ therapy, indicating a
`
`Figure 2. Contrasting the mechanisms of
`glatiramer acetate (GA) and interferon-␤
`on antigen presentation. In panel A, the
`high affinity of GA for the major histocom-
`patibility complex groove or the uptake of
`GA by an antigen presenting cell (APC)
`leads to the presentation of GA as an anti-
`gen and the generation of GA-specific cells
`that are T helper 2 biased. In the case of
`interferon-␤, which acts on its receptor on
`T cells and APC, this decreases the expres-
`sion of molecules needed for antigen pre-
`sentation. Together with a further activity
`of interferon-␤on T cell expansion and
`survival, this leads to the decreased gener-
`ation of antigen-specific T cells. In both
`panels, x refers to an antigen that sits on
`the MHC groove.
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`more general suppression of both subsets.17 Differ-
`ences in experimental conditions, patient sampling,
`and duration of treatment may have affected the
`outcome of results. Overall, however, the majority of
`studies do indicate a suppression of the generation of
`autoreactive CD4⫹ Th1 cells and decrease of Th1
`cytokines following interferon-␤ treatment, but a
`clear deviation away from a Th1 milieu to a Th2
`environment has been difficult to demonstrate.
`In summary, both GA and interferon-␤ alter anti-
`gen presentation and the cytokine milieu but by dif-
`ferent mechanisms (see figure 2). GA leads to the
`formation of GA-specific Th2 cells with immunoregu-
`latory properties, whereas interferon-␤ inhibits sev-
`eral aspects of antigen presentation that leads to the
`generation and expansion of autoreactive T cells.
`The net result of both treatments in the periphery is
`the decrease of a proinflammatory milieu.
`
`Other mechanisms in the periphery. Although
`the above discussions have focused on the CD4 sub-
`set of T cells, the CD8 suppressor/cytotoxic T cells
`may also be altered. Particularly, GA therapy up-
`regulates the CD8 responses and restore these to
`levels observed in healthy individuals;18 a subset of
`CD8 T cells is thought to have regulatory roles in MS
`and EAE.
`Finally, since CD4⫹ Th2 cells activate B cells to
`produce immunoglobulins (see figure 1), it is reason-
`able to address whether the latter is elevated in pa-
`tients with MS on GA therapy. Indeed, in a study of
`130 patients on GA treatment, all developed GA-
`specific antibodies that peaked at 3 months after
`initiation of treatment. The role, if any, of these an-
`tibodies in mediating the beneficial actions of GA is
`unclear; however, these antibodies did not appear to
`negate clinical activity.19 A large literature exists on
`the generation of antibodies to interferon-␤, and the
`field remains divided as to the significance of these
`antibodies.
`
`Mechanisms of action of drugs at the blood-
`brain barrier. Trafficking of inflammatory cells
`into the CNS. The migration of activated T cells
`into the CNS is critical to initiating and sustaining
`the pathology of MS.3 In correspondence, areas of
`CNS demyelination or axonal loss contain high num-
`bers of various inflammatory cell types.20 Thus, it is
`logical to address whether interferon-␤ and GA impact
`on the influx of inflammatory cells into the CNS.
`For T cells to infiltrate into the CNS, a number of
`events are necessary. First, adhesion molecules on T
`cells interact with their counter receptors on endo-
`thelial cells. These ligand pairs include the integrins
`very late activation antigen-4 (VLA-4) and leukocyte
`function antigen (LFA-1) on T cells, and vascular cell
`adhesion molecule-1 (VCAM-1) and intercellular cell
`adhesion molecule-1 (ICAM-1) on endothelial cells.
`In general, these molecules are upregulated in MS.
`Second, there is the expression of chemokines, which
`provide a directional gradient for leukocytes to enter
`804 NEUROLOGY 59 September (2 of 2) 2002
`
`the CNS, and also increase the affinity of integrins
`(e.g., VLA-4) for their counterligands on endothelial
`cells. Specific chemokines (e.g., IP10, MIG, and
`RANTES) are present in MS lesions, and their corre-
`sponding receptors are upregulated on circulating T
`cells.21,22
`Once past the endothelial barrier, the leukocyte
`encounters a barrier of extracellular matrix (ECM)
`proteins present within the basement membrane.
`Transit across the ECM barrier into the CNS paren-
`chyma appears to require the coordinate action of
`proteolytic enzymes including the matrix metallopro-
`teinases (MMP).23
`Interferon-␤ inhibits the trafficking of T cells but
`Interferon-␤ has profound activities
`GA does not.
`on several components of the process required for the
`migration of inflammatory cells into the CNS. At the
`level of adhesion molecules, interferon-␤ decreases
`their expression. Many cell-anchored adhesion mole-
`cules are processed into a soluble form, which then
`interacts with receptors on T cells, preventing the
`latter from interacting with endothelial cells. The
`conversion of cell-associated VCAM-1 into soluble
`VCAM-1 is facilitated by interferon-␤.24 Coordi-
`nately, these mechanisms decrease the ability of T
`cells to adhere on the endothelium.
`At the level of chemokine and chemokine receptor
`expression, interferon-␤ treatment decreases the ex-
`pression of several chemokines and the CCR5 recep-
`tor,25,26 although this was not confirmed.17 These
`actions should decrease the chemokine gradient that
`facilitates the entry of cells into the CNS.
`With respect to MMP, the production of MMP-9 by
`activated T cells is decreased by interferon-␤, and
`this corresponded with a decrease in the capacity of
`T cells to transmigrate across a matrix barrier.27,28
`Interferon-␤ treatment of patients with MS results
`in the decrease of the serum content of MMP-929 and
`of the number of mononuclear cells that express var-
`ious MMP members.30 More recently, mononuclear
`cells from patients with MS on interferon-␤ treatment
`for 12 months were found to have reduced MMP-7 and
`MMP-9 transcript levels; moreover, this occurred only
`in patients with relapsing remitting but not secondary
`progressive MS.31 The sum of the above activities of
`interferon-␤ is the reduction in the number of inflam-
`matory cells that infiltrate into the CNS (figure 3).
`This is borne out in EAE where interferon-␤ treatment
`decreases the number of infiltrates in afflicted
`animals.32
`In contrast to interferon-␤, GA does not appear to
`affect the transmigration of leukocytes into the CNS
`(see figure 3). Thus, GA treatment does not alter the
`expression of adhesion molecules on cultured endo-
`thelial cells33 and does not affect MMP production by
`leukocytes (Giuliani and Yong, manuscript in prepa-
`ration). High concentrations of GA applied to glioma
`cells in vitro block the cytokine-induced production
`of the chemokine RANTES,34 but the importance of
`this to lymphocytes is unclear. In correspondence
`with the lack of activity of GA on molecules that
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`Figure 3. Contrasting the effects of
`interferon-␤ and GA at the blood-brain
`barrier and within the CNS.
`Interferon-␤ decreases the production of
`matrix metalloproteinases by T cells and
`also affects the adhesion of T cells onto
`the endothelium. These reduce the influx
`of T cells into the CNS and lead to a
`rapid resolution of Gd-enhancing MRI
`activity. In contrast, GA-specific T
`helper 2 cells traffic into the CNS to
`produce bystander suppression and pos-
`sible neuroprotection. The lack of action
`of GA in excluding T cell infiltration
`does not produce a rapid decrease of
`Gd-enhancing MRI activity. Rather, due
`to actions within the CNS, a delayed
`reduction of MRI activity results.
`
`affect transmigration, Th2 polarized GA-reactive
`cells traffic readily into the CNS of EAE-afflicted
`animals.35
`Does the differential activity of interferon-␤ and GA
`at the blood-brain barrier account for the observed clin-
`ical differences in MRI activity? A striking finding in
`patients with MS who are initiated on interferon-␤
`therapy is the rapidity of resolution of the gadolinium
`(Gd)-enhancing activity on MRI.36 In contrast, Gd-
`enhancing MRI activity is decreased more gradually in
`patients on GA.37 Gd-enhancing MRI activity is corre-
`lated with lymphocyte infiltration and increase of
`MMP levels leading to blood-brain barrier (BBB) dis-
`ruption.38,39 The multiple ways by which interferon-␤
`decreases lymphocyte infiltration, and especially its re-
`duction of proteolytic MMP levels, likely accounts for
`its rapid resolution of Gd-enhancing MRI activity (see
`figure 3).
`In contrast, by not having any direct action on
`MMP or lymphocyte infiltration, GA does not pro-
`duce a rapid resolution of Gd-enhancing MRI activ-
`ity. It is important to point out that GA-reactive Th2
`cells should have entered the CNS early in treat-
`ment to begin to achieve their effects within the CNS
`(discussed below). Over the longer term, the resolu-
`tion of the Gd-enhancing MRI activity would be a
`reflection of the activity of GA on elements within
`the CNS, which then helps repair the BBB from
`within the CNS (see figure 3). These observations
`caution against the mere use of Gd-enhancing MRI
`signatures to document the effectiveness of a partic-
`ular therapy for MS. The lack of acute effects on the
`BBB does not equate with lack of efficacy, if other
`modes of action predominate for such drugs.
`In summary, interferon-␤ exerts multiple actions
`
`at the BBB to exclude leukocytes from entering the
`CNS, but GA does not. This major differential may
`help account for the finding that interferon-␤ rapidly
`resolves Gd-enhancing MRI activity, while GA does
`not (see figure 3).
`
`Mechanisms of action of drugs within the
`CNS. Bystander suppression as a mechanism for
`GA within the CNS. By virtue of excluding cells
`from entering the CNS parenchyma, and because
`interferon-␤ itself is not thought to enter the CNS, it
`seems prudent to state that interferon-␤ has no di-
`rect activity within the brain and spinal cord. Thus,
`the resolution of CNS inflammation by interferon-␤
`could be considered indirect, since this would be the
`result of inhibiting the infiltration of inflammatory
`cells into the CNS.
`In contrast, GA-polarized Th2 cells enter the
`CNS35 and, within the CNS, are thought to decrease
`CNS inflammation by a phenomenon described as
`bystander suppression. In this regard, GA-specific
`Th2 cells within the CNS become reactivated by an-
`tigen presentation through cells that are likely mi-
`croglia or macrophages that have infiltrated the
`CNS. Here, the antigen that is presented by micro-
`glia/macrophages is likely not GA, since this drug is
`rapidly metabolized following administration and is
`not thought to enter the CNS. There is evidence to
`indicate that GA-specific T cells recognize a variety
`of antigens presented by APC.40 For instance, GA-
`specific T cells from animal studies proliferate in
`response to various myelin proteins in vitro;7 indeed,
`GA was originally designed to simulate the structure
`of MBP. Thus, it is likely that the presentation of
`degraded myelin components by microglia or macro-
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`Table Similarities and contrasts of the mechanisms of interferon-
`␤ and GA in MS
`
`Biology
`
`Interferon-␤
`
`GA
`
`Antigen presentation
`Decreased expression of MHC II
`expression
`Reduced level of costimulatory
`molecules
`Inhibition of clonal expansion of
`autoreactive T cells
`Increased apoptosis of autoreactive
`T cells
`Decrease of proinflammatory
`cytokines
`Th1 to Th2 deviation
`Leukocyte trafficking across the BBB
`Decreased expression of adhesion
`molecules
`Inhibition of chemokine expression
`Inhibition of MMPs
`Excludes leukocytes from entering
`the CNS
`Events within the CNS
`Bystander suppression
`Direct neuroprotection
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`No
`
`No
`
`Yes
`
`Not clear
`
`Yes
`
`Not clear
`
`Yes
`
`Yes
`
`Yes
`Yes
`Yes
`
`No
`
`No
`No
`No
`
`No
`Not clear
`
`Yes
`Possibly
`
`GA ⫽ glatiramer acetate; MHC ⫽ major histocompatibility com-
`plex; BBB ⫽ blood-brain barrier; MMP ⫽ matrix metalloproteinase.
`
`phages within the CNS leads to the reactivation of
`GA-specific T cells. The expansion of these Th2 po-
`larized cells within the CNS results in the release of
`anti-inflammatory cytokines, which then impair the
`expansion of myelin autoreactive T cells that are
`within the CNS. This is bystander suppression. In-
`deed, the phenomenon of bystander suppression
`means that GA may be potentially useful in other
`autoimmune diseases where Th1 cells predominate.
`In contrast to
`Protective autoimmunity and GA.
`the commonly accepted idea that autoreactive T cells
`produce the CNS pathology in MS, recent evidence
`demonstrates that some autoreactive T cells have
`neuroprotective functions. This was first demon-
`strated in an optic nerve crush model in rats, which
`produced loss of retinal ganglion neurons. If animals
`were injected with MBP-reactive T cells immediately
`after the crush injury, which led to these cells accu-
`mulating in the injured optic nerve, the subsequent
`loss of retinal ganglion neurons was attenuated.41
`The neuroprotective effect of T cells has also been
`observed after spinal cord injuries.42 These results
`have generated much interest in the idea of protec-
`tive autoimmunity, whereby autoreactive T cells pro-
`tect against the loss of axons or neurons. Thus, it
`may be disadvantageous to limit the entire T cell
`immune response in the CNS following injury.
`The mechanism(s) by which autoreactive T cells
`alleviate injury is still unclear, but it has become
`806 NEUROLOGY 59 September (2 of 2) 2002
`
`evident that T cells, B cells, and macrophages secrete
`a variety of neurotrophic factors.43 Indeed, brain-
`derived neurotrophic factor was localized by immuno-
`histochemistry to inflammatory infiltrates in MS
`lesions43 and in EAE.44 Thus, the increased availability
`of neurotrophic factors resulting from the infiltration of
`inflammatory cells may attenuate injury. Alterna-
`tively, neurotrophins have many beneficial immuno-
`regulatory functions and this may favor a reduction of
`the undesirable effects of CNS inflammation.45
`It is obvious that much remains to be done to
`define whether, when, and how autoreactive T cells
`are beneficial or detrimental to CNS recovery. Where
`myelin reactive T cells were used to alleviate neuro-
`nal loss after a traumatic injury to the optic nerve or
`the spinal cord,41,44 symptoms of EAE appeared in
`animals. It is unlikely that myelin reactive T cells
`would be used to alleviate injury in MS, but can
`other more benign T cell lines be used? Specifically,
`does the generation of GA-specific T cells that enter
`the CNS provide for neuroprotection? In this regard,
`it is noteworthy that when rats were subjected to an
`optic nerve crush, and then immediately injected
`with GA-specific T cells, the number of surviving
`retinal ganglion neurons after 2 weeks was higher in
`treated animals compared to injured controls.46 More
`recently, using a model where the intraocular injec-
`tion of glutamate in mice destroyed retinal ganglion
`neurons, the toxicity of glutamate was alleviated in
`mice immunized with GA, but not with MBP or my-
`elin oligodendrocyte glycoprotein.47 Collectively,
`these results suggest that in patients with MS
`treated with GA, the GA-reactive Th2 cells that en-
`ter the CNS have the potential to provide neuropro-
`tection. Indeed, in an MRI study evaluating the
`proportion of new MS lesions that evolved into ‘black
`holes,’ which are thought to represent lesions where
`severe tissue disruption has occurred, the proportion
`was lower in GA-treated compared to placebo pa-
`tients after 7 and 8 months of therapy.48
`In summary, both interferon-␤ and GA decrease
`CNS inflammation but by different means (see figure
`3). Interferon-␤ excludes inflammatory leukocytes
`from the CNS, whereas GA-reactive Th2 cells enter
`the CNS to dampen neuroinflammation through by-
`stander suppression. The presence of GA-reactive
`cells within the CNS may confer protective autoim-
`munity and alleviate the loss of CNS tissue. It is
`likely that interferon-␤ treatment also decreases
`CNS neuronal and axonal loss, but the mechanism
`for this would be indirect, i.e., by the exclusion of the
`largely pathogenic inflammatory cells that enter the
`CNS, even at the expense of excluding some protec-
`tive lymphocytes.
`
`Combination therapy? It is logical to ask whether
`GA and interferon-␤ can be combined to increase their
`effectiveness. Until the results of a formal combination
`trial are available, the answer is not immediately ap-
`parent, and is dependent on what the pivotal mecha-
`nism of each drug would ultimately prove to be. Thus,
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`if the main mechanism of interferon-␤ and GA is to
`decrease T cell proliferation and proinflammatory cyto-
`kine levels in the periphery, then the combination
`treatment would suggest better efficacy, since both
`have such actions albeit by different mechanisms. In
`support, in vitro studies have shown that both drugs
`have a greater effect on reducing the proliferation of
`MBP-specific T cells than either alone.49 Conversely,
`it is possible that interferon-␤ may inhibit the expan-
`sion of GA-reactive Th2 cells. Finally, if the main
`target of GA is by having GA-reactive cells enter the
`CNS to produce bystander suppression, then the
`multiple effects of interferon-␤ on the BBB would
`counteract the activity of GA by preventing GA Th2
`cells access to the CNS. Until the pivotal mecha-
`nisms of interferon-␤ and GA in MS are precisely
`identified, it would be prudent to await the results of
`a formal combination trial of interferon-␤ and GA
`(being conducted by Dr. Fred Lublin et al.).
`What about other combinations? Antimitotic im-
`munosuppressants, including cyclophosphamide and
`mitoxantrone, may be rationally combined with
`interferon-␤, as their simultaneous use may result in
`a greater inhibition of the generation of autoreactive
`cells. In contrast, the concurrent use of these anti-
`proliferative agents with GA would likely impair the
`expansion of GA-specific Th2 cells, thus negating the
`efficacy of GA. Conceivably, cyclophosphamide and
`mitoxantrone may be used prior to GA to eradicate
`autoreactive Th1 cells; the subsequent introduction
`of GA would expand GA-specific Th2 cells in a milieu
`containing relatively few proinflammatory Th1 cells.
`It should be apparent that both interferon-␤ and
`GA are potent drugs that affect several stages of the
`process that contribute to MS pathology. While both
`ultimately lead to the reduction of a proinflamma-
`tory response in the periphery and within the CNS,
`the mechanisms by which they do so are remarkably
`distinct (table).
`
`Acknowledgment
`The author thanks Fiona Yong, who drew the figures for this
`review and for all of the slide presentations, and his colleagues,
`Fabrizio Giuliani, Jennifer Takahashi, and Christopher Power for
`critically reading through a draft of this manuscript.
`
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