V/38_V/45_Ziemssen_Suppl_V_JON 18.10.2005 08:30 Uhr Seite 38
`
`J Neurol (2005) 252 [Suppl 5]: V/38–V/45
`DOI 10.1007/s00415-005-5007-2
`
`Tjalf Ziemssen
`
`Abstract Historically consid-
`ered to be an autoimmune de-
`myelinating disease, multiple scle-
`rosis is now recognized to be
`characterized by significant axonal
`and neuronal pathology. Address-
`ing this neurodegenerative compo-
`nent of the disease is an important
`treatment objective, since axonal
`injury is believed to underlie the
`accumulation of disability and dis-
`ease progression. The precise rela-
`tionship between the inflammatory
`and neurodegenerative compo-
`nents in multiple sclerosis remains
`
`T. Ziemssen (쾷)
`Neurological University Clinic
`Technical University of Dresden
`Medical Faculty “Carl Gustav Carus”
`Fetscherstr. 74
`01307 Dresden, Germany
`Tel.: + 49-351/458-6614
`Fax: +49-351/458-5873
`E-Mail: ziemssen@web.de
`
`Introduction
`
`Modulating processes within the central
`nervous system is central to therapeutic
`control of multiple sclerosis
`
`poorly elucidated, although neu-
`rodegeneration appears to be at
`least partially independent from
`neuroinflammation. The mecha-
`nisms underlying axonal injury ap-
`pear complex and are likely to be
`multifactorial. Specific treatment
`strategies need to be developed
`that act within the central nervous
`system to prevent neurodegenera-
`tion and need to be provided from
`the earliest stages of disease. It is
`likely that immunomodulatory
`treatments acting purely in the pe-
`riphery will provide only indirect
`and not direct neuroprotection. A
`promising approach is to enhance
`neuroprotective autoimmunity in-
`side the brain, believed to be medi-
`ated, at least in part, by the release
`of neurotrophic factors within the
`nervous system from infiltrating
`immune cells. Such a beneficial
`process would be inhibited by a
`non-selective immunosuppressive
`
`strategy. In summary, treatments of
`multiple sclerosis should take into
`account the heterogeneous patho-
`physiology of the disease. The
`pathogenic process in the central
`nervous system itself should be the
`major focus in multiple sclerosis
`therapy in order to protect against
`demyelination and axonal loss and
`to promote remyelination and re-
`generation directly in the target tis-
`sue, independently of peripheral
`immune status. In conclusion, se-
`lective treatment strategies aimed
`at preventing axonal injury within
`the central nervous system are re-
`quired to complement existing, pe-
`ripherally acting treatments target-
`ing the immune system.
`
`Key words multiple sclerosis ·
`neurodegeneration ·
`neuroprotection · inflammation ·
`treatment
`
`[42]. In the central nervous system, these cells infiltrate
`discrete areas of tissue, where they cause damage to
`oligodendrocytes (e.g., demyelination) and neurons
`(e.g., axonal transection), resulting in the formation of a
`sclerotic plaque. The interactions between these differ-
`ent immune cell populations itself and between immune
`cells, neurons and glia are highly complex. However, a
`better understanding of these interactions in the central
`nervous system itself is necessary for the development
`of more rational treatment strategies which can modu-
`late these interactions in a specific way and thereby pre-
`vent disease activity. Of particular interest is the poten-
`
`Multiple sclerosis is a complex autoimmune disease in-
`volving disturbances to the peripheral immune system,
`although the detailed pathogenic cascade remains un-
`known. Many different immune cells are believed to be
`involved in the disease process, including myelin-reac-
`tive CD4 + T cells which carry the immune response to
`the nervous system,CD25 + regulatory T cells,which can
`control autoreactive CD4 + cells, myelin-reactive B cells,
`CD8 + killer cells, macrophages and brain microglia
`
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`tial to prevent the neurodegenerative changes in the ner-
`vous system that are thought to be responsible for the
`accumulation of permanent neurological disability.
`
`Table 1 Comparison between outcomes of treatment in clinical trials in multiple
`sclerosis (MS) and
`in animal models of experimental autoimmune en-
`cephalomyelitis (EAE)
`
`Treatment targets in the periphery
`
`To date, treatments for multiple sclerosis have been de-
`veloped with the intention of intervening at the level of
`certain autoimmune responses in the periphery. This
`approach is hampered by limited knowledge of the
`pathogenic cascade in human multiple sclerosis, which
`compromises the development of rationally designed
`immune treatments. Peripherally acting drugs targeting
`the immune system in multiple sclerosis include
`immunosuppressants, such as mitoxantrone, which pro-
`duce a non-specific inhibition of immune cell function,
`or immunomodulators such as the beta-interferons,
`glatiramer acetate and natalizumab which target more
`or less well-defined processes involved in the assumed
`pathogenic autoimmune response. Unfortunately, since
`there is no specific immunological abnormality in pa-
`tients with multiple sclerosis,it is not possible to develop
`treatments that selectively target these processes. For
`this reason, a major limitation of such drugs is that the
`immune processes targeted are more or less non-spe-
`cific, leading to unwanted effects on immune function
`such as immunosuppression.
`Because of the limited pathogenetic data in multiple
`sclerosis, nearly all studies of agents targeting the dis-
`ease have been performed not in the human disease but
`in animal models. In particular, the experimental au-
`toimmune encephalomyelitis (EAE) model has been
`used widely to evaluate immunomodulatory treatments
`for multiple sclerosis as well as to explore the patho-
`physiology of the disease. This model involves the gen-
`eration of an autoimmune response in the immunolog-
`ical periphery by immunizing animals with myelin
`proteins such as myelin basic protein (MBP). In this
`quite simple model, the disease can also be transferred
`from affected animals to healthy recipients by adoptive
`transfer of myelin-reactive T cells. The animals develop
`a clinical and pathological pattern which is quite differ-
`ent from human multiple sclerosis (spinal cord lesions
`in EAE) although several histopathological hallmarks of
`multiple sclerosis, including focal inflammatory lesions
`in the nervous system can be found.
`As more and more scientific data from animal exper-
`iments accumulate, it is important to keep in mind that
`EAE is not human multiple sclerosis. In fact, each EAE
`experiment only represents a small part of the still un-
`known pathogenetic cascade of autoimmune demyeli-
`nation.It is perhaps for this reason that divergent results
`have been observed for a number of treatments assessed
`in both the EAE model and in clinical trials in multiple
`sclerosis [39] (Table 1). The most striking example is
`
`Therapy
`IFN-γ, systemic
`Anti-TNF-α, systemic
`IL-4 transduced T cells
`TNF-α transduced T cells
`Glatiramer acetate
`Beta-interferons
`Anti-α4 integrin antibodies
`
`MS
`
`Worsens
`Worsens
`Not tested
`Not tested
`Improves
`Improves
`Improves
`
`EAE
`
`Cures
`Cures
`Cures
`Worsens
`Cures
`Improves
`Cures
`
`perhaps that of lenercept, a recombinant TNF receptor
`p55 immunoglobulin fusion protein. In the EAE model,
`such TNF receptor fusion proteins ameliorate clinical
`symptoms [22, 23]. However, a double-blind, random-
`ized placebo-controlled trial in relapsing-remitting
`multiple sclerosis found that treatment with lenercept
`was associated with a higher proportion of patients ex-
`periencing relapses, a shorter time to first relapse and
`more severe neurological deficits [36]. Other examples
`include glatiramer acetate (GA) and natalizumab which
`provide complete abrogation of the disease process in
`the EAE model in contrast to their limited clinical
`benefit in MS patients.For these reasons,all information
`obtained from the EAE model should be interpreted
`with caution and within the context of what is known of
`the overall pathophysiology of multiple sclerosis.
`Developing treatments that target the immune re-
`sponse within the central nervous system may be more
`promising than peripherally acting treatments. Brain
`targets have the advantage over peripheral targets in
`that they directly address the core disease process and
`will have less non-selective effects on systemic immune
`function. Interesting potential targets include activation
`of microglia, antibody-mediated injury to myelin and
`axons and B cell interactions with oligodendrocyte pre-
`cursor cells [29]. A drug that appears to down-regulate
`microglial activation is minocycline [37] and this agent
`also slows the appearance of EAE and attenuates its
`severity [6, 31]. Preliminary clinical data in multiple
`sclerosis indicate that minocycline may reduce lesion
`activity [26] and these findings merit confirmation in a
`randomized controlled trial.
`
`The two faces of multiple sclerosis: inflammation
`and neurodegeneration
`
`It is now clear that the pathophysiology of multiple scle-
`rosis cannot be adequately explained uniquely by acute,
`focal inflammatory attack inside the central nervous
`system [21]. Our understanding also needs to take into
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`account the neurodegenerative processes of axonal loss,
`which may occur to some extent independently from in-
`flammation, and certainly arise very early in the disease
`process.
`These two facets of the pathology of multiple sclero-
`sis provide an elegant model to explain the heteroge-
`neous clinical presentation and course of the disease
`[12].If it has been accepted for many years that the acute
`relapses observed in relapsing-remitting multiple scle-
`rosis reflect flairs of inflammatory activity, it is now
`thought that permanent clinical disability is mainly
`determined by the extent of axonal loss. Once axonal
`loss has reached a certain critical threshold, irreversible
`neurological deficits emerge. During the course of the
`disease, inflammatory events become rarer, whereas
`neurodegeneration continues or even becomes more
`prominent (Fig. 1). This picture would account for the
`transition from a relapsing-remitting to a secondary
`progressive form of the disease. However, if inflamma-
`tion and neurodegeneration are to some extent inde-
`pendent, the relative importance of the two processes in
`individual patients may account for the different pat-
`terns of clinical presentation seen between patients and
`explain the imperfect correlation between exacerba-
`tions, inflammatory activity in MRI and accumulation
`of disability.
`The biochemical events underlying the inflammatory
`
`and neurodegenerative phases of the disease are not
`known in detail and may be quite different [33]. Inflam-
`mation involves activation of T and B cells in the pe-
`riphery, crossing the blood brain barrier and homing
`to the lesion site. In the lesion, T cells are reactivated
`by myelin antigens, release cytokines that attract
`macrophages and activate microglia which start to de-
`stroy the myelin sheath. Anti-myelin antibodies bind
`complement, attract macrophages and stimulate op-
`sonization of myelin [42]. Demyelination leads to re-
`versible and to some extent irreversible impairment of
`function of the axon whose conduction properties are
`deteriorated, thus accounting for the clinical symptoms
`associated with relapses.
`Neurodegeneration is likely to be a complex process
`[11, 18], especially when it takes place in inflammatory
`disorders like multiple sclerosis. To a significant extent,
`axonal loss seems to be a major consequence of de-
`myelination and inflammation, for example by binding
`of CD8 + T cells to exposed axons and secretion of toxic
`factors. However, other mechanisms not directly related
`to demyelination and inflammation are also likely to be
`important. An example is excitotoxicity: glutamic acid
`can bind to excitatory amino acid receptors on the cell
`bodies, dendrites or axon terminals of neurons and ini-
`tiate a process of necrotic cell death [34]. Theoretically,
`there are several possible relationships between inflam-
`
`Fig. 1 Different clinical phenotypes of multiple sclerosis and the underlying pathology. Adapted from [13]
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`mation and neurodegeneration in multiple sclerosis
`(Fig. 2). Three exclusive hypotheses can be envisaged:
`(a) that neurodegeneration is entirely secondary to in-
`flammation, (b) that inflammation is entirely secondary
`to neurodegeneration or (c) that inflammation and neu-
`rodegeneration are entirely independent. On the other
`hand, non-exclusive hypotheses where neurodegenera-
`tion is partially dependent and partially independent of
`inflammation or vice versa can also be put forward, and
`these seem intuitively more likely.
`There are a number of clinical arguments in favor of
`some independence between the inflammatory and
`neurodegenerative processes. For example, in a clinical
`trial of alatuzemab (Campath-1H), a monoclonal anti-
`body directed against CD52 which leads to T cell deple-
`tion, in secondary progressive multiple sclerosis, a grad-
`ual extinction of exacerbations and lesion activity
`visible on MRI was demonstrated [12]. However, dis-
`ability continued to progress in about half the patients
`in whom progressive brain atrophy and axonal degener-
`ation could be observed using MRI and magnetic reso-
`nance spectroscopy (MRS). The investigators con-
`cluded, first that inflammation and demyelination were
`responsible for relapses of multiple sclerosis and could
`be prevented by alatuzemab treatment and, second that
`continuing axonal degeneration accounted for the pro-
`gressive phase of disability. Even though axonal injury
`may have been conditioned by prior inflammation, this
`process can continue despite complete suppression of
`inflammatory activity or it is for example the case in
`bone narrow transplanted MS patient.
`There is also neuropathological evidence for a disso-
`ciation between inflammatory demyelination and ax-
`onal injury from a series of 42 biopsy samples obtained
`from patients with multiple sclerosis [3]. Acute axonal
`injury was visualized by amyloid precursor protein
`
`Fig. 2 Possible hypotheses for the causal relationship between inflammation and
`neurodegeneration in the pathogenesis of multiple sclerosis
`
`V/41
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`(APP) staining. There was no relationship between the
`expression of APP or axonal density and the extent of
`demyelination, with axonal injury being observed even
`in lesions that were successfully remyelinating. Simi-
`larly, there was no association between the extent of ax-
`onal injury and markers of acute inflammation such as
`TNF-α or inducible NO synthase. However, axonal in-
`jury was correlated to some extent with the extent of in-
`filtration by CD8 + T lymphocytes and by macrophages.
`A dissociation between neurodegeneration and inflam-
`matory demyelination is also observed in lesions within
`the cortex. These lesions are characterized by a signifi-
`cant degree of axonal transection and apoptosis of neu-
`ronal cell bodies. However, the extent of infiltration by T
`lymphocytes and macrophages and the expression of in-
`flammatory markers is low [4, 30].
`MRI studies in very early disease also suggest that
`inflammation and neuronal injury are not strictly re-
`lated. A study of 31 subjects presenting with a clinically
`isolated syndrome evaluated inflammatory lesion activ-
`ity with classical T2- and T1-weighted images after
`gadolinium enhancement and measured a surrogate
`marker of axonal injury,the size of the N-acetylaspartate
`peak (NAA) determined in the whole brain [14].In these
`patients the mean size of the NAA peak was some 20 %
`lower than that observed in matched controls. No corre-
`lation was observed between the size of the NAA peak
`and lesion volume on either T1 or T2 images. The inves-
`tigators concluded that significant axonal injury occurs
`early in the disease and that this is only indirectly linked
`to inflammatory activity.
`Studies such as these suggest that treatment strate-
`gies for multiple sclerosis need to address both the in-
`flammatory and neurodegenerative components of the
`disease, and that anti-inflammatory therapies may only
`be able to control the inflammation-related neurode-
`generative process adequately [11].
`
`The pathogenic process takes place in the brain
`
`Degeneration of oligodendrocytes, neurons and axons
`are the key pathological features of multiple sclerosis
`which are responsible for the irreversible neurological
`handicap that accumulates in the course of disease. For
`this reason, rational therapies need to target these core
`disease processes in a more specific and a more effective
`way than it is possible with only peripherally acting
`treatments [11]. Nevertheless, the processes underlying
`axonal damage in multiple sclerosis are extremely com-
`plex and certainly multifactorial [16, 18], which has
`hampered development of neuroprotective treatments
`in the past. However, recent developments have identi-
`fied several promising avenues of research for develop-
`ing such drugs.
`Treatments targeting the brain are also more appro-
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`priate with respect to the phase of the disease at which
`treatment is initiated.Although the initial trigger of dis-
`ease in multiple sclerosis is likely to occur in the periph-
`eral immune system, by the time the disease is diag-
`nosed, it is already a localized disease in the central
`nervous system. The initial symptoms correspond to re-
`activation of autoimmune cells, their entry into the
`brain and the triggering of a local demyelinating event.
`However, at this stage, the disease process is already
`characterized by primary and secondary axonal and
`neuronal degeneration and the local environment has
`become to some extent inhospitable for repair and re-
`generation of axons and myelin. Due to the built-in re-
`dundancy of the nervous system, clinical manifestations
`are only apparent once a critical degree of neuronal
`damage has been reached. That is why the earliest stages
`of the disease are as a consequence clinically silent. This
`can be visualized by the reduced brain volume and NAA
`compartments observed by imaging studies performed
`at the first clinical presentation of disease.
`Therapeutic strategies need to take into account this
`burden of tissue damage inside the brain that is already
`present when treatment decisions are first being made.
`Although prevention of future flairs of inflammatory at-
`tack on the nervous system are obviously required, it is
`also important to address existing damage and vulnera-
`bility. For example, strategies could be implemented to
`promote oligodendrocyte survival and repair,to prevent
`further axonal degeneration and neuronal dysfunction
`and to promote axonal and neuronal regeneration. De-
`livery of growth factors to the areas of tissue damage
`would be an interesting possibility to achieve these ob-
`jectives.
`
`The neuroprotective side of neuroinflammation
`
`A promising avenue of research for drug development in
`multiple sclerosis is the concept of protective autoim-
`munity. Although the traditional view has been that
`autoimmune responses are exclusively deleterious,espe-
`cially inside the brain, it now appears clear that autoim-
`mune cells can, under certain conditions, promote
`neural repair. This was first demonstrated in an animal
`model of traumatic optic nerve injury [27] in rats. If the
`rats were injected with activated anti-MBP T cells, they
`retained three times as many retinal ganglion cells with
`functionally intact axons than did rats injected with ac-
`tivated T cells specific for other antigens. Since then, this
`concept has been extended to many other experimental
`paradigms and appears to be a universal principle for
`both immune and non-immune degenerative diseases of
`the central nervous system [32]. For example, in Parkin-
`son’s disease, activated microglia is present in the sub-
`stantia nigra. On the one hand, these cells may con-
`tribute to tissue damage by, for example, the release of
`
`reactive oxygen species or pro-inflammatory cytokines,
`but, on the other, they may protect neurons by the re-
`lease of neurotrophic factors or by removal of excito-
`toxic glutamic acid from the extracellular milieu [35].
`Regulation of activated microglia in Parkinson’s disease
`as a potential target for new neuroprotective therapies is
`an exciting new prospect which is receiving much inter-
`est.
`A possible explanation of this neuroprotective role of
`T cells may be the release of neurotrophic factors from
`immune cells that promote neuronal repair or protect
`against injury [20] (Fig. 3). In particular, brain-derived
`neurotrophic factor (BDNF) has been shown to be pro-
`duced and secreted by a variety of immunocompetent
`cells [2, 5, 19]. BDNF is a potent neurotrophic factor
`which can rescue neurons following axonal transection
`[17]. In autopsy material from multiple sclerosis pa-
`tients, BDNF is present in T cells and macrophages infil-
`trating the lesions [33]. BDNF expression is higher in
`immune cells from active lesions compared to inactive
`ones, consistent with the observation in vitro that ex-
`pression is up-regulated following activation of T cells
`[19]. In addition, the BDNF receptor trkB appears to be
`up-regulated in damaged neurons in the immediate
`vicinity of active lesions [33]. The cellular machinery is
`therefore in place for BDNF-mediated neuroprotective
`immunity in multiple sclerosis lesions.
`The potential neuroprotective effects of growth fac-
`tors have been evaluated extensively in the EAE model
`of human multiple sclerosis. These studies have con-
`cerned nerve growth factor (NGF), leukemia inhibitory
`factor (LIF), insulin-like growth factor-1 (IGF-1) and
`glial growth factor-2 (GGF-2), but not BDNF. In the ma-
`jority of studies, administration of growth factors either
`delayed the onset of disease or reduced the severity of
`the neurological deficit (Table 2).
`
`Fig. 3 Potential neuroprotective effects of neurotrophins released from immune
`cells in inflammatory diseases of the nervous system. Reproduced from [20] with
`permission
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`Table 2 Studies of growth factors in murine models
`of experimental autoimmune encephalitis (EAE)
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`
`Growth factor
`administration
`
`NGF (ICV pump)
`NGF (transduced T cells)
`NGF (IP injection)
`LIF (IP injection)
`IGF-1 (IV injection)
`
`IGF-1/ILGFBP3
`(IP injection)
`IGF-1 (SC injection)
`GGF-2 (SC injection)
`
`EAE model
`
`Clinical outcome
`
`Reference
`
`Delay of EAE onset
`Active MOG EAE
`Suppression of EAE
`Passive MPB EAE Lewis rat
`Delay of EAE onset
`Active and passive MBP EAE
`앗 EAE severity
`TCR-tg mice
`Passive MBP EAE Lewis rat 앗 Mean cumulative
`clinical score
`Delay of EAE onset
`앖 Severity of disease
`앗 Severity of acute EAE
`Delay of EAE onset
`
`Passive MBP EAE PLxSJL
`mice
`Passive MBP EAE SJL mice
`Passive MBP EAE SJL mice
`
`Villoslada [38]
`Flügel [15]
`Arredondo [1]
`Butzkueven [7]
`Liu [24]
`
`Lovett-Racke [25]
`Cannella [9]
`Cannella [8]
`
`GGF-2 glial growth factor-2; IGF-1 insulin-like growth factor-1; LIF leukemia inhibitory factor; MBP myelin basic
`protein; MOG myelin oligodendrocyte glycoprotein; NGF nerve growth factor; TCR-tg T cell receptor transgenic
`
`An interesting study with NGF [15] evaluated the ef-
`fect of transfecting MBP-reactive CD4 + T cells with a
`vector driving NGF expression and synthesis on the
`ability of these T cells to induce EAE when injected into
`rats. These transfected cells produced only a very mild
`EAE syndrome in recipient animals and when co-in-
`jected with non-transfected MBP-reactive T cells atten-
`uated significantly the symptoms of EAE induced by the
`latter (Fig. 4). This suppression of EAE by the trans-
`fected cells was associated with a general reduction of
`immune cells infiltrating the nervous system, notably
`macrophages. This study clearly demonstrates the ben-
`eficial effect of neurotrophins released from immune
`cells on clinical expression of disease.
`The ability of T cells to secrete BDNF when activated
`may be harnessed by GA to endow this drug with a neu-
`roprotective effect in multiple sclerosis that comple-
`
`ments its longer-established anti-inflammatory activity.
`If GA-reactive T cells are recovered from the circulation
`and activated in vitro with GA in the presence of anti-
`gen-presenting cells, secretion of BDNF is stimulated
`[10, 40]. Such BDNF-secreting, GA-reactive T cells can
`be recovered from the circulation of most patients
`treated with GA. These studies have important implica-
`tions for the mechanism of action of GA, supporting the
`hypothesis that GA-reactive T cells activated in the pe-
`riphery may enter the brain and release BDNF in the site
`of active lesions besides their anti-inflammatory factors,
`thus contributing to repair, regeneration and protection
`of axons and neurons (Fig. 5).
`
`Fig. 4 Clinical severity of experimental autoimmune encephalomyelitis in rats in-
`: control T cells; ■
`: T cells
`jected with myelin basic protein-reactive T lymphocytes. ●
`: co-injection of control and transfected
`transfected with nerve growth factor; ▲
`T cells. Adapted from [15] with permission
`
`Fig. 5 Increased production of brain-derived growth factor from GA-reactive T
`cells in the presence of antigen-presenting cells in vitro. BDNF secretion of the TH2-
`like GA-specific T cell line BK-M6-COP-7 of a GA-treated patient, measured by BDNF
`ELISA (top), by RT-PCR (middle) and by intracellular BDNF staining (bottom). Re-
`produced from [41] with permission
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`Conclusions
`
`Multiple sclerosis is no longer considered to be simply
`an autoimmune demyelinating disease. In addition to
`neuroinflammation and demyelination, axonal injury
`and neuronal loss are now also recognized to be hall-
`marks of the disease, and these seem to be the major
`contributors to the accumulation of disability and dis-
`ease progression.
`The mechanism underlying axonal pathology has
`not been clarified so far, but does not appear to be sim-
`ple. The relationship between axonal damage and other
`components of the pathological process such as de-
`myelination, inflammation and remyelination are still
`under intense investigation. Especially in the later
`phases of diseases, most irreversible damage does not
`seem to result from active immune attack resulting in
`new lesions; consequently, reduction of inflammatory
`disease activity produces only marginal effects on ner-
`vous tissue degeneration in these patients. In addition,
`suppression of immune-mediated inflammation does
`not prevent progressive loss of neurological function in
`patients with primary progressive multiple sclerosis.
`Animal models, such as experimental autoimmune
`encephalomyelitis, have been used widely to decipher
`the pathophysiology of multiple sclerosis and predict re-
`sponses to therapy. However, numerous pieces of data
`which are incompatible with this simple autoimmune
`hypothesis have been accumulated over past decades.
`This would suggest that other immunological mecha-
`nisms apart from T cell activation, involving, for ex-
`ample, microglia, or a neurodegenerative component
`within the target tissue,might contribute significantly to
`the initiation, propagation and evolution of disease.
`
`The critical question at the moment is the relation-
`ship between inflammation and axonal injury. If inflam-
`mation is the only factor leading to neurodegeneration
`in multiple sclerosis, immunosuppressants should be
`able to cure multiple sclerosis, which of course is not the
`case with the currently available drugs. On the other
`hand, if inflammation and axonal injury are at least
`partly independent pathologies, axonal injury has to be
`addressed therapeutically in a separate and specific way.
`Treatment of the peripheral immune system (i.e., im-
`munosuppression) will probably only allow modest in-
`direct effects on the inflammatory component of the
`disease process in the brain, which may be of relevance
`in the early stages of the disease. However, a new poten-
`tially beneficial role for neuroinflammation has been
`proposed in some stages of disease, based on data show-
`ing that immune cells in multiple sclerosis lesions can
`demonstrate neuroprotective activity. Such a beneficial
`process would be inhibited by an non-selective im-
`munosuppressive strategy.
`In summary, treatments of multiple sclerosis should
`take into account the heterogeneous pathophysiology of
`the disease. The pathogenic process in the central ner-
`vous system itself should be the major focus in multiple
`sclerosis therapy in order to protect against demyelina-
`tion and axonal loss and to promote remyelination and
`regeneration directly in the target tissue, independently
`of peripheral immune status. In particular, in order to
`produce significant long-term effects in the treatment of
`MS patients, the modulation of processes within the
`central nervous system will be central to therapeutic
`control of the disease – including neuroinflammation
`and neurodegeneration which both take place inside the
`central nervous system.
`
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