- Email: [email protected]
The pathogenesis and basis for treatment in multiple sclerosis
Clinical Neurology and Neurosurgery 106 (2004) 246–248
The pathogenesis and basis for treatment in multiple sclerosis Alastair Compston∗ School of Clinical Medicine, University of Cambridge Neurology, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
Abstract The central concept underlying ideas on the pathogenesis of multiple sclerosis is that inflammatory events cause acute injury of axons and myelin. The phases of symptom onset, recovery, persistence and progression in multiple sclerosis can be summarized as functional impairment with intact structure due to direct effects of inflammatory mediators, demyelination and axonal injury with recovery through plasticity and remyelination, and chronic axonal loss due to failure of enduring remyelination from loss of trophic support for axons normally provided by cells of the oligodendrocyte lineage. © 2004 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; Axonal injury; Demyelination; Remyelination; Pathogenesis; Immunology
1. Discussion The clinical course in multiple sclerosis (MS) is initially characterised by episodes with full recovery, later with attacks that leave persistent deficits and as the frequency of new exacerbations gradually decreases, by the onset of secondary progression. Transition between these three stages is usually gradual and indistinct making for many intermediate forms of the disease. This clinical course is the expression of focal tissue injury affecting the brain and spinal cord and resulting from the complex interplay of inflammation, axonal injury, demyelination, remyelination, astrocytosis and tissue atrophy. Investigators have sought to understand the relative contributions and sequence of these events, so as to be optimally placed to interfere with the pathogenesis—logically and effectively. The main aims of treatment are to prevent the accumulation of disability and disease progression. The emphasis has been on treatments that inhibit inflammation. Taken together, three principles emerge: imaging-based surrogates of disease activity are easily reduced but proved not to be reliable predictors of clinical outcome; therapies that target the complex interactions of immune cells and their mediators involved in the end game of tissue injury may have unexpected and paradoxical effects; and the most consistent clinical achievement is reduction in relapse rate without an effect on disability suggesting that more than mechanism must underlie the complex clinical course in MS. ∗
Tel.: +44-1223-217-091; fax: +44-1223-336-941. E-mail address: [email protected] (A. Compston).
0303-8467/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2004.02.007
The central concept underlying ideas on the pathogenesis of MS is that the cascade of inflammatory events that culminates in demyelination of axons depends on the peripheral activation of T lymphocytes. Activated T cells express adhesion molecules on their surface and up-regulate complementary molecules on the luminal surface of blood vessels, allowing them to cross the blood–brain-barrier by diapedesis. Within the central nervous system, these T cells re-encounter specific antigen and set up an inflammatory process that resembles delayed-type hypersensitivity, dominated by lymphocytes and microglia. Various immunological effector mechanisms are initiated: cytotoxic T-cell proliferation, antibody production and activation of microglia. These then act as antigen presenting cells, increasing the expression of class II major histocompatability antigens and amplifying the local inflammatory response; they also engage opsonised myelin and oligodendrocytes, causing demyelination by cell–cell adherence and local release of inflammatory mediators [1]. As a result, the myelin-oligodendroctye unit is damaged, saltatory conduction breaks down and the symptoms of MS follow. But this is not the whole story, the impact of axonal injury has recently been re-visited and more fully defined. Toxic inflammatory mediators lead to acute injury of neurones and their axonal processes [2]. Nitric oxide may act directly on normal or hypomyelinated axons transiently blocking conduction and reversibly increasing deficits arising from already compromised pathways [3]. As acute inflammation resolves, pathways are released from nitric oxide-induced physiological conduction block. Symptoms also improve as
A. Compston / Clinical Neurology and Neurosurgery 106 (2004) 246–248
surviving functional pathways are re-organised at the cellular and systems level. Together, these mechanisms account for remission early in the disease. Tissue vulnerability is easily exposed. When compounded by high axonal firing frequency, nitric oxide causes structural and hence irreversible changes in axons [4]. Axonal transection in acute inflammatory plaques is shown histologically [5,6] and radiologically through reduction in the neuronal spectroscopic marker, N-acetyl aspartate (NAA) [7]. However, most axonal loss is seen in secondary progressive MS. Embryonic cortical rat neurons, co-cultured with purified oligodendrocytes at different developmental stages and separately with oligodendrocyte conditioned medium, show a marked increase in cell number when co-cultured directly with oligodendrocytes providing experimental evidence that myelin or glia provide survival factors for neurones [8]. Neutralising antibodies to IGF-1, but not other candidate trophic factors, block this soluble survival effect of oligodendrocytes. Cells of the oligodendrocyte lineage produce IGF-1 and recombinant IGF-1 promotes neuronal survival under identical conditions. Oligodendrocyte-conditioned medium increases levels of phosphorylated Akt within neurons. Neurons exposed to oligodendrocyte conditioned medium show increased neurite and axonal length, detected by antibodies to phosphorylated neurofilaments and activation of the MAPkinase/Erk pathway [9]. Erk inhibition reduces oligodendrocyte mediated enhancement of axonal length but, unlike inhibition of PI3 kinase, this has no effect on neuronal survival. Taken together, this in vitro evidence suggests that cells of the oligodendrocyte lineage support neuronal survival by both contact mediated and soluble mechanisms and that IGF-1 contributes this effect through the PI3 kinase/Akt signalling pathway. Conversely, differentiated oligodendrocytes increase neurofilament phosphorylation and axonal length due to an effect of glial cell derived nerve growth factor (GDNF) acting through the MAP kinase/Erk pathways. Loss of these mechanisms may explain the chronic axonal attrition characteristic of MS. Cytokines and growth-promoting factors released by reactive astrocytes and microglia as part of the acute inflammatory process promote endogenous remyelination. But, over time, astrocyte reactivity seals the lesion and gliosis causes a physical barrier to further remyelination, reducing the capacity to accommodate cumulative deficits and marking transition to the stage of persistent deficit. The critical therapeutic issue is the relationship between this neuronal injury and the cerebral inflammation of MS [10]. For instance, if axons degenerate solely because of the metabolic and physiological consequences of prolonged demyelination, as suggested by some radiological studies, then therapies that reduce demyelination should prevent disability and progression. Alternatively, if axons are transected in acute inflammatory plaques [5,6,11] and degenerate chronically through loss of trophic support from cells of the oligodendrocyte lineage [8,9] cerebral inflammation should be suppressed as early and profoundly as possible. Conversely, if, as others have argued, axonal loss and
247
inflammation are fully independent pathologies in multiple sclerosis, immunotherapy may not be capable of influencing progression of disability however early it is deployed. Endogenous remyelination is limited to the acute inflammatory phase and this timing raises the issue of whether, paradoxically, anti-inflammatory treatment might contribute to the failure of repair. For those axons which degenerate early as a direct result of the inflammatory process, efforts at remyelination may have little to offer; conversely, if the naked axon is resistant to the inflammatory milieu but has poor survival properties, remyelination may be neuroprotective and its timing very important. The therapeutic challenge is, whether to enhance endogenous remyelination or develop exogenous cell-based therapies. Experimentally, endogenous remyelination restores conduction and function both in young and adult nervous systems [12,13]. The lesions of multiple sclerosis do contain oligodendrocyte progenitors but these seem unable usefully to engage naked axons [14,15]. Manipulation of mechanisms involved in receptor–ligand growth factor interactions during the inflammatory phase of tissue injury might energise these indolent progenitors and improve remyelination. Thus, one option is to wait until a therapy is available which can be given systemically and delivered simultaneously to all affected parts of the central nervous system. The alternative is first to prove that structure and function can usefully be restored in a single informative lesion before tackling the secondary task of making this intervention diffusely available in the central nervous system. Until recently, the latter seemed the only option. The ideal lesion would be safely accessible, responsible for clinically significant and stable deficits resulting from persistent demyelination of intact axons and at a site where the risks of failure would be acceptable through the presence of an intact paired structure or pathway. An unsuitable lesion would be at an inaccessible site, where intervention would risk a strategic pathway, with an unstable or clinically irreversible deficit and evidence for axon degeneration. Attempts to enhance remyelination would need to be combined with adequate suppression of disease activity [16]. Most is known about the spinal cord and this might appear the obvious choice for a first clinical intervention. The symptoms are a major cause of disability and can to some extent be measured using physiological and imaging techniques. But the risks of failure or increasing deficits within densely packed tracts would be high especially since it would be necessary to avoid patients with established chronic progressive disease and extensive axon degeneration. Magnetic resonance imaging usually shows many lesions in series within the corticospinal tracts so that remyelinating any one would be of limited value. Cord atrophy indicating axon degeneration is usually present in patients with stable or progressive deficits. The optic nerve is attractive because the symptoms are clinically eloquent, physiological assessment and imaging are well developed and there is a paired structure. Failure would not compromise vision in the intact eye. However, the natural history of optic neuritis is usually for recovery which may
248
A. Compston / Clinical Neurology and Neurosurgery 106 (2004) 246–248
occur over many months making it difficult to demonstrate that intervention had altered the natural history of visual recovery and the timing would need fine judgement —waiting for the establishment of persistent visual deficits but avoiding transplantation of a nerve with degenerate axons. Although, the responsible lesion can usually be identified this is often long making for difficulty in placing implanted cells and there is evidence for early atrophy after unilateral optic neuritis despite the expected recovery of vision [17]. The cerebellar peduncle is in some ways the most attractive option since this gives rise to symptoms which can be measured and at a site where remyelination is known to occur and can be imaged. The typical severe proximal tremor is usually unilateral. It presents early and rarely recovers spontaneously. Failure would not be catastrophic and the pathway which involves the superior cerebellar peduncle and red nucleus has long been the target for stereotactic procedures. The responsible lesion can often be identified and has spectroscopic features indicating consistent with preserved axons with near normal tissue. In making the difficult transition between experimental and applied work, neurologists might feel more comfortable about early intervention here than in either the optic nerve or spinal cord. However, the situation may have changed with the demonstration of remyelination and acute neuro-protection following intravenous delivery of murine neural stem cells. Murine neural stem cells injected intravenously into animals with experimental allergic encephalomyelitis expressed the adhesion molecules needed to adhere to and penetrate the blood–brain barrier [18]; they then successfully sought out the areas of demyelination and, once in place, differentiated into myelinating cells re-coating naked but surviving axons, not only achieving structural repair but also restoring physiological conduction and function in affected animals. Furthermore, remyelination protected axons from the degeneration that other wise ensued. These results from Milan suggest a remarkable set of attributes for cells that have not been manipulated in vitro. Indeed, their courage and achievements are reminiscent of a former Venetian explorer—Marco Polo. Clearly, many practical, clinical, ethical and biological problems remain to be overcome before remyelination can become a reality for individual patients with MS.
[2]
[3]
[4] [5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15] [16]
[17]
References [18] [1] Zajicek J, Wing M, Scolding N, Compston D. Interactions between oligodendrocytes and microglia, a major role for complement and
tumor necrosis factor in oligodendrocyte adherence and killing. Brain 1992;115:1611–31. Golde S, Chandran S, Brown G, Compston A. Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J Neurochem 2002;82:269–82. Redford E, Kapoor R, Smith K. Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 1997;120:2149–57. Smith K, Kapoor R, Hall S, Davies M. Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001;49:470–6. Ferguson B, Matyszak M, Esiri M, Perry V. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393–9. Trapp B, Peterson J, Ransohoff R, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–85. Davie C, Barker G, Webb S, Tofts P, Thompson A, Harding A, et al. Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 1995;118:1583–92. Wilkins A, Chandran S, Compston A. A role for oligodendrocytederived IGF-1 in trophic support of cortical neurons. Glia 2001;36: 48–57. Wilkins A, Majed H, Layfield R, Compston A, Chandran S. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci 2003;23:4967– 74. Coles A, Wing M, Molyneux P, Paolillo A, Davie C, Hale G, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46:296– 304. Bitsch A, Schuchardt S, Bunkowski S, Kuhlmann T, Brück W. Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000;123:1174–83. Barnett S, Alexander C, Iwashita Y, Gilson M, Crowther J, Clark L, et al. Identification of a human olfactory unsheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 2000;123:1581–8. Kohama I, Lankford K, Preiningerova J, White F, Vollmer T, Kocsis J. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci 2001;21:944–50. Scolding N, Franklin R, Stevens S, Heldin C, Compston A, Newcombe J. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 1998;121:2221–8. Wolswijk G. Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 2002;125:338–49. Hickman S, Brex P, Brierley C, Silver N, Barker G, Scolding N, et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat saturated short echo fast FLAIR sequence. Neuroradiology 2001;43:123–8. Compston D. Remyelination in multiple sclerosis: a challenge for therapy. The Charcot Lecture: European Charcot Foundation. Int J Multiple Sclerosis 1996;3:51–70. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003;422:688–94.
The pathogenesis and basis for treatment in multiple sclerosis Alastair Compston∗ School of Clinical Medicine, University of Cambridge Neurology, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
Abstract The central concept underlying ideas on the pathogenesis of multiple sclerosis is that inflammatory events cause acute injury of axons and myelin. The phases of symptom onset, recovery, persistence and progression in multiple sclerosis can be summarized as functional impairment with intact structure due to direct effects of inflammatory mediators, demyelination and axonal injury with recovery through plasticity and remyelination, and chronic axonal loss due to failure of enduring remyelination from loss of trophic support for axons normally provided by cells of the oligodendrocyte lineage. © 2004 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; Axonal injury; Demyelination; Remyelination; Pathogenesis; Immunology
1. Discussion The clinical course in multiple sclerosis (MS) is initially characterised by episodes with full recovery, later with attacks that leave persistent deficits and as the frequency of new exacerbations gradually decreases, by the onset of secondary progression. Transition between these three stages is usually gradual and indistinct making for many intermediate forms of the disease. This clinical course is the expression of focal tissue injury affecting the brain and spinal cord and resulting from the complex interplay of inflammation, axonal injury, demyelination, remyelination, astrocytosis and tissue atrophy. Investigators have sought to understand the relative contributions and sequence of these events, so as to be optimally placed to interfere with the pathogenesis—logically and effectively. The main aims of treatment are to prevent the accumulation of disability and disease progression. The emphasis has been on treatments that inhibit inflammation. Taken together, three principles emerge: imaging-based surrogates of disease activity are easily reduced but proved not to be reliable predictors of clinical outcome; therapies that target the complex interactions of immune cells and their mediators involved in the end game of tissue injury may have unexpected and paradoxical effects; and the most consistent clinical achievement is reduction in relapse rate without an effect on disability suggesting that more than mechanism must underlie the complex clinical course in MS. ∗
Tel.: +44-1223-217-091; fax: +44-1223-336-941. E-mail address: [email protected] (A. Compston).
0303-8467/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2004.02.007
The central concept underlying ideas on the pathogenesis of MS is that the cascade of inflammatory events that culminates in demyelination of axons depends on the peripheral activation of T lymphocytes. Activated T cells express adhesion molecules on their surface and up-regulate complementary molecules on the luminal surface of blood vessels, allowing them to cross the blood–brain-barrier by diapedesis. Within the central nervous system, these T cells re-encounter specific antigen and set up an inflammatory process that resembles delayed-type hypersensitivity, dominated by lymphocytes and microglia. Various immunological effector mechanisms are initiated: cytotoxic T-cell proliferation, antibody production and activation of microglia. These then act as antigen presenting cells, increasing the expression of class II major histocompatability antigens and amplifying the local inflammatory response; they also engage opsonised myelin and oligodendrocytes, causing demyelination by cell–cell adherence and local release of inflammatory mediators [1]. As a result, the myelin-oligodendroctye unit is damaged, saltatory conduction breaks down and the symptoms of MS follow. But this is not the whole story, the impact of axonal injury has recently been re-visited and more fully defined. Toxic inflammatory mediators lead to acute injury of neurones and their axonal processes [2]. Nitric oxide may act directly on normal or hypomyelinated axons transiently blocking conduction and reversibly increasing deficits arising from already compromised pathways [3]. As acute inflammation resolves, pathways are released from nitric oxide-induced physiological conduction block. Symptoms also improve as
A. Compston / Clinical Neurology and Neurosurgery 106 (2004) 246–248
surviving functional pathways are re-organised at the cellular and systems level. Together, these mechanisms account for remission early in the disease. Tissue vulnerability is easily exposed. When compounded by high axonal firing frequency, nitric oxide causes structural and hence irreversible changes in axons [4]. Axonal transection in acute inflammatory plaques is shown histologically [5,6] and radiologically through reduction in the neuronal spectroscopic marker, N-acetyl aspartate (NAA) [7]. However, most axonal loss is seen in secondary progressive MS. Embryonic cortical rat neurons, co-cultured with purified oligodendrocytes at different developmental stages and separately with oligodendrocyte conditioned medium, show a marked increase in cell number when co-cultured directly with oligodendrocytes providing experimental evidence that myelin or glia provide survival factors for neurones [8]. Neutralising antibodies to IGF-1, but not other candidate trophic factors, block this soluble survival effect of oligodendrocytes. Cells of the oligodendrocyte lineage produce IGF-1 and recombinant IGF-1 promotes neuronal survival under identical conditions. Oligodendrocyte-conditioned medium increases levels of phosphorylated Akt within neurons. Neurons exposed to oligodendrocyte conditioned medium show increased neurite and axonal length, detected by antibodies to phosphorylated neurofilaments and activation of the MAPkinase/Erk pathway [9]. Erk inhibition reduces oligodendrocyte mediated enhancement of axonal length but, unlike inhibition of PI3 kinase, this has no effect on neuronal survival. Taken together, this in vitro evidence suggests that cells of the oligodendrocyte lineage support neuronal survival by both contact mediated and soluble mechanisms and that IGF-1 contributes this effect through the PI3 kinase/Akt signalling pathway. Conversely, differentiated oligodendrocytes increase neurofilament phosphorylation and axonal length due to an effect of glial cell derived nerve growth factor (GDNF) acting through the MAP kinase/Erk pathways. Loss of these mechanisms may explain the chronic axonal attrition characteristic of MS. Cytokines and growth-promoting factors released by reactive astrocytes and microglia as part of the acute inflammatory process promote endogenous remyelination. But, over time, astrocyte reactivity seals the lesion and gliosis causes a physical barrier to further remyelination, reducing the capacity to accommodate cumulative deficits and marking transition to the stage of persistent deficit. The critical therapeutic issue is the relationship between this neuronal injury and the cerebral inflammation of MS [10]. For instance, if axons degenerate solely because of the metabolic and physiological consequences of prolonged demyelination, as suggested by some radiological studies, then therapies that reduce demyelination should prevent disability and progression. Alternatively, if axons are transected in acute inflammatory plaques [5,6,11] and degenerate chronically through loss of trophic support from cells of the oligodendrocyte lineage [8,9] cerebral inflammation should be suppressed as early and profoundly as possible. Conversely, if, as others have argued, axonal loss and
247
inflammation are fully independent pathologies in multiple sclerosis, immunotherapy may not be capable of influencing progression of disability however early it is deployed. Endogenous remyelination is limited to the acute inflammatory phase and this timing raises the issue of whether, paradoxically, anti-inflammatory treatment might contribute to the failure of repair. For those axons which degenerate early as a direct result of the inflammatory process, efforts at remyelination may have little to offer; conversely, if the naked axon is resistant to the inflammatory milieu but has poor survival properties, remyelination may be neuroprotective and its timing very important. The therapeutic challenge is, whether to enhance endogenous remyelination or develop exogenous cell-based therapies. Experimentally, endogenous remyelination restores conduction and function both in young and adult nervous systems [12,13]. The lesions of multiple sclerosis do contain oligodendrocyte progenitors but these seem unable usefully to engage naked axons [14,15]. Manipulation of mechanisms involved in receptor–ligand growth factor interactions during the inflammatory phase of tissue injury might energise these indolent progenitors and improve remyelination. Thus, one option is to wait until a therapy is available which can be given systemically and delivered simultaneously to all affected parts of the central nervous system. The alternative is first to prove that structure and function can usefully be restored in a single informative lesion before tackling the secondary task of making this intervention diffusely available in the central nervous system. Until recently, the latter seemed the only option. The ideal lesion would be safely accessible, responsible for clinically significant and stable deficits resulting from persistent demyelination of intact axons and at a site where the risks of failure would be acceptable through the presence of an intact paired structure or pathway. An unsuitable lesion would be at an inaccessible site, where intervention would risk a strategic pathway, with an unstable or clinically irreversible deficit and evidence for axon degeneration. Attempts to enhance remyelination would need to be combined with adequate suppression of disease activity [16]. Most is known about the spinal cord and this might appear the obvious choice for a first clinical intervention. The symptoms are a major cause of disability and can to some extent be measured using physiological and imaging techniques. But the risks of failure or increasing deficits within densely packed tracts would be high especially since it would be necessary to avoid patients with established chronic progressive disease and extensive axon degeneration. Magnetic resonance imaging usually shows many lesions in series within the corticospinal tracts so that remyelinating any one would be of limited value. Cord atrophy indicating axon degeneration is usually present in patients with stable or progressive deficits. The optic nerve is attractive because the symptoms are clinically eloquent, physiological assessment and imaging are well developed and there is a paired structure. Failure would not compromise vision in the intact eye. However, the natural history of optic neuritis is usually for recovery which may
248
A. Compston / Clinical Neurology and Neurosurgery 106 (2004) 246–248
occur over many months making it difficult to demonstrate that intervention had altered the natural history of visual recovery and the timing would need fine judgement —waiting for the establishment of persistent visual deficits but avoiding transplantation of a nerve with degenerate axons. Although, the responsible lesion can usually be identified this is often long making for difficulty in placing implanted cells and there is evidence for early atrophy after unilateral optic neuritis despite the expected recovery of vision [17]. The cerebellar peduncle is in some ways the most attractive option since this gives rise to symptoms which can be measured and at a site where remyelination is known to occur and can be imaged. The typical severe proximal tremor is usually unilateral. It presents early and rarely recovers spontaneously. Failure would not be catastrophic and the pathway which involves the superior cerebellar peduncle and red nucleus has long been the target for stereotactic procedures. The responsible lesion can often be identified and has spectroscopic features indicating consistent with preserved axons with near normal tissue. In making the difficult transition between experimental and applied work, neurologists might feel more comfortable about early intervention here than in either the optic nerve or spinal cord. However, the situation may have changed with the demonstration of remyelination and acute neuro-protection following intravenous delivery of murine neural stem cells. Murine neural stem cells injected intravenously into animals with experimental allergic encephalomyelitis expressed the adhesion molecules needed to adhere to and penetrate the blood–brain barrier [18]; they then successfully sought out the areas of demyelination and, once in place, differentiated into myelinating cells re-coating naked but surviving axons, not only achieving structural repair but also restoring physiological conduction and function in affected animals. Furthermore, remyelination protected axons from the degeneration that other wise ensued. These results from Milan suggest a remarkable set of attributes for cells that have not been manipulated in vitro. Indeed, their courage and achievements are reminiscent of a former Venetian explorer—Marco Polo. Clearly, many practical, clinical, ethical and biological problems remain to be overcome before remyelination can become a reality for individual patients with MS.
[2]
[3]
[4] [5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15] [16]
[17]
References [18] [1] Zajicek J, Wing M, Scolding N, Compston D. Interactions between oligodendrocytes and microglia, a major role for complement and
tumor necrosis factor in oligodendrocyte adherence and killing. Brain 1992;115:1611–31. Golde S, Chandran S, Brown G, Compston A. Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J Neurochem 2002;82:269–82. Redford E, Kapoor R, Smith K. Nitric oxide donors reversibly block axonal conduction: demyelinated axons are especially susceptible. Brain 1997;120:2149–57. Smith K, Kapoor R, Hall S, Davies M. Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 2001;49:470–6. Ferguson B, Matyszak M, Esiri M, Perry V. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393–9. Trapp B, Peterson J, Ransohoff R, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–85. Davie C, Barker G, Webb S, Tofts P, Thompson A, Harding A, et al. Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 1995;118:1583–92. Wilkins A, Chandran S, Compston A. A role for oligodendrocytederived IGF-1 in trophic support of cortical neurons. Glia 2001;36: 48–57. Wilkins A, Majed H, Layfield R, Compston A, Chandran S. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci 2003;23:4967– 74. Coles A, Wing M, Molyneux P, Paolillo A, Davie C, Hale G, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46:296– 304. Bitsch A, Schuchardt S, Bunkowski S, Kuhlmann T, Brück W. Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000;123:1174–83. Barnett S, Alexander C, Iwashita Y, Gilson M, Crowther J, Clark L, et al. Identification of a human olfactory unsheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 2000;123:1581–8. Kohama I, Lankford K, Preiningerova J, White F, Vollmer T, Kocsis J. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci 2001;21:944–50. Scolding N, Franklin R, Stevens S, Heldin C, Compston A, Newcombe J. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 1998;121:2221–8. Wolswijk G. Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 2002;125:338–49. Hickman S, Brex P, Brierley C, Silver N, Barker G, Scolding N, et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat saturated short echo fast FLAIR sequence. Neuroradiology 2001;43:123–8. Compston D. Remyelination in multiple sclerosis: a challenge for therapy. The Charcot Lecture: European Charcot Foundation. Int J Multiple Sclerosis 1996;3:51–70. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003;422:688–94.