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Role of IL-1 and potential therapies in multiple sclerosis
Drug Discovery Today: Therapeutic Strategies
Vol. 4, No. 1 2007
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Immunological disorders
Role of IL-1 and potential therapies in multiple sclerosis Yoko Warabi1,2 1 2
Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai Fuchu, Tokyo 183-0042, Japan Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
According to studies using animal models of multiple sclerosis (MS), the pathogenesis of Interleukin-1 (IL-1) and the effects of the IL-1 inhibition therapy for MS
Section Editor: Martin Braddock – Discovery BioScience, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, England, UK
have been clarified. In both MS and neuromyelitis optica, systemic IL-1 inhibition will be a therapeutic target. However, studies to clarify whether maintenance therapy for MS with IL-1 inhibitor will prevent the next relapse will be needed, because IL-1ra gene therapy after disease onset was not effective in the animal study.
Introduction Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) of unknown etiology. Antigen-specific T cell activation is crucial in the development of the pathogenic process for the relapse of MS [1]. Moreover, pro-inflammatory cytokines are important for sustaining MS as these cytokines represent the main mediators of mononuclear cell activation in the periphery. Interleukin-1 (IL-1) is one of the major pro-inflammatory cytokines. IL-1 inhibition have been tried to treat various human diseases such as rheumatoid arthritis and cerebral ischemia. According to studies using animal models of MS, the pathogenesis of IL-1 and the effects of IL-1 inhibition therapy for MS have been clarified. In this article, I review the function of IL-1, especially the inflammation and glial reaction, and discuss the possibility for the future use of IL-1-related molecules in MS therapy. E-mail address: Y. Warabi ([email protected]) 1740-6773/$ ß 2007 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2007.08.006
Interleukin-1: IL-1 family and the transduction mechanism The IL-1 family consists of ten members that are named IL1F1 to IL-1F10 [2]. The agonists IL-1a (IL-1F1) and IL-1b (IL1F2), the IL-1 receptor antagonist (IL-1ra, IL-1F3), and IL-18 (IL-1F4) are well known from early research. Except for IL-18, the genes of the IL-1 family have been mapped to chromosome 2. IL-1a and IL-1b have a difference in the isoelectric point. IL-1 is expressed in the monocytes and macrophages in the periphery. In the brain, IL-1 has been demonstrated in most cells including neurons, astrocytes, oligodendrocytes and endothelial cells. In addition, activated microglia and invading macrophages may be important sources of IL-1, particularly after brain damage or breakdown of the blood brain barrier [3]. Constitutive expression of IL-1a in normal rat brain tissue is mainly because of the expression by neurons, and IL-1a is distributed pan-neuronally throughout the brain [4]. About IL-1b, several studies have demonstrated that constitutive expression of IL-1b is very low in the brain; however, levels of IL-1b increase dramatically after injury. Conversely, there have also been many reports that IL-1b is constitutively expressed in the cerebral cortex, hippocampus and basal forebrain [4]. It is suspected that IL-1a is produced in various somatic cells and contributes to the daily maintenance of the body. IL-1b is considered to be produced in large quantities especially during emergencies such as infections and injury, and acts during those situations. 19
Drug Discovery Today: Therapeutic Strategies | Immunological disorders
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Role of IL-1 in inflammation and glial reaction
Figure 1. Signal transduction mechanism of IL-1. ICE: interleukin-1b converting enzyme (caspase-1); IL-1 AcP: IL-1 accessory protein; IRAK: interleukin-1 receptor associated kinase; TRAF6: tumor necrosis factor receptor-associated factor 6; NIK: NF-kB inducing kinase.
IL-1a, IL-1b and IL-1ra share the same receptors and bind to two types of specific membrane receptors of which only the type I IL-1 receptor (IL-1RI) transduces signals while type II IL1 receptor (IL-1RII) functions as a decoy receptor without participating in IL-1 signaling [5] (Fig. 1). IL-1RI expression is demonstrated in T cells and fibroblasts. IL-1RII is present in B cells, macrophages, neutrophils and hepatocytes. Actions of IL-1 are inhibited by the highly competitive endogenous IL1ra that blocks the binding of IL-1a and IL-1b to IL-1RI, preventing the generation of an intracellular signal [6]. Intracellular signal transduction of the IL-1 family has several routes. Representative one that activates NF-kB is demonstrated in Fig. 1. 20
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IL-1 is one of the major pro-inflammatory cytokines and is an upstream mediator of the innate immune response. IL-1 induces the production of various growth and trophic factors, inflammatory mediators, adhesion molecules and other cytokines directly and indirectly, as well as using a positive feedback loop (Table 1) [7,8]. Therefore, IL-1 is related to the onset of various inflammatory, autoimmune and infectious diseases. Conversely, IL-1 has multiple aspects of the response of the brain injury. Penetrating brain injury model of IL-1RI null mice demonstrated other roles of IL-1 in the central nervous system [7]. Lacking IL-1RI induced: (1) diminished activation of resting microglia toward a reactive state, (2) deficient recruitment of peripheral macrophages and (3) an abated astroglial response. If IL-1 activates microglia, it release a diverse set of cytokines and other toxic molecules including toxic oxygen radicals, peroxides, nitric oxide and lipid mediators of inflammation, such as prostaglandins, leukotrienes and platelet-activating factor. Thus, IL-1 increases inflammation indirectly using these responses of glial network. Moreover, glia plays a key role in the production and actions of endogenous IL-1ra. IL-1ra critically regulates the balance between anti- and pro inflammatory (IL-1a/IL-1b) influences on ischemic cell death [9]. Antagonizing IL-1 protects neurons and glia not only from direct inflammatory process but also from glial reaction. The pathomechanism of MS involves the activation of autoantigen-reactive T cells in the periphery, followed by invasion into the CNS and leading to organ-specific autoimmune disease. IL-1 is crucial in the development of the pathogenic process sustaining MS as they participate not only in myelin-specific T cell activation but also represent the main mediator of macrophage activation in periphery [10]
Table 1. Factors induced by IL-1 Growth and trophic factors on CNS neurons Fibroblast growth factor-2 (FGF-2) Transforming growth factor b1 (TGF-b1) Nerve growth factor (NGF) Inflammatory mediators Phospholipase A2 Cyclooxygenase-2 (Cox-2) Prostaglandins Nitric oxide Matrix metalloprotainases Collagenase Adhesion molecules and other cytokines Vascular cell adhesion molecule-1 (VCAM-1) Intracellular cell adhesion molecule-1 (ICAM-1) E-selectin Interleukin-6 (IL-6) Tumor necrosis factor-a (TNF-a) Colony-stimulating factors (CSFs)
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Drug Discovery Today: Therapeutic Strategies | Immunological disorders
Figure 2. The pathomechanism of MS and the role of IL-1 in MS. IL-1 is crucial in the development of the pathogenic process sustaining MS as they participate not only in myelin-specific T cell activation but also represent the main mediator of macrophage activation in periphery. Disruption of blood– brain barrier by activated CD4-positive T cells will increase endothelial cell transport of cells and other molecules into the brain parenchyma. Then, CNSinfiltrating macrophages, resident microglial cells and oligodendrocytes themselves will secrete IL-1, and complicated set of inflammatory processes and glial reactions will lead to the demyelination of the CNS directly and indirectly.
(Fig. 2). Disruption of blood–brain barrier by activated CD4positive T cells will increase endothelial cell transport of cells and other molecules into the brain parenchyma. Then, CNSinfiltrating macrophages, resident microglial cells and oligodendrocytes themselves will secrete IL-1, and the above mentioned inflammatory process and glial reaction will lead to the demyelination of the CNS directly and indirectly.
Clinical trials for human diseases involving IL-1-related molecules Rheumatoid arthritis IL-1 inhibition is considered to have a therapeutic effect and has been tried to treat various human diseases. The recombinant methionylated form of human IL-1 receptor antagonist (rhIL-1ra; anakinra) is a specific IL-1 inhibitor approved for human use and various levels of clinical trials for this agent are now in progress. Especially, autoimmune diseases and inflammatory diseases are targets for this therapy and have mostly been reported to show a good prognosis; that is rheumatoid arthritis (RA), juvenile arthritis, gout, Behcet’s disease, ulcerative colitis, uvitis, dermatolo-
gical diseases, renal amyloidosis and type II diabetes mellitus [11,12]. Over the past decade, the treatment of RA has changed with the advent of biologic agents such as anakinra. In patients with persistent disease despite aggressive management with traditional disease modifying antirheumatic drugs (DMARD), biologics are now considered the standard of care. Gartlehner et al. reported a metaanalysis of randomized placebo-controlled trials of 1039 RA patients who were methotrexate-resistant and analyzed the efficacy and safety of anakinra [13]. Anakinra is effective, but it is less efficacious than anti-tumor necrosis factor (TNF) drugs. Moreover, subcutaneous injection of anakinra has a substantially higher rate of injection site reactions than that of anti-TNF drugs. The rate of serious adverse events such as infections, lymphoma, or neutropenia did not differ significantly between patients treated with anakinra and placebo.
Acute stroke IL-1 does not induce brain damage when injected into the brain of naı¨ve animals, but strongly exacerbates brain damage www.drugdiscoverytoday.com
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induced by cerebral ischemia [3]. Endogenous IL-1ra produced by microglia is neuroprotective in cerebral ischemia in mice [9]. IL-1ra reduces lesion size, increases neuronal survival, reduces edema, glial activation, and invasion of peripheral immune cells, and improves behavioral outcome. Exogenous IL-1ra administration also reduces ischemic brain damage and deletion of both IL-1a and IL-1b in animals confers neuroprotection against ischemic brain damage [14]. In humans, randomized, double blind, placebo-controlled study of anakinra (Kineret1; Amgen Thousand Oaks, CA, USA) in 34 acute stroke patients was undertaken [15]. Test treatment was administered intravenously with a 100 mg loading dose over 60 s, followed by a 2 mg/kg/h infusion over 72 h. Both during the first 72 h and after 3 months, there were no serious adverse events. The most frequently occurring non-serious adverse event was infection because IL-1 plays an important role in host defense against infection. On analysis of biological activity, peripheral total white blood cell counts, neutrophil counts, plasma C reactive protein and IL-6 concentrations were lower in the anakinra-treated group than in the placebo-treated group during the test treatment infusion period. Clinical outcomes at 3 months in the anakinra-treated group were better than those in placebo-treated group.
Therapeutic efficacy of selective IL-1 inhibition for experimental autoimmune encephalomyelitis In experimental autoimmune encephalomyelitis (EAE), an animal model for MS, both IL-1a and IL-1b have been shown to be mediators of the inflammatory process. Peripheral levels of IL-1b correlate with the clinical course and IL-1b reactivity has been shown during EAE in CNS-infiltrating macrophages and in resident microglial cells [16–18]. Therefore, IL-1 is considered to be a suitable therapeutic target in EAE and MS. To inhibit IL-1 selectively in EAE, there have been several reported methods. Soluble IL-1 receptor (sIL-1R) treatment was considered as an IL-1 antagonist to block competitively endogenous IL-1 from binding and activating cells expressing membrane IL-1R [16]. Lewis rats were immunized with guinea pig myelin (GPM) and treated with i.p. injections of recombinant human sIL-1R. Daily injections of sIL-1R were initiated 1 day before GPM immunization and continued until day 11. sIL-1R treatment exhibited a delay in mean day of onset and suppressed clinical paralysis and weight loss. Thus, systemic administration of sIL-1R was considered to inhibit the CNS inflammation. rhIL-1ra was also reported to be beneficial for treatment of EAE. Lewis rats immunized with myelin basic protein (MBP) were treated with subcutaneous rhIL-1ra every day starting on day 9 post-immunization with MBP during the effector phase of EAE [19]. This treatment delayed the onset, reduced the severity of paralysis and weight loss, and shortened the duration of disease. Badovinac et al. treated EAE during the induction phase of disease with IL-1ra [20]. EAE was actively 22
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induced in DA rats using rat spinal cord tissue homogenate. IL-1ra was given i.p. daily starting from the day of immunization (day 0) until day 6. They demonstrated that a beneficial effect was obtained after administering IL-1ra during the inductive phase. Disease recovery and weight gain continued to occur even after cessation of IL-1ra treatment, as a result of suppressing the cascade of IL-1-dependent events associated with disease progression. They also demonstrated that in vitro treatment with IL-1ra had direct effects on T cell growth for EAE. Selective IL-1 inhibition by gene therapy was also reported in EAE. Furlan et al. constructed an IL-1ra producing nonreplicative Herpes simplex virus-1 derived vector (TH:IL-1ra) [10]. C57BL/6 mice affected by myelin oligodendrocyte glycoprotein (MOG)-induced EAE were treated with intracisternal injection of TH:IL-1ra on the day of immunization and again after 7 days. As a result, in mice treated with TH:IL-1ra, disease onset was significantly delayed and disease severity was significantly reduced. Perimeningeal macrophages were significantly reduced in EAE mice injected with TH:IL-1ra, although a comparable number of T cells entered the CNS. Conversely, TH:IL-1ra treatment after disease onset was not effective and EAE progressed. As a non-specific immunosuppressive therapy, my research group reported the treatment of EAE rats with a preliminary anti-rheumatic drug [21]. T-614, 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, had been shown to significantly inhibit the production of proinflammatory cytokines including IL-1 and IL-6 by human monocytes/macrophages. Lewis rats immunized with MBP were treated with oral T-614 once a day starting from the day of immunization. T-614 exhibited significant inhibitory effects on the incidence and clinical severity of EAE. T-614 inhibited not only inflammatory infiltration into the CNS, but also activation of microglial cells leading to inflammation. Although T-614 treatment during the pre-symptomatic induction phase (day 0–7) is not effective, the effector phase of autoimmune processes was disrupted by T-614.
Future challenges in the use of IL-1-related molecules for MS therapy Selective inhibition versus non-selective inhibition of IL-1 It is clear from the above EAE experiments that IL-1 inhibition is a potential therapeutic target in the treatment of MS. Furthermore, genetic studies have shown the relationship between IL-1 gene polymorphisms and disease severity of MS [22]. Because IL-1 is an upstream mediator of the innate immune response, therapies directed at IL-1 may prove far more effective than inhibiting any other single inflammatory mediator. Moreover, because glial cells are the mainly affected system in MS, regulation of the IL-1 family is expected to have direct modulatory effects on the pathogenic glial reactions in MS.
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Currently, highly selective IL-1 inhibitors, like anakinra, have not been approved for the treatment of human MS. To inhibit the functions of the pathogenic IL-1 selectively, I agree with the suggestions by Touzani et al. about the strategies for IL-1 blocking [3]. Several strategies have been proposed to block IL-1 mediated injury: (1) inhibition of the synthesis of IL-1, (2) inhibition of maturation with IL1b converting enzyme (ICE; caspase-1), (3) buffering IL-1 with binding proteins or soluble receptors, (4) antagonism of IL-1 receptors with IL-1ra or other non peptide antagonists, and (5) inhibition of signal transduction or other mediators of IL-1 (Fig. 1). Thus, there will be several candidate therapeutic agents to research for MS therapy that block IL-1 selectively; that is IL-1ra, IL-1 blocking antibodies, sIL-1R, gene therapies, RNA aptamers or cytokine trap [23]. ICE inhibition has been studied in vitro and in vivo using experimental models of the septic disease, inflammatory disease and seizures [24–28]. To inactivate ICE, ICE inhibitor such as a highly selective, irreversible inhibitor of ICE (YVADcmk), pralnacasan (Vertex Pharmaceuticals, Inc., Cambridge, MA, USA), VX-765 and the organotellurium compound (AS101) or caspase-1 gene deletion method is used. The precursors of IL-1b and IL-18 have been identified as substrates for ICE. Therefore, ICE deficiency is associated with a more pronounced effect compared with single blockade of either IL-1b or IL-18. However, studies showing the effectiveness of IL-18 antagonism have been mostly against bacterial infection rather than autoimmune diseases. In the light of the recent discoveries on the role of the P2X7 receptor (P2X7R), blockers of P2X7R may have a future as antiinflammatory drugs [29]. Extracellular ATP is considered as a candidate danger signal locally released at the inception of inflammation. ATP-driven maturation and release of IL-1b are specifically mediated by the P2X7R for extracellular ATP, and caspase-1 activity is showed to be necessary for P2X7Rdependent release of mature IL-1b. However, far more studies on the characterization of the P2X7R and the effect on the autoimmune diseases will be needed for treating MS. A non-selective inhibitory mechanism of IL-1 has been shown in existing therapeutic agents for MS; that is interferon beta, anti-inflammatory glucocorticoids, immunosuppressants, atorvastatin and omega-3 polyunsaturated fatty acids [30–32].
Maintenance therapy versus treatment for acute relapse of MS Which step in a complex cascade of immunological events leading to CNS tissue damage requires IL-1 is a critical factor for developing a treatment for MS. However, it is impossible to prevent healthy subjects from the initial onset of MS. Thus, if the IL-1ra gene therapy after disease onset is absolutely not effective as in the EAE study [10], this method may not be promising. Moreover, if diagnosis of MS is made, it is impossible to predict the next relapse accurately. So, starting the
Drug Discovery Today: Therapeutic Strategies | Immunological disorders
therapy during the effector phase of MS relapse would be extremely difficult. Studies to clarify whether maintenance therapy of MS with IL-1 inhibitor would prevent the next relapse and disease progression will be needed. For acute relapse of MS, although intravenous methylprednisolone, intravenous immunoglobulin or plasmapheresis are the current treatments of choice, study of intravenous anakinra in acute stroke patients will provide us with useful information [15].
Systemic administration versus local injection in MS lesions of CNS The pathomechanism of MS involves the activation of autoantigen-reactive T cells in the periphery, followed by invasion into the CNS and leading to organ-specific autoimmune disease. Moreover, the EAE studies discussed above were effective with i.p. administration. Thus, I think that IL-1 inhibition as maintenance therapy for MS may be beneficial with peripheral and systemic administration to prevent the initial autoimmune response rather than local therapy to the CNS. Conversely, CNS administration may be effective for the very acute phase of relapse, but studies on the safety of such treatment will be needed.
MS versus Neuromyelitis optica Neuromyelitis optica (NMO) was defined as an inflammatory demyelinating disease in the central nervous system in which the lesions are localized in the optic nerve and spinal cord [33]. An autoantibody called NMO-IgG is found in the serum of NMO patients and is reported to be the same as antiaquaporin-4 antibody [34,35]. The role of IL-1 in the pathogenesis of NMO is not well understood. The therapeutic strategy for NMO is different from that for MS, especially interferon beta rather exacerbates the clinical status of NMO [36]. However, I think that IL-1 inhibition may be beneficial for NMO as well as MS for the following two reasons. One is that anti-aquaporin-4 antibody is considered not only a disease marker of NMO but also it has a direct destructive function for CNS. Humoral immune response and the direct invasion of macrophages into the CNS lesion are shown to be pathological characterizations of NMO [37]. Therefore, NMO lesion will be a good target for IL-1 inhibition. The second reason is that the T cell immunity represented by antigenspecific activation of the T cell receptor is stronger in NMO than in MS [38]. IL-1 affects for the activation of T helper cells directly and indirectly, as well as using a positive feedback loop. Thus, peripheral inhibition of IL-1 will also be beneficial in the treatment of NMO.
Conclusions Selective and non-selective IL-1 inhibition is effective for EAE during the inductive phase and effector phase of autoimmune processes because of anti-inflammation and glial reaction. Human use of rhIL-1ra; anakinra, is in progress for other www.drugdiscoverytoday.com
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diseases especially RA and cerebral infarctions. In both MS and NMO, IL-1 inhibition will be a therapeutic target. In MS, autoantigen-reactive T cells are activated in periphery, invade into CNS and lead to the organ-specific autoimmune disease; therefore, IL-1 inhibition as a maintenance therapy by peripheral administration to prevent the initial autoimmune response of MS may be more beneficial than local therapy to the CNS. However, studies to clarify whether maintenance therapy for MS with IL-1 inhibitor will prevent the next relapse and disease progression will be needed, because IL1ra gene therapy after disease onset was not effective in the EAE study. If it were possible to predict the first onset of MS in healthy subjects or to predict the next relapse in patients already diagnosed as having MS, IL-1 inhibition could be administered at the most effective step in a complex cascade of immunological events leading to CNS tissue damage.
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Acknowledgements I thank Dr Yoh Matsumoto for helpful discussion and critical reading of the article. This article was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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Boutin, H. et al. (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J. Neurosci. 21, 5528–5534 Emsley, H.C. et al. (2005) A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J. Neurol. Neurosurg. Psychiatry 76, 1366–1372 Jacobs, C.A. et al. (1991) Experimental autoimmune encephalomyelitis is exacerbated by IL-1 alpha and suppressed by soluble IL-1 receptor. J. Immunol. 146, 2983–2989 Furlan, R. et al. (1999) Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. J. Immunol. 163, 2403–2409 Bauer, J. et al. (1993) Demonstration of interleukin-1 beta in Lewis rat brain during experimental allergic encephalomyelitis by immunocytochemistry at the light and ultra structural level. J. Neuroimmunol. 48, 13–21 Martin, D. and Near, S.L. (1995) Protective effect of the interleukin-1 receptor antagonist (IL-1ra) on experimental allergic encephalomyelitis in rats. J. Neuroimmunol. 61, 241–245 Badovinac, V. et al. (1998) Interleukin-1 receptor antagonist suppresses experimental autoimmune encephalomyelitis (EAE) in rats by influencing the activation and proliferation of encephalitogenic cells. J. Neuroimmunol. 85, 87–95 Aikawa, Y. et al. (1998) A new anti-rheumatic drug, T-614, effectively suppresses the development of autoimmune encephalomyelitis. J. Neuroimmunol. 89, 35–42 Schrijver, H.M. et al. (2003) Interleukin (IL)-1 gene polymorphisms: relevance of disease severity associated alleles with IL-1beta and IL-1ra production in multiple sclerosis. Mediators. Inflamm. 12, 89–94 Economides, A.N. et al. (2003) Cytokine traps: multi-component, highaffinity blockers of cytokine action. Nat. Med. 9, 47–52 Paszkowski, A.S. et al. (2002) Therapeutic application of caspase 1/ interleukin-1beta-converting enzyme inhibitor decreases the death rate in severe acute experimental pancreatitis. Ann. Surg. 235, 68–76 Messerli, S.M. et al. (2004) A novel method for imaging apoptosis using a caspase-1 near-infrared fluorescent probe. Neoplasia 6, 95–105 Ravizza, T. et al. (2006) Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47, 1160–1168 Brodsky, M. et al. (2007) The synthetic tellurium compound, AS101, is a novel inhibitor of IL-1beta converting enzyme. J. Interferon. Cytokine Res. 27, 453–462 Siegmund, B. et al. (2001) IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation. Proc. Natl. Acad. Sci. U. S. A. 98, 13249–13254 Ferrari, D. et al. (2006) The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol. 176, 3877–3883 Sciacca, F.L. et al. (2000) Induction of IL-1 receptor antagonist by interferon beta: implication for the treatment of multiple sclerosis. J. Neurovirol. 6 (Suppl. 2), S33–S37 Pannu, R. et al. (2005) Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats. J. Neurosci. Res. 79, 340–350 Simopoulos, A.P. (2002) Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr. 21, 495–505 Wingerchuk, D.M. et al. (1999) The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 53, 1107–1114 Lennon, V.A. et al. (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106–2112 Lennon, V.A. et al. (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J. Exp. Med. 202, 473–477 Warabi, Y. et al. (2007) Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination. J. Neurol. Sci. 252, 57–61 Misu, T. et al. (2007) Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 130 (Pt 5), 1224–1234 Warabi, Y. et al. (2006) Characterization of the T cell receptor repertoire in the Japanese neuromyelitis optica: T cell activity is up-regulated compared to multiple sclerosis. J. Neurol. Sci. 249, 145–152
Vol. 4, No. 1 2007
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Immunological disorders
Role of IL-1 and potential therapies in multiple sclerosis Yoko Warabi1,2 1 2
Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai Fuchu, Tokyo 183-0042, Japan Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
According to studies using animal models of multiple sclerosis (MS), the pathogenesis of Interleukin-1 (IL-1) and the effects of the IL-1 inhibition therapy for MS
Section Editor: Martin Braddock – Discovery BioScience, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, England, UK
have been clarified. In both MS and neuromyelitis optica, systemic IL-1 inhibition will be a therapeutic target. However, studies to clarify whether maintenance therapy for MS with IL-1 inhibitor will prevent the next relapse will be needed, because IL-1ra gene therapy after disease onset was not effective in the animal study.
Introduction Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) of unknown etiology. Antigen-specific T cell activation is crucial in the development of the pathogenic process for the relapse of MS [1]. Moreover, pro-inflammatory cytokines are important for sustaining MS as these cytokines represent the main mediators of mononuclear cell activation in the periphery. Interleukin-1 (IL-1) is one of the major pro-inflammatory cytokines. IL-1 inhibition have been tried to treat various human diseases such as rheumatoid arthritis and cerebral ischemia. According to studies using animal models of MS, the pathogenesis of IL-1 and the effects of IL-1 inhibition therapy for MS have been clarified. In this article, I review the function of IL-1, especially the inflammation and glial reaction, and discuss the possibility for the future use of IL-1-related molecules in MS therapy. E-mail address: Y. Warabi ([email protected]) 1740-6773/$ ß 2007 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2007.08.006
Interleukin-1: IL-1 family and the transduction mechanism The IL-1 family consists of ten members that are named IL1F1 to IL-1F10 [2]. The agonists IL-1a (IL-1F1) and IL-1b (IL1F2), the IL-1 receptor antagonist (IL-1ra, IL-1F3), and IL-18 (IL-1F4) are well known from early research. Except for IL-18, the genes of the IL-1 family have been mapped to chromosome 2. IL-1a and IL-1b have a difference in the isoelectric point. IL-1 is expressed in the monocytes and macrophages in the periphery. In the brain, IL-1 has been demonstrated in most cells including neurons, astrocytes, oligodendrocytes and endothelial cells. In addition, activated microglia and invading macrophages may be important sources of IL-1, particularly after brain damage or breakdown of the blood brain barrier [3]. Constitutive expression of IL-1a in normal rat brain tissue is mainly because of the expression by neurons, and IL-1a is distributed pan-neuronally throughout the brain [4]. About IL-1b, several studies have demonstrated that constitutive expression of IL-1b is very low in the brain; however, levels of IL-1b increase dramatically after injury. Conversely, there have also been many reports that IL-1b is constitutively expressed in the cerebral cortex, hippocampus and basal forebrain [4]. It is suspected that IL-1a is produced in various somatic cells and contributes to the daily maintenance of the body. IL-1b is considered to be produced in large quantities especially during emergencies such as infections and injury, and acts during those situations. 19
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Role of IL-1 in inflammation and glial reaction
Figure 1. Signal transduction mechanism of IL-1. ICE: interleukin-1b converting enzyme (caspase-1); IL-1 AcP: IL-1 accessory protein; IRAK: interleukin-1 receptor associated kinase; TRAF6: tumor necrosis factor receptor-associated factor 6; NIK: NF-kB inducing kinase.
IL-1a, IL-1b and IL-1ra share the same receptors and bind to two types of specific membrane receptors of which only the type I IL-1 receptor (IL-1RI) transduces signals while type II IL1 receptor (IL-1RII) functions as a decoy receptor without participating in IL-1 signaling [5] (Fig. 1). IL-1RI expression is demonstrated in T cells and fibroblasts. IL-1RII is present in B cells, macrophages, neutrophils and hepatocytes. Actions of IL-1 are inhibited by the highly competitive endogenous IL1ra that blocks the binding of IL-1a and IL-1b to IL-1RI, preventing the generation of an intracellular signal [6]. Intracellular signal transduction of the IL-1 family has several routes. Representative one that activates NF-kB is demonstrated in Fig. 1. 20
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IL-1 is one of the major pro-inflammatory cytokines and is an upstream mediator of the innate immune response. IL-1 induces the production of various growth and trophic factors, inflammatory mediators, adhesion molecules and other cytokines directly and indirectly, as well as using a positive feedback loop (Table 1) [7,8]. Therefore, IL-1 is related to the onset of various inflammatory, autoimmune and infectious diseases. Conversely, IL-1 has multiple aspects of the response of the brain injury. Penetrating brain injury model of IL-1RI null mice demonstrated other roles of IL-1 in the central nervous system [7]. Lacking IL-1RI induced: (1) diminished activation of resting microglia toward a reactive state, (2) deficient recruitment of peripheral macrophages and (3) an abated astroglial response. If IL-1 activates microglia, it release a diverse set of cytokines and other toxic molecules including toxic oxygen radicals, peroxides, nitric oxide and lipid mediators of inflammation, such as prostaglandins, leukotrienes and platelet-activating factor. Thus, IL-1 increases inflammation indirectly using these responses of glial network. Moreover, glia plays a key role in the production and actions of endogenous IL-1ra. IL-1ra critically regulates the balance between anti- and pro inflammatory (IL-1a/IL-1b) influences on ischemic cell death [9]. Antagonizing IL-1 protects neurons and glia not only from direct inflammatory process but also from glial reaction. The pathomechanism of MS involves the activation of autoantigen-reactive T cells in the periphery, followed by invasion into the CNS and leading to organ-specific autoimmune disease. IL-1 is crucial in the development of the pathogenic process sustaining MS as they participate not only in myelin-specific T cell activation but also represent the main mediator of macrophage activation in periphery [10]
Table 1. Factors induced by IL-1 Growth and trophic factors on CNS neurons Fibroblast growth factor-2 (FGF-2) Transforming growth factor b1 (TGF-b1) Nerve growth factor (NGF) Inflammatory mediators Phospholipase A2 Cyclooxygenase-2 (Cox-2) Prostaglandins Nitric oxide Matrix metalloprotainases Collagenase Adhesion molecules and other cytokines Vascular cell adhesion molecule-1 (VCAM-1) Intracellular cell adhesion molecule-1 (ICAM-1) E-selectin Interleukin-6 (IL-6) Tumor necrosis factor-a (TNF-a) Colony-stimulating factors (CSFs)
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Figure 2. The pathomechanism of MS and the role of IL-1 in MS. IL-1 is crucial in the development of the pathogenic process sustaining MS as they participate not only in myelin-specific T cell activation but also represent the main mediator of macrophage activation in periphery. Disruption of blood– brain barrier by activated CD4-positive T cells will increase endothelial cell transport of cells and other molecules into the brain parenchyma. Then, CNSinfiltrating macrophages, resident microglial cells and oligodendrocytes themselves will secrete IL-1, and complicated set of inflammatory processes and glial reactions will lead to the demyelination of the CNS directly and indirectly.
(Fig. 2). Disruption of blood–brain barrier by activated CD4positive T cells will increase endothelial cell transport of cells and other molecules into the brain parenchyma. Then, CNSinfiltrating macrophages, resident microglial cells and oligodendrocytes themselves will secrete IL-1, and the above mentioned inflammatory process and glial reaction will lead to the demyelination of the CNS directly and indirectly.
Clinical trials for human diseases involving IL-1-related molecules Rheumatoid arthritis IL-1 inhibition is considered to have a therapeutic effect and has been tried to treat various human diseases. The recombinant methionylated form of human IL-1 receptor antagonist (rhIL-1ra; anakinra) is a specific IL-1 inhibitor approved for human use and various levels of clinical trials for this agent are now in progress. Especially, autoimmune diseases and inflammatory diseases are targets for this therapy and have mostly been reported to show a good prognosis; that is rheumatoid arthritis (RA), juvenile arthritis, gout, Behcet’s disease, ulcerative colitis, uvitis, dermatolo-
gical diseases, renal amyloidosis and type II diabetes mellitus [11,12]. Over the past decade, the treatment of RA has changed with the advent of biologic agents such as anakinra. In patients with persistent disease despite aggressive management with traditional disease modifying antirheumatic drugs (DMARD), biologics are now considered the standard of care. Gartlehner et al. reported a metaanalysis of randomized placebo-controlled trials of 1039 RA patients who were methotrexate-resistant and analyzed the efficacy and safety of anakinra [13]. Anakinra is effective, but it is less efficacious than anti-tumor necrosis factor (TNF) drugs. Moreover, subcutaneous injection of anakinra has a substantially higher rate of injection site reactions than that of anti-TNF drugs. The rate of serious adverse events such as infections, lymphoma, or neutropenia did not differ significantly between patients treated with anakinra and placebo.
Acute stroke IL-1 does not induce brain damage when injected into the brain of naı¨ve animals, but strongly exacerbates brain damage www.drugdiscoverytoday.com
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induced by cerebral ischemia [3]. Endogenous IL-1ra produced by microglia is neuroprotective in cerebral ischemia in mice [9]. IL-1ra reduces lesion size, increases neuronal survival, reduces edema, glial activation, and invasion of peripheral immune cells, and improves behavioral outcome. Exogenous IL-1ra administration also reduces ischemic brain damage and deletion of both IL-1a and IL-1b in animals confers neuroprotection against ischemic brain damage [14]. In humans, randomized, double blind, placebo-controlled study of anakinra (Kineret1; Amgen Thousand Oaks, CA, USA) in 34 acute stroke patients was undertaken [15]. Test treatment was administered intravenously with a 100 mg loading dose over 60 s, followed by a 2 mg/kg/h infusion over 72 h. Both during the first 72 h and after 3 months, there were no serious adverse events. The most frequently occurring non-serious adverse event was infection because IL-1 plays an important role in host defense against infection. On analysis of biological activity, peripheral total white blood cell counts, neutrophil counts, plasma C reactive protein and IL-6 concentrations were lower in the anakinra-treated group than in the placebo-treated group during the test treatment infusion period. Clinical outcomes at 3 months in the anakinra-treated group were better than those in placebo-treated group.
Therapeutic efficacy of selective IL-1 inhibition for experimental autoimmune encephalomyelitis In experimental autoimmune encephalomyelitis (EAE), an animal model for MS, both IL-1a and IL-1b have been shown to be mediators of the inflammatory process. Peripheral levels of IL-1b correlate with the clinical course and IL-1b reactivity has been shown during EAE in CNS-infiltrating macrophages and in resident microglial cells [16–18]. Therefore, IL-1 is considered to be a suitable therapeutic target in EAE and MS. To inhibit IL-1 selectively in EAE, there have been several reported methods. Soluble IL-1 receptor (sIL-1R) treatment was considered as an IL-1 antagonist to block competitively endogenous IL-1 from binding and activating cells expressing membrane IL-1R [16]. Lewis rats were immunized with guinea pig myelin (GPM) and treated with i.p. injections of recombinant human sIL-1R. Daily injections of sIL-1R were initiated 1 day before GPM immunization and continued until day 11. sIL-1R treatment exhibited a delay in mean day of onset and suppressed clinical paralysis and weight loss. Thus, systemic administration of sIL-1R was considered to inhibit the CNS inflammation. rhIL-1ra was also reported to be beneficial for treatment of EAE. Lewis rats immunized with myelin basic protein (MBP) were treated with subcutaneous rhIL-1ra every day starting on day 9 post-immunization with MBP during the effector phase of EAE [19]. This treatment delayed the onset, reduced the severity of paralysis and weight loss, and shortened the duration of disease. Badovinac et al. treated EAE during the induction phase of disease with IL-1ra [20]. EAE was actively 22
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induced in DA rats using rat spinal cord tissue homogenate. IL-1ra was given i.p. daily starting from the day of immunization (day 0) until day 6. They demonstrated that a beneficial effect was obtained after administering IL-1ra during the inductive phase. Disease recovery and weight gain continued to occur even after cessation of IL-1ra treatment, as a result of suppressing the cascade of IL-1-dependent events associated with disease progression. They also demonstrated that in vitro treatment with IL-1ra had direct effects on T cell growth for EAE. Selective IL-1 inhibition by gene therapy was also reported in EAE. Furlan et al. constructed an IL-1ra producing nonreplicative Herpes simplex virus-1 derived vector (TH:IL-1ra) [10]. C57BL/6 mice affected by myelin oligodendrocyte glycoprotein (MOG)-induced EAE were treated with intracisternal injection of TH:IL-1ra on the day of immunization and again after 7 days. As a result, in mice treated with TH:IL-1ra, disease onset was significantly delayed and disease severity was significantly reduced. Perimeningeal macrophages were significantly reduced in EAE mice injected with TH:IL-1ra, although a comparable number of T cells entered the CNS. Conversely, TH:IL-1ra treatment after disease onset was not effective and EAE progressed. As a non-specific immunosuppressive therapy, my research group reported the treatment of EAE rats with a preliminary anti-rheumatic drug [21]. T-614, 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, had been shown to significantly inhibit the production of proinflammatory cytokines including IL-1 and IL-6 by human monocytes/macrophages. Lewis rats immunized with MBP were treated with oral T-614 once a day starting from the day of immunization. T-614 exhibited significant inhibitory effects on the incidence and clinical severity of EAE. T-614 inhibited not only inflammatory infiltration into the CNS, but also activation of microglial cells leading to inflammation. Although T-614 treatment during the pre-symptomatic induction phase (day 0–7) is not effective, the effector phase of autoimmune processes was disrupted by T-614.
Future challenges in the use of IL-1-related molecules for MS therapy Selective inhibition versus non-selective inhibition of IL-1 It is clear from the above EAE experiments that IL-1 inhibition is a potential therapeutic target in the treatment of MS. Furthermore, genetic studies have shown the relationship between IL-1 gene polymorphisms and disease severity of MS [22]. Because IL-1 is an upstream mediator of the innate immune response, therapies directed at IL-1 may prove far more effective than inhibiting any other single inflammatory mediator. Moreover, because glial cells are the mainly affected system in MS, regulation of the IL-1 family is expected to have direct modulatory effects on the pathogenic glial reactions in MS.
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Currently, highly selective IL-1 inhibitors, like anakinra, have not been approved for the treatment of human MS. To inhibit the functions of the pathogenic IL-1 selectively, I agree with the suggestions by Touzani et al. about the strategies for IL-1 blocking [3]. Several strategies have been proposed to block IL-1 mediated injury: (1) inhibition of the synthesis of IL-1, (2) inhibition of maturation with IL1b converting enzyme (ICE; caspase-1), (3) buffering IL-1 with binding proteins or soluble receptors, (4) antagonism of IL-1 receptors with IL-1ra or other non peptide antagonists, and (5) inhibition of signal transduction or other mediators of IL-1 (Fig. 1). Thus, there will be several candidate therapeutic agents to research for MS therapy that block IL-1 selectively; that is IL-1ra, IL-1 blocking antibodies, sIL-1R, gene therapies, RNA aptamers or cytokine trap [23]. ICE inhibition has been studied in vitro and in vivo using experimental models of the septic disease, inflammatory disease and seizures [24–28]. To inactivate ICE, ICE inhibitor such as a highly selective, irreversible inhibitor of ICE (YVADcmk), pralnacasan (Vertex Pharmaceuticals, Inc., Cambridge, MA, USA), VX-765 and the organotellurium compound (AS101) or caspase-1 gene deletion method is used. The precursors of IL-1b and IL-18 have been identified as substrates for ICE. Therefore, ICE deficiency is associated with a more pronounced effect compared with single blockade of either IL-1b or IL-18. However, studies showing the effectiveness of IL-18 antagonism have been mostly against bacterial infection rather than autoimmune diseases. In the light of the recent discoveries on the role of the P2X7 receptor (P2X7R), blockers of P2X7R may have a future as antiinflammatory drugs [29]. Extracellular ATP is considered as a candidate danger signal locally released at the inception of inflammation. ATP-driven maturation and release of IL-1b are specifically mediated by the P2X7R for extracellular ATP, and caspase-1 activity is showed to be necessary for P2X7Rdependent release of mature IL-1b. However, far more studies on the characterization of the P2X7R and the effect on the autoimmune diseases will be needed for treating MS. A non-selective inhibitory mechanism of IL-1 has been shown in existing therapeutic agents for MS; that is interferon beta, anti-inflammatory glucocorticoids, immunosuppressants, atorvastatin and omega-3 polyunsaturated fatty acids [30–32].
Maintenance therapy versus treatment for acute relapse of MS Which step in a complex cascade of immunological events leading to CNS tissue damage requires IL-1 is a critical factor for developing a treatment for MS. However, it is impossible to prevent healthy subjects from the initial onset of MS. Thus, if the IL-1ra gene therapy after disease onset is absolutely not effective as in the EAE study [10], this method may not be promising. Moreover, if diagnosis of MS is made, it is impossible to predict the next relapse accurately. So, starting the
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therapy during the effector phase of MS relapse would be extremely difficult. Studies to clarify whether maintenance therapy of MS with IL-1 inhibitor would prevent the next relapse and disease progression will be needed. For acute relapse of MS, although intravenous methylprednisolone, intravenous immunoglobulin or plasmapheresis are the current treatments of choice, study of intravenous anakinra in acute stroke patients will provide us with useful information [15].
Systemic administration versus local injection in MS lesions of CNS The pathomechanism of MS involves the activation of autoantigen-reactive T cells in the periphery, followed by invasion into the CNS and leading to organ-specific autoimmune disease. Moreover, the EAE studies discussed above were effective with i.p. administration. Thus, I think that IL-1 inhibition as maintenance therapy for MS may be beneficial with peripheral and systemic administration to prevent the initial autoimmune response rather than local therapy to the CNS. Conversely, CNS administration may be effective for the very acute phase of relapse, but studies on the safety of such treatment will be needed.
MS versus Neuromyelitis optica Neuromyelitis optica (NMO) was defined as an inflammatory demyelinating disease in the central nervous system in which the lesions are localized in the optic nerve and spinal cord [33]. An autoantibody called NMO-IgG is found in the serum of NMO patients and is reported to be the same as antiaquaporin-4 antibody [34,35]. The role of IL-1 in the pathogenesis of NMO is not well understood. The therapeutic strategy for NMO is different from that for MS, especially interferon beta rather exacerbates the clinical status of NMO [36]. However, I think that IL-1 inhibition may be beneficial for NMO as well as MS for the following two reasons. One is that anti-aquaporin-4 antibody is considered not only a disease marker of NMO but also it has a direct destructive function for CNS. Humoral immune response and the direct invasion of macrophages into the CNS lesion are shown to be pathological characterizations of NMO [37]. Therefore, NMO lesion will be a good target for IL-1 inhibition. The second reason is that the T cell immunity represented by antigenspecific activation of the T cell receptor is stronger in NMO than in MS [38]. IL-1 affects for the activation of T helper cells directly and indirectly, as well as using a positive feedback loop. Thus, peripheral inhibition of IL-1 will also be beneficial in the treatment of NMO.
Conclusions Selective and non-selective IL-1 inhibition is effective for EAE during the inductive phase and effector phase of autoimmune processes because of anti-inflammation and glial reaction. Human use of rhIL-1ra; anakinra, is in progress for other www.drugdiscoverytoday.com
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diseases especially RA and cerebral infarctions. In both MS and NMO, IL-1 inhibition will be a therapeutic target. In MS, autoantigen-reactive T cells are activated in periphery, invade into CNS and lead to the organ-specific autoimmune disease; therefore, IL-1 inhibition as a maintenance therapy by peripheral administration to prevent the initial autoimmune response of MS may be more beneficial than local therapy to the CNS. However, studies to clarify whether maintenance therapy for MS with IL-1 inhibitor will prevent the next relapse and disease progression will be needed, because IL1ra gene therapy after disease onset was not effective in the EAE study. If it were possible to predict the first onset of MS in healthy subjects or to predict the next relapse in patients already diagnosed as having MS, IL-1 inhibition could be administered at the most effective step in a complex cascade of immunological events leading to CNS tissue damage.
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Acknowledgements I thank Dr Yoh Matsumoto for helpful discussion and critical reading of the article. This article was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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