Suppression of experimental allergic encephalomyelitis by mitoxantrone

Ridge, Susan C.; Sloboda, Adolph E.; McReynolds, Richard A.; Levine, Seymour; Oronsky, Arnold L.; Kerwar, S.S.

doi:10.1016/0090-1229(85)90075-3

Cited by 91 publications

(47 citation statements)

References 9 publications

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“…This has significant implications both for the presumed pathogenesis and for therapeutic opportunities. As regards the pathogenesis, such a restricted receptor use could imply an inciting or causative infectious agent such as a virus; it could also explain Tolerizing DNA vaccines (Waisman et al, 1996;Lobell et al, 1998;Selmaj et al, 2000) ( Bar-Or et al, 2007;Garren et al, 2008) Antibiotics with immunomodulatory and neuroprotective functions: minocycline (Brundula et al, 2002;Giuliani et al, 2005a,b) Zabad et al, 2007;Zhang et al, 2008) Immunosuppressants Azathioprine Cyclophosphamide Mitoxantrone (Blaszczyk et al, 1978) (Mangano et al, 2010) (Ridge et al, 1985;Lublin et al, 1987) Hauser Hafler et al, 1991;Noseworthy et al, 1993;van de Wyngaert et al, 2001;Hartung et al, 2002;Krapf et al, 2005;Massacesi et al, 2005;Smith et al, 2005;Casetta et al, 2007 Haematopoietic stem cell transplantation (Karussis et al, 1992;Karussis et al, 1993b;Burt et al, 1995;Burt et al, 1998;Karussis et al, 1999;van Bekkum, 2000;Cassiani-Ingoni et al, 2007) ( Muraro et al, 2003;Burt et al, 2009;Muraro and Uccelli, 2010;Pasquini et al, 2010) i.v. immunoglobulins (Achiron et al, 1994;Achiron et al, 2000;Ephrem et al, 2008) ( Achiron et al, 1998;Haas, 2000;Strasser-Fuchs et al, 2000;Katz et al, 2006) BJP CS Constantinescu et al…”

Section: Discrepancies Between Eae and Ms Treatment Successmentioning

confidence: 99%

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Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Constantinescu

Farooqi

O’Brien

et al. 2011

British J Pharmacology

1,225

989

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Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter-regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell-mediated organ-specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro-and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune-mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2011.164.issue-4 Abbreviations ADEM, acute disseminated encephalomyelitis; ADNP, activity dependent neuroprotective protein; AHR, aryl hydrocarbon receptor; APC, antigen-presenting cells; APL, altered peptide ligand; AT, adoptive transfer; C1 and CB2 receptors, cannabinoid receptors 1 and 2; CIS, clinically isolated syndrome; CNS, central nervous system; DA, dark agouti; DMT, disease-modifying treatment; EAE, experimental autoimmune (allergic) encephalomyelitis; EAN, experimental autoimmune (allergic) neuritis; EBV, Epstein-Barr virus; GA, glatiramer acetate; IFN, interferon; IL, interleukin; IL-1RA, interleukin 1 receptor antagonist; JCV, John Cunningham virus; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NABT, normal appearing brain tissue; NAWM, normal appearing white matter; NMO, neuromyelitis optica; NK1 receptor, neurokinin 1 receptor; PGE, prostaglandin E; PLP, proteolipid protein; PP, primary progressive; PR, progressive relapsing; ROR, retinoid orphan receptor; RR, relapsing-remitting; SP, secondary progressive; TCR, T-cell receptor; TGF, transforming growth...

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Section: Discrepancies Between Eae and Ms Treatment Successmentioning

confidence: 99%

“…It was developed in 1971 by Teitelbaum and colleagues in the laboratory of M. Sela, who was conducting extensive studies (Ridge et al, 1985;Levine and Saltzman, 1986;Lublin et al, 1987;Tischner and Reichardt, 2007;Mangano et al, 2010;) Cyclophosphamide Yes Glucocorticoids…”

Section: Eae and Ms Treatment Successmentioning

confidence: 99%

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Constantinescu

Farooqi

O’Brien

et al. 2011

British J Pharmacology

1,225

989

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“…It demonstrated therapeutic efficacy in the treatment of a wide range of solid tumours, such as breast cancer, and haematological malignancies [1]. Based on beneficial results from the experimental allergic encephalomyelitis (EAE) animal model of multiple sclerosis (MS), where mitoxantrone suppressed relapses and lesions 10–20 times more effectively than cyclophosphamide [5, 6, 7], pilot studies showed positive effects on relapse and progression rate in heterogeneous groups of patients who had an unfavourable course of disease not responsive to other established immunotherapies [9, 10]. Recent studies indicated that mitoxantrone is a well-tolerated and clinically effective substance for treating rapidly progressive MS [2, 3, 4, 8, 9].…”

Section: Introductionmentioning

confidence: 99%

Effects of Mitoxantrone on Multiple Sclerosis Patients’ Lymphocyte Subpopulations and Production of Immunoglobulin, TNF-alpha and IL-10

Gbadamosi¹,

Buhmann²,

Tessmer³

et al. 2003

Eur Neurol

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We designed this longitudinal study to clarify the short- and long-term effects of mitoxantrone on the immune system in a subgroup of multiple sclerosis patients treated at our centre. After 14 days we found a highly significant sustained reduction of leucocytes, primarily affecting neutrophils and most lymphocyte subsets except for naive and activated T lymphocytes. The CD4/CD8 ratio and serum immmunoglobulin levels were not affected. Furthermore, whole blood-stimulated mononuclear cell IL-10 production showed a significant lower level 2 weeks treatment, whereas basal IL-10 as well as stimulated and basal TNF-α secretion showed no significant changes. Longitudinal data disclosed a persistent decrease of B lymphocytes, while secretion of immunoglobulins, IL-10, and TNF-α was not altered in the follow-up. In conclusion, we confirmed a selective short-term effect of mitoxantrone therapy on most lymphocyte subpopulations, but not on immunoglobulines or the pro- and anti-inflammatory cytokines TNF-α and IL-10, which do not serve as possible response markers.

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“…Following its successful use in the treatment of experimental allergic encephalomyelitis, 14,15 mitoxantrone was initially studied in an open label, single arm pilot trial (Class IV evi-dence; see table for definition of levels of evidence), which has been presented in preliminary form. 16 A small phase II pilot trial 17 studied 10 patients with clinically definite MS (CDMS), 18 six of whom had RRMS and four of whom had SPMS.…”

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confidence: 99%

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

et al. 2003

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Abstract-Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS. NEUROLOGY 2003;61:1332-1338 Mitoxantrone hydrochloride (Novantrone) is an anthracenedione that has been used as an antineoplastic agent to treat hormone-refractory prostate cancer and acute nonlymphocytic leukemia in adults. It exerts its antineoplastic action by intercalating into DNA and producing both DNA strand-breaks and interstrand cross-links; it also interferes with RNA synthesis and markedly inhibits the enzyme topoisomerase II, which aids in the DNA repair process. [1][2][3][4] In the treatment of MS, mitoxantrone represents the latest in a long line of general immunosuppressive agents studied in this disease. Previously, most such agents have not shown clear-cut benefits in this condition. [5][6][7][8][9][10] On the basis of a phase III clinical trial in Europe, 11,12 and an earlier phase II study, 13 mitoxantrone recently received an expanded indication from the Food and Drug Administration (FDA) for use in secondary progressive MS (SPMS), in progressiverelapsing MS, and for patients with worsening relapsing-remitting (RR) MS. This last category is defined as patients whose neurologic status remains significantly abnormal between MS attacks.Mitoxantrone is the first drug approved for these indications in the United States, and it is the purpose of this assessment to consider both the evidence leading to the recent FDA approval as well as the appropriate clinical role of this agent in the management of patients with MS.Description of the analytic process. Articles for this review were searched in Medline under the keywords mitoxantrone and MS. Forty-one articles were identified by this search. The abstracts of these articles were reviewed and the original articles were selected for inclusion in the analysis only if they were either controlled trials or case series using mitoxantrone in the treatment of MS. Five such articles were identified, in addition to the phase III trial. 11,12 In addition, the reference lists of the articles found in this manner were also reviewed to identify articles or abstracts not found by the computer search.Analysis of the evidence. Followi...

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Suppression of experimental allergic encephalomyelitis by mitoxantrone

Cited by 91 publications

References 9 publications

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Effects of Mitoxantrone on Multiple Sclerosis Patients’ Lymphocyte Subpopulations and Production of Immunoglobulin, TNF-alpha and IL-10

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

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