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Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Short report

Amelioration of experimental autoimmune encephalomyelitis by clozapine is not associated with defective CD4 T cell responses

Authors: Pirooz Zareie, Bronwen Connor, Anne Camille La Flamme

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Atypical antipsychotic agents, such as clozapine, are used for treating psychosis and depression and have recently been found to modulate neuroinflammation. We have shown previously that treatment of mice with the atypical antipsychotic agents, clozapine or risperidone, attenuates disease severity in experimental autoimmune encephalomyelitis (EAE); however, the mechanism by which they are protective is unknown. In this study, we investigated the effects of clozapine on CD4+ T cell responses and found that clozapine did not significantly affect the expansion of myelin-specific T cells, their differentiation into pathogenic subsets, or their encephalitogenic capacity to induce EAE. Interestingly, although clozapine enhanced differentiation of regulatory T (Treg) cells, in vivo neutralization of Tregs indicated that Tregs were not responsible for the protective effects of clozapine during the induction and effector phase of EAE. Taken together, our studies indicate that clozapine does not mediate its protective effects by directly altering CD4 T cells.
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Literature
2.
go back to reference Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.CrossRefPubMed Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.CrossRefPubMed
3.
go back to reference Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–93.CrossRefPubMed Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–93.CrossRefPubMed
5.
go back to reference Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376:209–220.CrossRefPubMed Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376:209–220.CrossRefPubMed
6.
go back to reference Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34.CrossRefPubMed Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22–34.CrossRefPubMed
7.
go back to reference Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19(1):11–38.CrossRefPubMed Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19(1):11–38.CrossRefPubMed
8.
go back to reference Potvin S, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801–8.CrossRefPubMed Potvin S, et al. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801–8.CrossRefPubMed
9.
go back to reference Sacre S, et al. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum. 2010;62(3):683–93.CrossRefPubMed Sacre S, et al. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum. 2010;62(3):683–93.CrossRefPubMed
10.
go back to reference O’Sullivan D, et al. Treatment with the antipsychotic agent, risperidone, reduces disease severity in experimental autoimmune encephalomyelitis. PLoS One. 2014;9(8):e104430.CrossRefPubMedPubMedCentral O’Sullivan D, et al. Treatment with the antipsychotic agent, risperidone, reduces disease severity in experimental autoimmune encephalomyelitis. PLoS One. 2014;9(8):e104430.CrossRefPubMedPubMedCentral
11.
go back to reference Mei F, et al. Quetiapine, an atypical antipsychotic, is protective against autoimmune-mediated demyelination by inhibiting effector T cell proliferation. PLoS ONE. 2012;7(8):e42746.CrossRefPubMedPubMedCentral Mei F, et al. Quetiapine, an atypical antipsychotic, is protective against autoimmune-mediated demyelination by inhibiting effector T cell proliferation. PLoS ONE. 2012;7(8):e42746.CrossRefPubMedPubMedCentral
12.
go back to reference Ribeiro BM, et al. Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: reversal by clozapine. Schizophr Res. 2013;151(1–3):12–9.CrossRefPubMed Ribeiro BM, et al. Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: reversal by clozapine. Schizophr Res. 2013;151(1–3):12–9.CrossRefPubMed
13.
go back to reference Miller BJ, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663–71.CrossRefPubMedPubMedCentral Miller BJ, et al. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663–71.CrossRefPubMedPubMedCentral
14.
go back to reference Green LK, et al. Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis. Mult Scler J Exp Trans Clin. 2017;1–13. do:10.1177/2055217317698724. Green LK, et al. Enhanced disease reduction using clozapine, an atypical antipsychotic agent, and glatiramer acetate combination therapy in experimental autoimmune encephalomyelitis. Mult Scler J Exp Trans Clin. 2017;1–13. do:10.​1177/​2055217317698724​.
15.
go back to reference Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.CrossRefPubMed Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.CrossRefPubMed
16.
go back to reference O’Sullivan D, et al. Microtubule-stabilizing agents delay the onset of EAE through inhibition of migration. Immunol Cell Biol. 2013;91(9):583–92.CrossRefPubMed O’Sullivan D, et al. Microtubule-stabilizing agents delay the onset of EAE through inhibition of migration. Immunol Cell Biol. 2013;91(9):583–92.CrossRefPubMed
17.
go back to reference Koutrolos M, et al. Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS. Acta Neuropathol Commun. 2014;2:163.CrossRefPubMedPubMedCentral Koutrolos M, et al. Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS. Acta Neuropathol Commun. 2014;2:163.CrossRefPubMedPubMedCentral
18.
go back to reference Chu C-Q, Wittmer S, Dalton DK. Failure to suppress the expansion of the activated Cd4 T cell population in interferon γ–deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J Exp Med. 2000;192(1):123–8.CrossRefPubMedPubMedCentral Chu C-Q, Wittmer S, Dalton DK. Failure to suppress the expansion of the activated Cd4 T cell population in interferon γ–deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. J Exp Med. 2000;192(1):123–8.CrossRefPubMedPubMedCentral
19.
go back to reference Levite M. Neurotransmitters activate T-cells and elicit crucial functions via neurotransmitter receptors. Curr Opin Pharmacol. 2008;8(4):460–71.CrossRefPubMed Levite M. Neurotransmitters activate T-cells and elicit crucial functions via neurotransmitter receptors. Curr Opin Pharmacol. 2008;8(4):460–71.CrossRefPubMed
20.
go back to reference Sanders VM, et al. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol. 1997;158(9):4200–10.PubMed Sanders VM, et al. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol. 1997;158(9):4200–10.PubMed
21.
go back to reference Cua DJ, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.CrossRefPubMed Cua DJ, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.CrossRefPubMed
23.
go back to reference Al-Amin MM, Nasir Uddin MM, Mahmud Reza H. Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clin Psychopharmacol Neurosci. 2013;11(3):144–51.CrossRefPubMedPubMedCentral Al-Amin MM, Nasir Uddin MM, Mahmud Reza H. Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clin Psychopharmacol Neurosci. 2013;11(3):144–51.CrossRefPubMedPubMedCentral
24.
go back to reference Szabo SJ, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655–69.CrossRefPubMed Szabo SJ, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655–69.CrossRefPubMed
25.
go back to reference Ivanov II, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33.CrossRefPubMed Ivanov II, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33.CrossRefPubMed
26.
go back to reference Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005;6(4):331–7.CrossRefPubMed Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005;6(4):331–7.CrossRefPubMed
27.
go back to reference Stephens LA, Gray D, Anderton SM. CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc Natl Acad Sci U S A. 2005;102(48):17418–23.CrossRefPubMedPubMedCentral Stephens LA, Gray D, Anderton SM. CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc Natl Acad Sci U S A. 2005;102(48):17418–23.CrossRefPubMedPubMedCentral
28.
go back to reference Koutrolos M, et al. Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS. Acta Neuropathol Commun. 2014;2(1):1–7.CrossRef Koutrolos M, et al. Treg cells mediate recovery from EAE by controlling effector T cell proliferation and motility in the CNS. Acta Neuropathol Commun. 2014;2(1):1–7.CrossRef
29.
go back to reference Lu LX, et al. Effect of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia. Di Yi Jun Yi Da Xue Xue Bao. 2004;24(11):1251–4.PubMed Lu LX, et al. Effect of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia. Di Yi Jun Yi Da Xue Xue Bao. 2004;24(11):1251–4.PubMed
30.
go back to reference Hu X, et al. Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. J Neuroimmune Pharmacol. 2012;7(1):187–201.CrossRefPubMed Hu X, et al. Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation. J Neuroimmune Pharmacol. 2012;7(1):187–201.CrossRefPubMed
31.
go back to reference Chen M-L, et al. Antipsychotic drugs suppress the AKT/NF-κB pathway and regulate the differentiation of T-cell subsets. Immunol Lett. 2011;140(1–2):81–91.CrossRefPubMed Chen M-L, et al. Antipsychotic drugs suppress the AKT/NF-κB pathway and regulate the differentiation of T-cell subsets. Immunol Lett. 2011;140(1–2):81–91.CrossRefPubMed
32.
go back to reference Panariello F, et al. Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance. J Cell Physiol. 2012;227(4):1485–92.CrossRefPubMed Panariello F, et al. Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance. J Cell Physiol. 2012;227(4):1485–92.CrossRefPubMed
33.
go back to reference Kang UG, et al. The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett. 2004;560(1–3):115–9.CrossRefPubMed Kang UG, et al. The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett. 2004;560(1–3):115–9.CrossRefPubMed
34.
go back to reference Schmid CL, et al. Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a [beta]arrestin2-independent activation of Akt. Neuropsychopharmacology. 2014;39(8):1902–13.CrossRefPubMedPubMedCentral Schmid CL, et al. Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a [beta]arrestin2-independent activation of Akt. Neuropsychopharmacology. 2014;39(8):1902–13.CrossRefPubMedPubMedCentral
36.
go back to reference Kopf H, et al. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol. 2007;7(13):1819–24.CrossRefPubMedPubMedCentral Kopf H, et al. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol. 2007;7(13):1819–24.CrossRefPubMedPubMedCentral
37.
38.
go back to reference Ajami B, et al. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011;14(9):1142–9.CrossRefPubMed Ajami B, et al. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011;14(9):1142–9.CrossRefPubMed
39.
go back to reference Popescu BF, Lucchinetti CF. Pathology of demyelinating diseases. Annu Rev Pathol. 2012;7:185–217.CrossRefPubMed Popescu BF, Lucchinetti CF. Pathology of demyelinating diseases. Annu Rev Pathol. 2012;7:185–217.CrossRefPubMed
40.
go back to reference Mishra MK, Yong VW. Myeloid cells—targets of medication in multiple sclerosis. Nat Rev Neurol. 2016;12(9):539–51.CrossRefPubMed Mishra MK, Yong VW. Myeloid cells—targets of medication in multiple sclerosis. Nat Rev Neurol. 2016;12(9):539–51.CrossRefPubMed
Metadata
Title
Amelioration of experimental autoimmune encephalomyelitis by clozapine is not associated with defective CD4 T cell responses
Authors
Pirooz Zareie
Bronwen Connor
Anne Camille La Flamme
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0842-5

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