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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Immune profile of an atypical EAE model in marmoset monkeys immunized with recombinant human myelin oligodendrocyte glycoprotein in incomplete Freund’s adjuvant

Authors: S. Anwar Jagessar, Nicole Heijmans, Erwin L A Blezer, Jan Bauer, Robert Weissert, Bert A. ‘t Hart

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Experimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS). Prior studies showed a core pathogenic role of T and B cells specific for myelin oligodendrocyte glycoprotein (MOG). However, in those studies, the quality of the response against MOG epitopes was strongly biased by bacterial antigens in the complete Freund’s adjuvant (CFA), in which the immunizing recombinant human (rh) MOG protein had been formulated. In response to the need of a more refined EAE model, we have tested whether disease could also be induced with rhMOG in incomplete Freund’s adjuvant (IFA).

Method

Marmosets were immunized with rhMOG emulsified in IFA in the dorsal skin. Monkeys that did not develop neurological deficit were given booster immunizations at 28-day interval with the same antigen preparation. In a second experiment, three marmoset twin pairs were sensitized against MOG peptides in IFA to study a possibility for suppressive activity towards pathogenic T cells directed against the encephalitogenic epitope MOG40-48.

Results

Despite the absence of strong danger signals in the rhMOG/IFA inoculum, all monkeys developed clinically evident EAE symptoms. Moreover, in all monkeys, demyelinated lesions were present in the white matter and in two cases also in the cortical grey matter. Immune profiling at height of the disease showed a dominant T cell response against the overlapping peptides 14–36 and 24–46, but reactivity against the pathogenically most relevant peptide 34–56 was conspicuously absent. In the second experiment, there was an indication for a possible suppressive mechanism.

Conclusions

Immunization of marmoset monkeys with rhMOG in IFA elicits clinical EAE in all animals. Moreover, rhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated.
Appendix
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Literature
1.
‘t Hart BA, Gran B, Weissert R. EAE: imperfect but useful models of multiple sclerosis. Trends Mol Med. 2011;17(3):119–25.CrossRefPubMed
2.
‘t Hart BA, van Kooyk Y, Geurts JJ, Gran B. The primate autoimmune encephalomyelitis model; a bridge between mouse and man. Ann Clin Transl Neurol. 2015;2(5):581–93.PubMedCentralCrossRefPubMed
3.
Amor S, Smith PA, Hart B, Baker D. Biozzi mice: of mice and human neurological diseases. J Neuroimmunol. 2005;165(1–2):1–10.CrossRefPubMed
4.
‘t Hart BA, Bauer J, Muller HJ, Melchers B, Nicolay K, Brok H, et al. Histopathological characterization of magnetic resonance imaging-detectable brain white matter lesions in a primate model of multiple sclerosis: a correlative study in the experimental autoimmune encephalomyelitis model in common marmosets (Callithrix jacchus). Am J Pathol. 1998;153(2):649–63.PubMedCentralCrossRef
5.
Smith PA, Heijmans N, Ouwerling B, Breij EC, Evans N, van Noort JM, et al. Native myelin oligodendrocyte glycoprotein promotes severe chronic neurological disease and demyelination in Biozzi ABH mice. Eur J Immunol. 2005;35(4):1311–9.CrossRefPubMed
6.
Jagessar SA, Smith PA, Blezer E, Delarasse C, Pham-Dinh D, Laman JD, et al. Autoimmunity against myelin oligodendrocyte glycoprotein is dispensable for the initiation although essential for the progression of chronic encephalomyelitis in common marmosets. J Neuropathol Exp Neurol. 2008;67(4):326–40.CrossRefPubMed
7.
Brok HP, Uccelli A, Kerlero De Rosbo N, Bontrop RE, Roccatagliata L, de Groot NG, et al. Myelin/oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis in common marmosets: the encephalitogenic T cell epitope pMOG24-36 is presented by a monomorphic MHC class II molecule. J Immunol. 2000;165(2):1093–101.CrossRefPubMed
8.
Brok HP, van Meurs M, Blezer E, Schantz A, Peritt D, Treacy G, et al. Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody. J Immunol. 2002;169(11):6554–63.CrossRefPubMed
9.
Kap YS, Smith P, Jagessar SA, Remarque E, Blezer E, Strijkers GJ, et al. Fast progression of recombinant human myelin/oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis in marmosets is associated with the activation of MOG34-56-specific cytotoxic T cells. J Immunol. 2008;180(3):1326–37.CrossRefPubMed
10.
Zaguia F, Saikali P, Ludwin S, Newcombe J, Beauseigle D, McCrea E, et al. Cytotoxic NKG2C+ CD4 T cells target oligodendrocytes in multiple sclerosis. J Immunol. 2013;190(6):2510–8.CrossRefPubMed
11.
Jagessar SA, Kap YS, Heijmans N, van Driel N, van Straalen L, Bajramovic JJ, et al. Induction of progressive demyelinating autoimmune encephalomyelitis in common marmoset monkeys using MOG34-56 peptide in incomplete freund adjuvant. J Neuropathol Exp Neurol. 2010;69(4):372–85.CrossRefPubMed
12.
Brok HP, Boven L, van Meurs M, Kerlero de Rosbo N, Celebi-Paul L, Kap YS, et al. The human CMV-UL86 peptide 981–1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34–56, but lacks the capacity to induce EAE in rhesus monkeys. J Neuroimmunol. 2007;182(1–2):135–52.CrossRefPubMed
13.
Jagessar SA, Heijmans N, Blezer EL, Bauer J, Blokhuis JH, Wubben JA, et al. Unravelling the T-cell-mediated autoimmune attack on CNS myelin in a new primate EAE model induced with MOG34-56 peptide in incomplete adjuvant. Eur J Immunol. 2012;42(1):217–27.CrossRefPubMed
14.
Anwar Jagessar S, Fagrouch Z, Heijmans N, Bauer J, Laman JD, Oh L, et al. The different clinical effects of anti-BLyS, anti-APRIL and anti-CD20 antibodies point at a critical pathogenic role of gamma-herpesvirus infected B cells in the marmoset EAE model. J Neuroimmune Pharmacol. 2013;8(3):727–38.CrossRefPubMed
15.
Jagessar SA, Heijmans N, Bauer J, Blezer EL, Laman JD, Hellings N, et al. B-cell depletion abrogates T cell-mediated demyelination in an antibody-nondependent common marmoset experimental autoimmune encephalomyelitis model. J Neuropathol Exp Neurol. 2012;71(8):716–28.CrossRefPubMed
16.
Menge T, von Büdingen HC, Lalive PH, Genain CP. Relevant antibody subsets against MOG recognize conformational epitopes exclusively exposed in solid-phase ELISA. Eur J Immunol. 2007;37(11):3229–39.CrossRefPubMed
17.
Haanstra KG, Jagessar SA, Bauchet AL, Doussau M, Fovet CM, Heijmans N, et al. Induction of experimental autoimmune encephalomyelitis with recombinant human myelin oligodendrocyte glycoprotein in incomplete Freund’s adjuvant in three non-human primate species. J Neuroimmune Pharmacol. 2013;8(5):1251–64.PubMedCentralCrossRefPubMed
18.
‘t Hart BA, van Kooyk Y, Geurts JJG, Gran B. The primate autoimmune encephalomyelitis model; a bridge between mouse and man. Ann Clin Transl Neurol. 2015;In press.
19.
Kerlero de Rosbo N, Hoffman M, Mendel I, Yust I, Kaye J, Bakimer R, et al. Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions. Eur J Immunol. 1997;27(11):3059–69.CrossRefPubMed
20.
Blezer EL, Bauer J, Brok HP, Nicolay K, ‘t Hart BA. Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis. NMR Biomed. 2007;20(2):90–103.CrossRefPubMed
21.
Jagessar SA, Vierboom M, Blezer EL, Bauer J, ‘t Hart BA, Kap YS. An overview of models, methods, and reagents developed for translational autoimmunity research in the common marmoset (Callithrix jacchus). Exp Anim. 2013;62(3):159–71.PubMedCentralCrossRefPubMed
22.
Garcia-Vallejo JJ, Ilarregui JM, Kalay H, Chamorro S, Koning N, Unger WW, et al. CNS myelin induces regulatory functions of DC-SIGN-expressing, antigen-presenting cells via cognate interaction with MOG. J Exp Med. 2014;211(7):1465–83.PubMedCentralCrossRefPubMed
23.
Norton WT, Poduslo SE. Myelination in rat brain: changes in myelin composition during brain maturation. J Neurochem. 1973;21(4):759–73.CrossRefPubMed
24.
Kap YS, van Driel N, Blezer E, Parren PW, Bleeker WK, Laman JD, et al. Late B cell depletion with a human anti-human CD20 IgG1kappa monoclonal antibody halts the development of experimental autoimmune encephalomyelitis in marmosets. J Immunol. 2010;185(7):3990–4003.CrossRefPubMed
25.
Benirschke K, Anderson JM, Brownhill LE. Marrow chimerism in marmosets. Science. 1962;138(3539):513–5.CrossRefPubMed
26.
Felix NJ, Suri A, Salter-Cid L, Nadler SG, Gujrathi S, Corbo M, et al. Targeting lymphocyte co-stimulation: from bench to bedside. Autoimmunity. 2010;43(7):514–25.CrossRefPubMed
27.
Racke MK, Ratts RB, Arredondo L, Perrin PJ, Lovett-Racke A. The role of costimulation in autoimmune demyelination. J Neuroimmunol. 2000;107(2):205–15.CrossRefPubMed
28.
Dahlman I, Wallstrom E, Weissert R, Storch M, Kornek B, Jacobsson L, et al. Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18. Hum Mol Genet. 1999;8(12):2183–90.CrossRefPubMed
29.
Billiau A, Matthys P. Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol. 2001;70(6):849–60.PubMed
30.
Lassmann H, Ransohoff RM. The CD4-Th1 model for multiple sclerosis: a critical [correction of crucial] re-appraisal. Trends Immunol. 2004;25(3):132–7.CrossRefPubMed
31.
Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796–804.CrossRefPubMed
32.
Durelli L, Bongioanni MR, Ferrero B, Imperiale D, Verdun E, Oggero A, et al. Long term recombinant interferon alpha treatment in MS with special emphasis to side effects. Mult Scler. 1996;1(6):366–71.PubMed
33.
Engering A, Geijtenbeek TB, van Vliet SJ, Wijers M, van Liempt E, Demaurex N, et al. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J Immunol. 2002;168(5):2118–26.CrossRefPubMed
34.
Geijtenbeek TB, van Vliet SJ, Engering A, Hart BA, van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu Rev Immunol. 2004;22:33–54.CrossRefPubMed
35.
‘t Hart BA, van Kooyk Y. Yin-Yang regulation of autoimmunity by DCs. Trends Immunol. 2004;25(7):353–9.CrossRefPubMed
36.
Cobbold SP, Adams E, Nolan KF, Regateiro FS, Waldmann H. Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link. Immunol Rev. 2010;236:203–18.CrossRefPubMed
Metadata
Title
Immune profile of an atypical EAE model in marmoset monkeys immunized with recombinant human myelin oligodendrocyte glycoprotein in incomplete Freund’s adjuvant
Authors
S. Anwar Jagessar
Nicole Heijmans
Erwin L A Blezer
Jan Bauer
Robert Weissert
Bert A. ‘t Hart
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0378-5

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