Active immunization using a single dose immunotherapeutic abates established EAE via IL-10 and regulatory T cells.
Stimulation of Ag-specific inducible Treg can enhance resolution of autoimmune disease. Conventional methods to induce Treg often require induction of autoimmune disease or subjection to infection. Reovirus adhesin, protein σ1 (pσ1), can successfully facilitate tolerance when fused to a tolerogen. We tested whether myelin oligodendrocyte glycoprotein (MOG) fused to pσ1 (MOG-pσ1) can stimulate Ag-specific Treg. We show that C57BL/6 mice treated nasally with MOG-pσ1 fail to induce MOG-specific Abs and delayed-type hypersensitivity (DTH) responses and resist EAE. Such resistance was attributed to stimulation of Foxp3(+) Treg, as well as Th2 cells. MOG-pσ1's protective capacity was abrogated in IL-10(-/-) mice, but restored when adoptively transferred with MOG-pσ1-induced Treg. As a therapeutic, MOG-pσ1 diminished EAE within 24 h of nasal application, unlike recombinant MOG (rMOG), pσ1, or pσ1+rMOG, implicating the importance of Ag specificity by pσ1-based therapeutics. MOG-pσ1-treated mice showed elevated IL-4, IL-10, and IL-28 production by CD4(+) T cells, unlike rMOG treated or control mice that produced elevated IFN-γ or IL-17, respectively. These data show the feasibility of using pσ1 as a tolerogen platform for Ag-specific tolerance induction and highlight its potential use as an immunotherapeutic for autoimmunity.
Department of Immunology & Infectious Diseases, Montana State University, Technology Blvd., Bozeman, MT 59717-3610, USA.
Agnieszka
A
Rynda-Apple
Eduardo
E
Huarte
Massimo
M
Maddaloni
Gayle
G
Callis
Jerod A
JA
Skyberg
David W
DW
Pascual
D019264:Adoptive Transfer; D000818:Animals; D036022:Capsid Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D013116:Spinal Cord / Q000166:cytology / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014611:Vaccination / Q000379:methods*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D007378:Interleukins; D000095022:Interferon Lambda
D036022:Capsid Proteins; D016207:Cytokines; D006023:Glycoproteins; D007074:Immunoglobulin G; D016753:Interleukin-10; D053645:Interleukin-2 Receptor alpha Subunit; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C556062:IL10 protein, mouse; C508018:Il2ra protein, mouse; C571327:Mog protein, mouse; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda; C445081:myelin oligodendrocyte glycoprotein (35-55); C571072:myelin oligodendrocyte glycoprotein-reovirus type 3 protein sigma 1 fusion protein; C031728:sigma 1 protein, reovirus
Eur J Immunol. 2000 Jul;30(7):1911-8
10940880
J Immunol. 2008 Jul 15;181(2):954-68
18606647
J Immunol. 2008 Apr 15;180(8):5187-200
18390700
J Immunol. 2005 Dec 1;175(11):7093-7
16301610
J Immunol. 2010 Jun 15;184(12):7144-53
20483737
Microbes Infect. 2001 Sep;3(11):947-54
11564443
Blood. 2006 Jun 1;107(11):4417-23
16478884
Purinergic Signal. 2007 Mar;3(1-2):171-80
18404431
Annu Rev Immunol. 2002;20:101-23
11861599
Pathophysiology. 2011 Feb;18(1):21-9
20537877
Annu Rev Immunol. 1993;11:165-90
8386517
Biotechnol Bioeng. 2001 Jul 5;74(1):62-9
11353411
J Exp Med. 2002 Jul 15;196(2):217-27
12119346
J Immunol. 2005 Nov 1;175(9):6107-16
16237107
Nat Immunol. 2005 Nov;6(11):1133-41
16200068
PLoS One. 2010 Jan 14;5(1):e8720
20090936
Brain. 2006 Aug;129(Pt 8):1953-71
16632554
Eur J Immunol. 2009 Apr;39(4):1108-17
19350586
J Immunol. 1989 Sep 15;143(6):1815-21
2550543
J Immunol. 2005 Nov 15;175(10):6733-40
16272329
J Immunol. 2008 Aug 15;181(4):2741-52
18684965
Nature. 2003 Feb 13;421(6924):744-8
12610626
Protein Expr Purif. 2004 Apr;34(2):249-56
15003258
J Exp Med. 2006 Jul 10;203(7):1685-91
16818675
Nat Med. 2007 Feb;13(2):139-45
17290272
Clin Exp Immunol. 2002 Nov;130(2):204-11
12390307
J Clin Immunol. 2001 May;21(3):155-70
11403222
J Immunol. 1998 Oct 1;161(7):3299-306
9759845
J Exp Med. 2001 Mar 19;193(6):713-26
11257138
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7196-201
8692968
CNS Drugs. 2008;22(3):175-98
18278975
J Immunol. 2006 Jul 1;177(1):566-73
16785554
J Autoimmun. 2003 Mar;20(2):135-45
12657527
J Exp Med. 2004 Nov 1;200(9):1123-34
15520244
Clin Dev Immunol. 2006 Jun-Dec;13(2-4):143-57
17162357
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3310-5
11248075
J Immunol. 2005 Jun 1;174(11):6772-80
15905518
J Immunol. 1998 Dec 1;161(11):6421-6
9834134
Gastroenterology. 2008 Sep;135(3):917-25
18565333
Cell Immunol. 2005 Oct;237(2):123-30
16386239
Nat Rev Immunol. 2003 Jul;3(7):569-81
12876559
Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9325-30
18591671
J Neuroimmunol. 2006 Sep;178(1-2):1-8
16872684
Nat Immunol. 2005 Nov;6(11):1123-32
16200070
J Immunol. 2007 Feb 1;178(3):1791-9
17237429