Cenerimod, a selective S1P
Animal models
Cenerimod
Immunomodulation
Sjögren’s syndrome
Sphingosine-1-phosphate receptor type 1
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
29 11 2021
29 11 2021
Historique:
received:
03
03
2021
accepted:
09
11
2021
entrez:
29
11
2021
pubmed:
30
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Sjögren's syndrome is a systemic autoimmune disease characterized by immune cells predominantly infiltrating the exocrine glands and frequently forming ectopic lymphoid structures. These structures drive a local functional immune response culminating in autoantibody production and tissue damage, associated with severe dryness of mucosal surfaces and salivary gland hypofunction. Cenerimod, a potent, selective and orally active sphingosine-1-phosphate receptor 1 modulator, inhibits the egress of lymphocytes into the circulation. Based on the mechanism of action of cenerimod, its efficacy was evaluated in two mouse models of Sjögren's syndrome. Cenerimod was administered in two established models of Sjögren's syndrome; firstly, in an inducible acute viral sialadenitis model in C57BL/6 mice, and, secondly, in the spontaneous chronic sialadenitis MRL/lpr mouse model. The effects of cenerimod treatment were then evaluated by flow cytometry, immunohistochemistry, histopathology and immunoassays. Comparisons between groups were made using a Mann-Whitney test. In the viral sialadenitis model, cenerimod treatment reduced salivary gland immune infiltrates, leading to the disaggregation of ectopic lymphoid structures, reduced salivary gland inflammation and preserved organ function. In the MRL/lpr mouse model, cenerimod treatment decreased salivary gland inflammation and reduced T cells and proliferating plasma cells within salivary gland ectopic lymphoid structures, resulting in diminished disease-relevant autoantibodies within the salivary glands. Taken together, these results suggest that cenerimod can reduce the overall autoimmune response and improve clinical parameters in the salivary glands in models of Sjögren's syndrome and consequently may reduce histological and clinical parameters associated with the disease in patients.
Sections du résumé
BACKGROUND
Sjögren's syndrome is a systemic autoimmune disease characterized by immune cells predominantly infiltrating the exocrine glands and frequently forming ectopic lymphoid structures. These structures drive a local functional immune response culminating in autoantibody production and tissue damage, associated with severe dryness of mucosal surfaces and salivary gland hypofunction. Cenerimod, a potent, selective and orally active sphingosine-1-phosphate receptor 1 modulator, inhibits the egress of lymphocytes into the circulation. Based on the mechanism of action of cenerimod, its efficacy was evaluated in two mouse models of Sjögren's syndrome.
METHODS
Cenerimod was administered in two established models of Sjögren's syndrome; firstly, in an inducible acute viral sialadenitis model in C57BL/6 mice, and, secondly, in the spontaneous chronic sialadenitis MRL/lpr mouse model. The effects of cenerimod treatment were then evaluated by flow cytometry, immunohistochemistry, histopathology and immunoassays. Comparisons between groups were made using a Mann-Whitney test.
RESULTS
In the viral sialadenitis model, cenerimod treatment reduced salivary gland immune infiltrates, leading to the disaggregation of ectopic lymphoid structures, reduced salivary gland inflammation and preserved organ function. In the MRL/lpr mouse model, cenerimod treatment decreased salivary gland inflammation and reduced T cells and proliferating plasma cells within salivary gland ectopic lymphoid structures, resulting in diminished disease-relevant autoantibodies within the salivary glands.
CONCLUSIONS
Taken together, these results suggest that cenerimod can reduce the overall autoimmune response and improve clinical parameters in the salivary glands in models of Sjögren's syndrome and consequently may reduce histological and clinical parameters associated with the disease in patients.
Identifiants
pubmed: 34839819
doi: 10.1186/s13075-021-02673-x
pii: 10.1186/s13075-021-02673-x
pmc: PMC8628476
doi:
Substances chimiques
Oxadiazoles
0
Propylene Glycols
0
cenerimod
Y333RS1786
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
289Informations de copyright
© 2021. The Author(s).
Références
Jpn Dent Sci Rev. 2019 Nov;55(1):139-144
pubmed: 31687053
Swiss Med Wkly. 2015 Sep 16;145:w14168
pubmed: 26375728
Front Immunol. 2020 Jul 28;11:1569
pubmed: 32849532
Genes Immun. 2006 Mar;7(2):156-68
pubmed: 16508641
Ann Rheum Dis. 2003 Apr;62(4):359-62
pubmed: 12634239
J Immunol. 1983 Jan;130(1):203-8
pubmed: 6600176
Diagn Pathol. 2014 Jan 20;9:5
pubmed: 24443980
Open Access Rheumatol. 2019 Jan 29;11:33-45
pubmed: 30774485
Br J Rheumatol. 1998 Jul;37(7):779-83
pubmed: 9714357
Front Immunol. 2018 Sep 12;9:1952
pubmed: 30258435
Autoimmunity. 2017 May;50(3):141-150
pubmed: 28276715
Ther Adv Musculoskelet Dis. 2010 Dec;2(6):325-34
pubmed: 22870458
Nat Immunol. 2002 Sep;3(9):822-9
pubmed: 12154359
Clin Immunol. 2017 Sep;182:4-13
pubmed: 28396235
J Autoimmun. 2020 Dec;115:102549
pubmed: 33059968
Drugs. 2014 Aug;74(12):1411-33
pubmed: 25063048
Pharmacol Res Perspect. 2017 Dec;5(6):
pubmed: 29226621
Methods Mol Biol. 2017;1591:225-234
pubmed: 28349486
J Clin Invest. 1998 Sep 1;102(5):938-46
pubmed: 9727062
Front Immunol. 2016 Oct 17;7:430
pubmed: 27799933
Lab Invest. 2000 Apr;80(4):575-85
pubmed: 10780673
Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):11024-9
pubmed: 26286991
Rheumatology (Oxford). 2020 Jan 1;59(1):165-170
pubmed: 31274159
Sci Rep. 2019 May 13;9(1):7319
pubmed: 31086200
Immunology. 1994 Sep;83(1):9-15
pubmed: 7821973
Lupus Sci Med. 2019 Nov 9;6(1):e000354
pubmed: 31798918
Curr Rheumatol Rev. 2017;13(1):5-22
pubmed: 27412602
Front Immunol. 2020 Apr 09;11:601
pubmed: 32328068
Arthritis Res Ther. 2015 Oct 07;17:278
pubmed: 26445930
Curr Top Microbiol Immunol. 2020;426:119-141
pubmed: 32483659
Clin Exp Med. 2004 Dec;4(3):148-51
pubmed: 15599664
Nat Rev Immunol. 2014 Jul;14(7):447-62
pubmed: 24948366
Ann Rheum Dis. 2019 May;78(5):641-647
pubmed: 30826774
Nat Rev Rheumatol. 2018 Mar;14(3):133-145
pubmed: 29416129
Neurology. 2011 Feb 22;76(8 Suppl 3):S15-9
pubmed: 21339486
J Biol Chem. 2004 Dec 10;279(50):52487-92
pubmed: 15459201
J Rheumatol. 1997 Jun;24(6):1089-91
pubmed: 9195514
J Immunol. 2009 Mar 15;182(6):3540-7
pubmed: 19265132
RMD Open. 2020 Sep;6(2):
pubmed: 32917831
J Autoimmun. 2021 Feb;117:102590
pubmed: 33310686
Nat Rev Rheumatol. 2017 Mar;13(3):141-154
pubmed: 28202919
Ann Rheum Dis. 2019 Feb;78(2):249-260
pubmed: 30472652
Clin Exp Rheumatol. 2011 Nov-Dec;29(6):970-6
pubmed: 22132900
Invest Ophthalmol Vis Sci. 2001 Apr;42(5):925-32
pubmed: 11274068
J Clin Pathol. 1968 Sep;21(5):656-60
pubmed: 5697370
Pharmacol Ther. 2007 Jul;115(1):84-105
pubmed: 17561264
Cell Mol Immunol. 2006 Feb;3(1):11-9
pubmed: 16549044
J Rheumatol. 2000 Apr;27(4):935-9
pubmed: 10782819
Mucosal Immunol. 2018 Jan;11(1):112-119
pubmed: 28422187
Rheumatology (Oxford). 2010 Sep;49(9):1747-52
pubmed: 20525739
Annu Rev Immunol. 2005;23:127-59
pubmed: 15771568
J Autoimmun. 2010 Jun;34(4):400-7
pubmed: 19889514
J Immunol. 2012 Oct 1;189(7):3767-76
pubmed: 22942425
PLoS One. 2018 Apr 2;13(4):e0193236
pubmed: 29608575
J Exp Med. 2007 Oct 1;204(10):2335-48
pubmed: 17875673
Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13490-13497
pubmed: 31213547
J Exp Med. 2005 Jan 17;201(2):291-301
pubmed: 15657295
Nature. 2004 Jan 22;427(6972):355-60
pubmed: 14737169
J Rheumatol. 2020 Jan;47(1):157
pubmed: 31523043
Arthritis Rheumatol. 2017 Jan;69(1):35-45
pubmed: 27785888
Nat Immunol. 2004 Jul;5(7):713-20
pubmed: 15184895
Tissue Antigens. 2005 Sep;66(3):163-72
pubmed: 16101827
Expert Rev Clin Immunol. 2014 Apr;10(4):469-81
pubmed: 24506531
J Immunol. 2008 Feb 1;180(3):1921-8
pubmed: 18209090
Arthritis Rheum. 2002 Oct;46(10):2730-41
pubmed: 12384933
Rheumatology (Oxford). 2011 Jul;50(7):1288-92
pubmed: 21330342