Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.
Animals
Antibodies, Monoclonal
/ therapeutic use
Arthritis, Infectious
/ etiology
Dependovirus
/ genetics
Disease Models, Animal
Female
Genetic Therapy
Genetic Vectors
/ metabolism
Interleukin-2
/ genetics
Interleukin-2 Receptor alpha Subunit
/ immunology
Male
Mice
Mice, Inbred C57BL
Recombinant Proteins
/ biosynthesis
Staphylococcus aureus
/ pathogenicity
T-Lymphocytes, Regulatory
/ cytology
Arthritis
IL2
Mice
S. aureus
T regulatory cells
Tregs
Journal
BMC infectious diseases
ISSN: 1471-2334
Titre abrégé: BMC Infect Dis
Pays: England
ID NLM: 100968551
Informations de publication
Date de publication:
28 Feb 2020
28 Feb 2020
Historique:
received:
01
11
2019
accepted:
12
02
2020
entrez:
1
3
2020
pubmed:
1
3
2020
medline:
6
5
2020
Statut:
epublish
Résumé
Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection. Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.
Sections du résumé
BACKGROUND
BACKGROUND
Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.
METHODS
METHODS
C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.
RESULTS
RESULTS
Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.
CONCLUSIONS
CONCLUSIONS
Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.
Identifiants
pubmed: 32111171
doi: 10.1186/s12879-020-4880-8
pii: 10.1186/s12879-020-4880-8
pmc: PMC7048135
doi:
Substances chimiques
Antibodies, Monoclonal
0
Interleukin-2
0
Interleukin-2 Receptor alpha Subunit
0
Recombinant Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
185Subventions
Organisme : Göteborgs Läkaresällskap
ID : -
Organisme : Vetenskapsrådet
ID : -
Organisme : Reumatikerförbundet
ID : -
Organisme : Stiftelsen Konung Gustaf V:s Jubileumsfond
ID : -
Organisme : IngaBritt och Arne Lundbergs Forskningsstiftelse
ID : -
Organisme : Rune och Ulla Amlövs Stiftelse för Neurologisk och Reumatologisk Forskning
ID : -
Organisme : Svenska Läkaresällskapet
ID : -
Organisme : National Natural Science Foundation of China
ID : 81460334
Références
Nat Genet. 2001 Jan;27(1):20-1
pubmed: 11137993
Clin Exp Immunol. 1999 Jul;117(1):63-9
pubmed: 10403917
Nat Rev Immunol. 2010 Jul;10(7):490-500
pubmed: 20559327
J Infect Dis. 2015 Oct 15;212(8):1308-16
pubmed: 25838268
J Immunol. 2015 Feb 1;194(3):1100-11
pubmed: 25548227
Atherosclerosis. 2012 Feb;220(2):329-36
pubmed: 22062588
Int J Med Microbiol. 2018 Aug;308(6):625-630
pubmed: 28939437
J Bone Miner Metab. 2019 Jan;37(1):2-8
pubmed: 30324535
J Biol Chem. 2001 Jan 5;276(1):563-8
pubmed: 11032840
J Immunol. 2009 Dec 15;183(12):7631-4
pubmed: 19923467
PLoS One. 2017 Feb 2;12(2):e0171222
pubmed: 28152087
Sci Immunol. 2018 Jul 6;3(25):
pubmed: 29980618
Ann Rheum Dis. 2016 Jul;75(7):1407-15
pubmed: 26324847
J Proteomics. 2018 May 30;180:53-60
pubmed: 29247803
J Immunol. 2010 Dec 1;185(11):6426-30
pubmed: 21037099
Annu Rev Immunol. 2008;26:453-79
pubmed: 18062768
Infect Immun. 2010 Sep;78(9):3783-90
pubmed: 20584972
J Autoimmun. 2015 Apr;58:48-58
pubmed: 25634360
Ann Rheum Dis. 2019 Feb;78(2):209-217
pubmed: 30472651
Lancet Diabetes Endocrinol. 2013 Dec;1(4):295-305
pubmed: 24622415
Arthritis Rheum. 1997 May;40(5):884-92
pubmed: 9153550
Circulation. 2012 Sep 4;126(10):1256-66
pubmed: 22851544
Infect Immun. 1997 Jul;65(7):2517-21
pubmed: 9199413
Clin Exp Immunol. 2002 Dec;130(3):409-14
pubmed: 12452830
J Immunol. 2002 Sep 15;169(6):3353-62
pubmed: 12218157
N Engl J Med. 2011 Dec 1;365(22):2067-77
pubmed: 22129253
Ann Rheum Dis. 1999 Apr;58(4):214-9
pubmed: 10364899
Clin Microbiol Rev. 2015 Jul;28(3):603-61
pubmed: 26016486
Infect Immun. 1992 Jul;60(7):2976-85
pubmed: 1612762
Arthritis Rheum. 1990 Nov;33(11):1739-44
pubmed: 2242071
Nat Rev Immunol. 2015 May;15(5):283-94
pubmed: 25882245
Eur J Immunol. 1994 May;24(5):1161-6
pubmed: 8181526
Infect Immun. 2000 May;68(5):2431-4
pubmed: 10768927
Sci Transl Med. 2013 Apr 3;5(179):179ra43
pubmed: 23552371
J Exp Med. 2010 Aug 30;207(9):1871-8
pubmed: 20679400
Arthritis Rheum. 2000 Oct;43(10):2276-82
pubmed: 11037887
Nat Rev Immunol. 2010 Dec;10(12):849-59
pubmed: 21107346
J Infect Dis. 2011 Aug 1;204(3):348-57
pubmed: 21742832
Rheumatology (Oxford). 2008 Nov;47(11):1635-40
pubmed: 18786965
Infect Immun. 2016 Mar 24;84(4):930-939
pubmed: 26787717
N Engl J Med. 2011 Dec 1;365(22):2055-66
pubmed: 22129252
Diabetologia. 2011 May;54(5):1075-86
pubmed: 21311856
J Infect Dis. 2015 Sep 1;212(5):830-8
pubmed: 25737563
J Immunol. 2011 Sep 1;187(5):2061-6
pubmed: 21856944
Clin Immunol. 2014 Apr;151(2):114-26
pubmed: 24576619
J Infect. 2016 May;72(5):525-36
pubmed: 26850357
JCI Insight. 2019 Mar 21;4(6):
pubmed: 30721149
Nat Med. 2016 Sep;22(9):991-3
pubmed: 27500725