Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4-Integrin Deficient NOD Mouse.
Adaptive Immunity
/ genetics
Animals
Antibodies, Monoclonal
Antigens
/ metabolism
Autoimmune Diseases
/ metabolism
Blood Glucose
/ metabolism
Diabetes Mellitus, Type 1
/ metabolism
Immunity, Humoral
Immunotherapy, Adoptive
Integrin alpha4
/ genetics
Islets of Langerhans
/ cytology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Natalizumab
/ therapeutic use
CD49d
VLA4
autoimmune diabetes
integrin
sialitis
type-1-diabetes
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
04 12 2020
04 12 2020
Historique:
received:
11
11
2020
revised:
30
11
2020
accepted:
02
12
2020
entrez:
9
12
2020
pubmed:
10
12
2020
medline:
10
7
2021
Statut:
epublish
Résumé
The spontaneously diabetic "non-obese diabetic" (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. α4 is a potential target for primary or secondary prevention of T1D.
Sections du résumé
BACKGROUND
The spontaneously diabetic "non-obese diabetic" (NOD) mouse is a faithful model of human type-1 diabetes (T1D).
METHODS
Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D.
RESULTS
NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis.
CONCLUSION
α4 is a potential target for primary or secondary prevention of T1D.
Identifiants
pubmed: 33291571
pii: cells9122597
doi: 10.3390/cells9122597
pmc: PMC7761835
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antigens
0
Blood Glucose
0
Natalizumab
0
Integrin alpha4
143198-26-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : U2C DK092993
Pays : United States
Références
J Autoimmun. 1999 Nov;13(3):290-5
pubmed: 10550216
Int Immunol. 1994 Feb;6(2):339-45
pubmed: 8155606
J Immunol. 2012 Oct 1;189(7):3271-83
pubmed: 22997230
Immunity. 2005 Aug;23(2):115-26
pubmed: 16111631
J Neuroinflammation. 2019 Nov 16;16(1):228
pubmed: 31733652
Nat Rev Endocrinol. 2016 Mar;12(3):154-67
pubmed: 26729037
PLoS One. 2010 Mar 10;5(3):e9490
pubmed: 20224823
Diabetes. 1993 Nov;42(11):1574-8
pubmed: 8405697
J Leukoc Biol. 2001 Oct;70(4):510-7
pubmed: 11590186
Annu Rev Immunol. 1992;10:645-74
pubmed: 1534242
J Clin Invest. 1994 Apr;93(4):1700-8
pubmed: 7512990
Exp Hematol. 2020 Jan;81:16-31.e4
pubmed: 31887343
Curr Diab Rep. 2014;14(9):520
pubmed: 25009119
Diabetes. 2013 Apr;62(4):1238-44
pubmed: 23274889
Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10494-8
pubmed: 7504266
Mol Biol Evol. 2013 Apr;30(4):772-80
pubmed: 23329690
Nat Methods. 2016 Jul;13(7):581-3
pubmed: 27214047
J Immunol. 2001 Dec 15;167(12):6834-40
pubmed: 11739500
J Immunol. 1988 Jun 1;140(11):3801-7
pubmed: 2897395
J Autoimmun. 1994 Dec;7(6):859-64
pubmed: 7534080
Exp Hematol. 2007 Apr;35(4):605-17
pubmed: 17379071
J Exp Med. 1987 Oct 1;166(4):823-32
pubmed: 3309126
N Engl J Med. 2013 Aug 22;369(8):699-710
pubmed: 23964932
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12604-8
pubmed: 7528925
Cell Stem Cell. 2011 Mar 4;8(3):281-93
pubmed: 21362568
Biochem Soc Trans. 1997 Feb;25(1):224-8
pubmed: 9056875
Diabetes. 2010 Nov;59(11):2846-53
pubmed: 20699420
Diabetes. 1997 Oct;46(10):1542-7
pubmed: 9313747
Exp Hematol. 2009 Jun;37(6):715-727.e3
pubmed: 19463772
J Immunol. 2016 Aug 1;197(3):701-5
pubmed: 27324130
Sci Rep. 2016 Feb 26;6:21618
pubmed: 26916743
Nucleic Acids Res. 2013 Jan;41(Database issue):D590-6
pubmed: 23193283
N Engl J Med. 2013 Aug 22;369(8):711-21
pubmed: 23964933
PLoS One. 2011;6(10):e25792
pubmed: 22043294
Exp Hematol. 2007 Aug;35(8):1256-65
pubmed: 17553614
J Clin Invest. 1993 Feb;91(2):577-87
pubmed: 7679412
Diabetes Care. 2003 Mar;26(3):832-6
pubmed: 12610045
N Engl J Med. 2006 Mar 2;354(9):899-910
pubmed: 16510744
Mol Cell Biol. 2003 Dec;23(24):9349-60
pubmed: 14645544
J Clin Invest. 1993 Jul;92(1):372-80
pubmed: 7686922
Gut Microbes. 2015;6(2):101-9
pubmed: 25648687
J Immunol. 2014 Jan 15;192(2):572-80
pubmed: 24337380
J Clin Invest. 2003 May;111(9):1357-63
pubmed: 12727927
Nat Protoc. 2009;4(11):1649-52
pubmed: 19876025
Stem Cells Dev. 2015 Mar 15;24(6):737-46
pubmed: 25316534
Curr Diab Rep. 2017 Sep 23;17(11):105
pubmed: 28942491
PLoS One. 2011 Feb 25;6(2):e17049
pubmed: 21364875
J Immunol. 1988 Jan 1;140(1):52-8
pubmed: 3275717
Nature. 1992 Mar 5;356(6364):63-6
pubmed: 1538783
J Immunol. 1995 Jan 1;154(1):180-91
pubmed: 7995938
Clin Exp Immunol. 2009 Feb;155(2):173-81
pubmed: 19128359
Diabetes. 1977 Feb;26(2):100-12
pubmed: 320072
ISME J. 2011 Feb;5(2):169-72
pubmed: 20827291
Nat Immunol. 2007 Dec;8(12):1337-44
pubmed: 17965716
Endocrinol Metab Clin North Am. 2010 Sep;39(3):513-25
pubmed: 20723817
Nature. 2004 May 6;429(6987):41-6
pubmed: 15129273
ISME J. 2011 Jan;5(1):82-91
pubmed: 20613793
J Exp Med. 2001 Mar 19;193(6):741-54
pubmed: 11257140
Diabetes. 2002 Dec;51(12):3353-61
pubmed: 12453886
Diabetes. 1999 May;48(5):967-74
pubmed: 10331399
Diabetes. 1993 Jan;42(1):44-55
pubmed: 8093606
Lancet. 2009 Jun 13;373(9680):2027-33
pubmed: 19481249