Neutralization Versus Reinforcement of Proinflammatory Cytokines to Arrest Autoimmunity in Type 1 Diabetes.
As physiological pathways of intercellular communication produced by all cells, cytokines are involved in the pathogenesis of inflammatory insulitis as well as pivotal mediators of immune homeostasis. Proinflammatory cytokines including interleukins, interferons, transforming growth factor-β, tumor necrosis factor-α, and nitric oxide promote destructive insulitis in type 1 diabetes through amplification of the autoimmune reaction, direct toxicity to β-cells, and sensitization of islets to apoptosis. The concept that neutralization of cytokines may be of therapeutic benefit has been tested in few clinical studies, which fell short of inducing sustained remission or achieving disease arrest. Therapeutic failure is explained by the redundant activities of individual cytokines and their combinations, which are rather dispensable in the process of destructive insulitis because other cytolytic pathways efficiently compensate their deficiency. Proinflammatory cytokines are less redundant in regulation of the inflammatory reaction, displaying protective effects through restriction of effector cell activity, reinforcement of suppressor cell function, and participation in islet recovery from injury. Our analysis suggests that the role of cytokines in immune homeostasis overrides their contribution to β-cell death and may be used as potent immunomodulatory agents for therapeutic purposes rather than neutralized.
The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202.
Ayelet
A
Kaminitz
The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202.
Shifra
S
Ash
The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202. anadir@012.net.il.
Nadir
N
Askenasy
D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D017209:Apoptosis; D015551:Autoimmunity; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D006706:Homeostasis; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018836:Inflammation Mediators / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000473:pathology*; D017211:Treatment Failure
D057134:Antibodies, Neutralizing; D016207:Cytokines; D018836:Inflammation Mediators
Autoimmunity; Immune homeostasis; Inflammatory insulitis; Proinflammatory cytokines; Regulatory T cells; Type 1 diabetes; β-cell death
Diabetes. 2015 Aug;64(8):2880-91
25784545
Diabetes. 2009 Jun;58(6):1302-11
19289457
J Exp Med. 1999 Apr 5;189(7):1053-62
10190896
Diabetes. 1994 May;43(5):613-21
8168635
PLoS One. 2012;7(5):e33254
22606220
J Biol Chem. 2010 Mar 5;285(10):7394-404
20038584
Clin Immunol. 2008 Nov;129(2):195-201
18801706
Diabetologia. 2006 Jan;49(1):83-9
16323002
J Exp Med. 1992 Dec 1;176(6):1719-31
1460428
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1913-8
17267600
J Immunol. 2014 Feb 15;192(4):1425-32
24446517
J Exp Med. 1997 Aug 18;186(4):613-8
9254659
J Clin Invest. 1998 Aug 1;102(3):516-26
9691088
Lancet. 2013 Jun 1;381(9881):1905-15
23562090
Diabetes. 1985 Nov;34(11):1205-9
3930327
J Exp Med. 1995 Feb 1;181(2):559-68
7530759
J Exp Med. 2005 Apr 18;201(8):1333-46
15837817
Nature. 2001 Dec 13;414(6865):792-8
11742411
Cell Biochem Biophys. 2007;48(2-3):159-63
17709885
Expert Opin Ther Targets. 2011 Feb;15(2):119-26
21073280
Clin Rheumatol. 2012 Apr;31(4):631-6
22147207
Nat Med. 2003 Sep;9(9):1202-8
12937416
Diabetes. 1995 Jan;44(1):112-7
7813805
Ann N Y Acad Sci. 2002 Apr;958:166-9
12021099
Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):107-19
16257256
Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1561-6
21220322
Cell. 1988 Mar 11;52(5):773-82
2449974
Clin Immunol. 1999 Jan;90(1):2-9
9884346
J Immunol. 2005 Sep 15;175(6):3516-24
16148094
J Immunol. 2011 Feb 15;186(4):2543-51
21217013
Clin Exp Immunol. 2016 Jan;183(1):16-29
26102289
J Exp Med. 1997 Feb 3;185(3):531-9
9053453
Inflamm Allergy Drug Targets. 2011 Jun;10(3):208-17
21495968
J Immunol. 1998 Apr 1;160(7):3513-21
9531313
J Immunol. 1987 Dec 15;139(12):4077-82
3320203
J Immunol. 2000 Mar 15;164(6):2931-6
10706679
J Autoimmun. 2002 Aug-Sep;19(1-2):9-22
12367555
J Immunol. 2004 Dec 15;173(12):7308-16
15585854
J Autoimmun. 1989 Dec;2(6):759-76
2533502
Physiol Genomics. 2005 Apr 14;21(2):201-11
15671250
J Immunol. 2008 Mar 1;180(5):2747-51
18292492
J Immunol. 2002 Jan 1;168(1):188-96
11751962
Diabetes. 2002 Feb;51(2):311-6
11812737
J Autoimmun. 1997 Jun;10(3):231-8
9218748
Int Immunol. 2006 Jun;18(6):837-46
16574667
Diabetes. 2003 Aug;52(8):1967-75
12882912
Autoimmunity. 1998;27(2):109-22
9583742
J Biochem Mol Biol. 2002 Jan 31;35(1):116-26
16248976
Int Immunol. 2004 Dec;16(12):1723-32
15492021
JAMA. 2006 May 17;295(19):2275-85
16705109
J Immunol. 2000 Sep 1;165(5):2841-9
10946317
Transplantation. 2005 May 15;79(9):1091-6
15880049
Endocrinology. 1995 Nov;136(11):4790-5
7588208
Blood. 2005 Feb 15;105(4):1396-404
15486063
Eur J Immunol. 2004 Feb;34(2):548-57
14768060
Transplantation. 2009 Jan 27;87(2):198-206
19155973
Trends Immunol. 2013 Jun;34(6):282-9
23434408
Diabetes. 1995 Jul;44(7):733-8
7540572
Immunol Cell Biol. 2009 Feb;87(2):178-85
19015667
J Autoimmun. 2012 Feb;38(1):20-8
22186068
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14028-33
18779574
J Immunol. 1998 Mar 15;160(6):2684-91
9510167
Islets. 2014;6(3):e950547
25322830
J Autoimmun. 2003 Jun;20(4):303-12
12791316
Eur J Immunol. 2000 Apr;30(4):1224-32
10760812
J Exp Med. 2010 Aug 30;207(9):1871-8
20679400
J Clin Invest. 2010 Dec;120(12):4558-68
21099113
Eur J Immunol. 2003 Dec;33(12):3255-64
14635033
J Exp Med. 1989 Oct 1;170(4):1243-62
2507727
Diabetes. 2013 Apr;62(4):1217-26
23248173
Diabetologia. 2008 Jul;51(7):1213-25
18463842
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15995-6000
16247001
Ann Med. 2010 Sep;42(6):426-38
20568978
Diabetologia. 1999 May;42(5):566-73
10333049
Immunity. 1998 Nov;9(5):733-43
9846494
J Immunol. 2007 Jul 1;179(1):154-61
17579033
Diabetologia. 1996 Sep;39(9):1005-29
8877284
Immunol Lett. 2015 Feb;163(2):199-205
25447401
J Autoimmun. 2004 Aug;23(1):27-35
15236750
J Immunol. 2001 Dec 1;167(11):6637-43
11714835
Eur J Immunol. 2009 Oct;39(10):2716-24
19658094
Rev Diabet Stud. 2006 Spring;3(1):39-46
17491711
J Interferon Res. 1994 Jun;14(3):111-6
7930757
Clin Exp Immunol. 2010 Jan;159(1):23-44
19912253
J Exp Med. 1994 Sep 1;180(3):995-1004
8064245
Autoimmunity. 1992;12(1):21-7
1510786
Diabetes. 2011 Aug;60(8):2112-9
21659501
J Investig Med. 2004 Jan;52(1):45-9
14989369
J Autoimmun. 2002 Nov;19(3):129-37
12419283
Cell Transplant. 2014;23 (10 ):1199-211
23635711
J Clin Endocrinol Metab. 1991 Nov;73(5):1044-50
1939517
J Clin Invest. 2006 May;116(5):1371-81
16628253
Diabetes. 1995 Oct;44(10):1161-4
7556951
J Immunol. 2011 Jun 15;186(12):6779-87
21572024
Immunol Cell Biol. 2006 Feb;84(1):20-7
16277639
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13644-9
18755894
J Exp Med. 1997 Oct 6;186(7):989-97
9314549
J Exp Med. 2002 Aug 5;196(3):369-77
12163565
Nat Rev Immunol. 2010 Jul;10(7):501-13
20577267
Diabetes. 2006 Sep;55(9):2437-45
16936191
Curr Pharm Des. 2007;13(7):749-60
17346189
J Immunol. 1999 Aug 1;163(3):1562-9
10415060
J Immunol. 2005 Mar 1;174(5):2746-55
15728483
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10845-50
11526215
Clin Exp Immunol. 2015 Dec;182(3):261-9
26250153
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10878-83
12949259
Trends Endocrinol Metab. 2010 May;21(5):261-7
20096598
Eur J Immunol. 1997 Jan;27(1):255-61
9022027
J Exp Med. 1997 Oct 20;186(8):1193-200
9334358
Immunity. 2000 May;12(5):459-69
10843379
Curr Pharm Des. 2011;17(29):3224-8
21864261
Blood. 2006 Jul 1;108(1):253-61
16537805
Nat Rev Immunol. 2002 Jan;2(1):37-45
11905836
Eur J Immunol. 2012 Jul;42(7):1717-22
22585671
Apoptosis. 2009 Dec;14(12):1389-404
19322660
J Biol Chem. 2015 Mar 6;290(10):6653-69
25586177
Adv Exp Med Biol. 2003;520:73-86
12613573
J Immunol. 1990 Sep 1;145(5):1395-9
2384663
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11548-53
21709219
J Cell Physiol. 2005 Jul;204(1):124-30
15622524
Cell Prolif. 2015 Jun;48(3):356-62
25871744
Clin Immunol. 2015 Oct;160(2):155-62
26073226
J Immunol. 2011 Aug 15;187(4):1702-12
21734073
Diabetologia. 1998 Sep;41(9):1101-8
9754830
J Autoimmun. 1991 Apr;4(2):237-48
1909135
J Clin Invest. 2000 Feb;105(4):459-68
10683375
Proc Natl Acad Sci U S A. 1990 Feb;87(3):968-72
2405400
J Clin Invest. 1989 Oct;84(4):1345-8
2794065
Blood Rev. 2015 Jan;29(1):11-5
25440916
J Immunol. 2001 Jun 15;166(12):7023-32
11390446
J Autoimmun. 1991 Apr;4(2):249-62
1909136
Rev Endocr Metab Disord. 2003 Sep;4(3):291-9
14501180
Eur J Immunol. 2009 Jan;39(1):216-24
19130584
Diabetes. 2012 Aug;61(8):2054-65
22751698
J Immunol. 1998 Apr 1;160(7):3585-93
9531322
Nat Rev Endocrinol. 2009 Apr;5(4):219-26
19352320
Diabetes. 2009 May;58(5):1144-55
19208913
J Immunol. 2010 Aug 1;185(3):1959-67
20592279
J Immunol. 2001 Apr 1;166(7):4481-9
11254704
Diabetes. 2001 Mar;50(3):551-7
11246874
J Exp Med. 2003 Oct 6;198(7):1103-6
14530378
Diabetologia. 2009 Jun;52(6):1092-101
19343319
Life Sci. 2008 Dec 19;83(25-26):865-70
18957297
Diabetes. 1998 May;47(5):727-32
9588443
Diabetes Care. 2009 Jul;32(7):1244-9
19366957
Diabetes. 1996 Jun;45(6):812-7
8635658
Front Immunol. 2012 Jul 12;3:196
22807927
J Immunol. 2005 Dec 1;175(11):7738-45
16301684
Immunol Cell Biol. 2007 Nov-Dec;85(8):582-9
17637698
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4572-7
15070759
Endocrinology. 2002 Sep;143(9):3490-7
12193562
Nat Rev Drug Discov. 2011 Jun;10(6):439-52
21629294
Acta Endocrinol (Copenh). 1986 Dec;113(4):551-8
3538741
J Immunol. 2009 Jul 1;183(1):332-9
19542444
J Immunol. 2000 Jul 15;165(2):1102-10
10878389
Int Immunol. 2009 Nov;21(11):1291-9
19778991
Int Immunol. 1992 May;4(5):611-4
1510787
Cytokine. 2011 Sep;55(3):353-61
21641234
J Immunol. 2003 Jun 1;170(11):5491-501
12759426
J Immunol. 1988 Oct 1;141(7):2325-9
3139756
J Interferon Cytokine Res. 2011 Oct;31(10):711-9
21851268
Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1567-72
21220309
J Clin Invest. 1998 Aug 1;102(3):499-506
9691086
J Autoimmun. 1989 Apr;2(2):163-71
2527507
Diabetes. 2000 Dec;49(12):2007-11
11118001
Nat Rev Endocrinol. 2010 Mar;6(3):158-66
20173777
Immunology. 2008 Jan;123(1):108-17
17983440
Immunity. 1998 May;8(5):601-13
9620681
J Clin Invest. 1999 Apr;103(8):1201-9
10207172
Bioessays. 2008 Sep;30(9):875-88
18693266
Lancet. 2011 Jul 23;378(9788):319-27
21714999
Immunity. 1997 Dec;7(6):821-30
9430227
J Pediatr Endocrinol Metab. 2000 Jan;13(1):91-8
10689643
J Exp Med. 1999 Jan 18;189(2):331-9
9892615
Nature. 1987 Mar 19-25;326(6110):304-6
3102976
J Mol Cell Biol. 2013 Apr;5(2):85-98
23243069
Science. 2003 Nov 14;302(5648):1223-7
14615542
Pediatr Diabetes. 2011 Nov;12(7):656-67
21518168
J Mol Med (Berl). 2003 Aug;81(8):455-70
12879149
J Exp Med. 1997 May 5;185(9):1573-84
9151895
Autoimmunity. 2002 Sep;35(6):369-75
12568116
Eur J Immunol. 2016 Apr;46(4):1030-46
26692253
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9317-22
20439719
Cell Mol Life Sci. 2005 Aug;62(16):1850-62
15968469
J Immunol. 1999 Oct 15;163(8):4335-41
10510373
Diabetes. 2004 Jan;53(1):113-21
14693705
Diabetes. 1997 May;46(5):750-7
9133540
Diabetologia. 1991 Nov;34(11):779-85
1722764
Autoimmun Rev. 2006 May;5(5):338-43
16782559
Clin Immunol. 2013 Dec;149(3):279-85
23510726
J Autoimmun. 1996 Oct;9(5):645-51
8933280
Development. 1993 May;118(1):33-46
8104143
Diabetes. 2006 Oct;55(10):2713-22
17003335
Diabetologia. 2009 Jul;52(7):1442-4
19440690
J Immunol. 1999 Aug 1;163(3):1696-703
10415077
J Immunol. 1993 May 1;150(9):4136-50
7682590
Diabetologia. 2013 Jan;56(1):126-35
23052055
J Immunol. 2010 Apr 1;184(7):3570-81
20181891
J Immunol. 2001 Jan 15;166(2):1352-9
11145720
Clin Exp Immunol. 1999 Jul;117(1):38-43
10403913
Autoimmunity. 1995;20(3):185-90
7578879
Diabetologia. 1993 Aug;36(8):759-66
8405744
Diabetes. 2000 Jul;49(7):1116-22
10909967
Endocr Rev. 1995 Apr;16(2):164-76
7781592
J Immunol. 2006 Jul 1;177(1):192-200
16785514
Cytokine. 2015 Feb;71(2):366-76
25510901
Diabetes. 2012 Jan;61(1):145-54
22043003
Pancreas. 2003 Nov;27(4):345-55
14576499
Diabetologia. 1996 Nov;39(11):1306-12
8932996
Diabetes. 1999 Jan;48(1):21-8
9892218
J Cell Physiol. 2000 Jul;184(1):46-57
10825233
Curr Diab Rep. 2012 Oct;12(5):499-509
22791179
Diabetes. 2000 Jan;49(1):39-47
10615948
J Immunol. 1998 Nov 1;161(9):4467-71
9794367
Circulation. 2012 Dec 4;126(23 ):2739-48
23129601
Am J Pathol. 2011 Jun;178(6):2716-25
21641394
Ann N Y Acad Sci. 2013 Apr;1283:81-6
23167495
Diabetes Metab Rev. 1998 Jun;14(2):129-51
9679667
PLoS One. 2009 Nov 17;4(11):e7863
19924236
Nat Med. 2002 Dec;8(12):1414-20
12415259
J Exp Med. 1996 Nov 1;184(5):1963-74
8920883
Mol Genet Metab. 2004 Sep-Oct;83(1-2):82-92
15464423
J Immunol. 2006 Jun 15;176(12):7278-87
16751371
Diabetes. 1988 Jan;37(1):133-6
3121415
Arthritis Rheum. 2000 Nov;43(11):2606-8
11083287
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12287-92
12221281
Autoimmunity. 2013 Jun;46(4):259-68
23256897
J Immunol. 1999 Apr 15;162(8):4598-605
10201999
J Immunol. 2010 May 1;184(9):4779-88
20363968
Cytokine. 1994 Jul;6(4):399-406
7948748
J Exp Med. 2008 Jan 21;205(1):207-18
18195074
Diabetes. 2012 Nov;61(11):2862-70
22773667
Diabetes. 2004 Nov;53(11):2797-803
15504959
Asian Pac J Cancer Prev. 2014;15(8):3403-10
24870729
Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):279-84
10618409
Immunity. 2008 May;28(5):687-97
18468463