Innate immunity as a therapeutic target in IBD. Elke Cario Division of Gastroenterology & Hepatology University Hospital of Essen Essen, Germany
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1 Innate immunity as a therapeutic target in IBD Elke Cario Division of Gastroenterology & Hepatology University Hospital of Essen Essen, Germany
2 The intestinal mucosa must rapidly recognize luminal pathogens to initiate controlled immune responses, but maintain hyporesponsiveness to harmless commensals Science :1920
3 The Principle of Pattern Recognition Innate immune cells express so-called pattern recognition receptors (PRRs( PRRs),, that specifically discriminate between self and microbial non-self, based on the recognition of broadly conserved molecular patterns. Janeway PRR pro/anti anti-inflammatoryinflammatory antimicrobial Adaptive Immunity
4 Families of PRRs: TLRs, NLRs, cell surface TREM CD11 CD18 Toll-like like receptors MD-2 mcd14 (TLRs) soluble LBP scd14...and many more Nods/CARDs intracellular
5 TLR-KO mice are susceptible to acute DSS colitis Mechanism Colitis - Model Activity Knockout WT MyD88-/- TLR2-/- Toxic damage (target: IEC) DSS - acute TLR2-/- TLR4-/- TLR9-/- MyD88-/- Gastro :1359 % Survival WT TLR2-/- MyD88-/- 25 Stop DSS Day Epithelial injury Cell 2004;118:229
6 Some TLR5KO develop spontaneous colitis which is TLR4-dependent J Clin Invest : 3909 TLR4/5KO
7 Treatment with TLR2 agonist ameliorates all clinical signs of DSS-induced colonic inflammation Day DSS 2.7% PCSK 150µg/ml % Body weight PCSK + PCSK Stop DSS * * * PCSK * # Day *p<0.001 # Blood score PCSK + PCSK Stop DSS Day * PCSK * *p<0.001 # Gastroenterology :1359 WT
8 The TLR2 ligand PCSK attenuates severity of DSS colitis Gastroenterology :1359
9 TLR2 stimulation induces ZO-1 redistribution via PKC which correlates with TER increase Time (mins( mins) Phospho- panpkc panpkc PMA PCSK 20µg/ml in vitro ZO-1 + PCSK 20µg/ml TER (% of negative controls) Time (mins) TLR2DN TLR4DN Gastroenterology 2004;127:224
10 PCSK-treatment leads to substantial preservation of TJ/AJ architecture of IEC in in DSS colitis -PCSK + PCSK * DSS 2.7%, Day 12 ZO-1 * * * E-cadherin * * * inflammatory infiltrate Gastro :1359
11 DSS-mice treated with TLR2 agonist demonstrate lower FITC-dextran serum levels Day 10 +DSS -PCSK Overlay FITC in situ + H&E + PCSK [FITC] ng/ml Control - PCSK + PCSK Gastroenterology :1359 DSS 2.7%, Day 10
12 Epithelial cell TLR engagement stimulates extension and antigen sampling of underlying dendritic cells TLR TLR J Immunol :4275 JEM :2841 Immunity :623 Science :254 Nat Immunol :361
13 TLR inhibition protects against TH1-mediated colitis Mechanism Toxic damage (IEC, T cell etc.) T-cell-mediated Cell Res 2006;16:70 TNBS IL-12 IL-18 Aktivity wt TLR9-/- TLR9-/- Knockout TLR4-/- TLR4-/- Colitis - Model DSS chronic TNBS x Stat3mutant x IL10-/- MyD88-/- Chron. DSS TNFα IL-6 IFNγ Gastroenterology 2005;129:913
14 TLR4/MyD88 trigger chronic intestinal inflammation through aberrant myeloid cell activation in in the absence of of IL-10 JCI :1297 MyD88/IL-10-/- TLR4/Stat3-/- IL /- TLR-/- Immunity :1 = TH1
15 TLR4 blockage with CRX-526 ameliorates spontaenous colitis in MDR1α-deficient mice MDR1α-deficient mice Severe colitis No colitis + CRX-526 synthetic lipid A mimetic TLR4 antagonist + vehicle J Immunol :6416
16 TLR signalling may not be involved in all forms of chronic murine colitis Mechanism T-cell-mediated Colitis - Model x IL2-/- CD4 + CD62L + T cell transfer Aktivity Knockout TLR9-/- MyD88-/- MyD88/IL2-/- itreg IL-27 STOP Th17 Immunity 2006;25:1 Eur J Immunol 2007;37:1809
17 Two autophagy-genes ATG16L1 and IRGM have been associated with CD ATG16L1 Nat Genet :207 Nat Genet :596 Nat Genet. 2007; 39:830
18 MyD88-dependent signalling pathways contribute to intestinal tumor progression Science 2007;317:124
19 NOD2-overexpression protects against peptidoglycan- and TNBS-colitis PGN Colitis WT NOD2-Tg TNBS WT +/- NOD2 plasmid TNBS J Clin Invest :545 Gastroenterology :1510 +NOD2 +empty +mutnod2
20 Basal innate immune signaling may be protective of the IEC barrier against acute injury Acute injury intestinal epithelial barrier Commensals PRR Healing Barrier protection Tolerance Epithelium Gut Aug;54(8):
21 Aberrant innate immune signaling may favor chronic intestinal inflammation through commensal-mediated mediated proinflammatory TH1-effects in the lamina propria Commensals PRR Invasion Cytokines Mucosa TH1-type Chronic inflammatory disease Gut Aug;54(8): Injury Barrier destruction Intolerance
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