Tissue microenvironments in therapeutic tolerance
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1 REPROGRAMMING THE IMMUNE SYSTEM IN AUTOIMMUNITY AND TOLERANCE Tissue microenvironments in therapeutic tolerance Malignant tissues use multiple mechanisms to limit immune damage. The tissue microenvironment in non-malignant tissues can be similarly protected from immune attack following short term treatment with immunomodulatory antibodies.
2 Exemplified in tolerance through antibodymediated coreceptor and costimulation blockade. T-CELL TCR (CD3) CORECEPTOR (CD4 or CD8) COSTIMULATORY MOLECULE (CD154) APC
3 THE AIM IS TO GUIDE IMMUNE RECONSTITUTION TOWARDS TOLERANCE REJECTION TOLERANCE T-CELLS THAT REGULATE CELLS THAT REJECT
4 REPROGRAMMING INVOLVES THE HARNESSINNG OF REGULATORY T-CELLS FoxP3+ Thymically induced- ttreg Peripherally induced-ptreg In vitro induced itreg Conditionally expressing FoxP3-cTreg Others e.g. Tr1 cells (IL-10)
5 TRANSPLANTION TOLERANCE FOLLOWING SHORT-TERM BLINDFOLDING OF THE T-CELLS GRAFT B RECIPIENT A RECIPIENT A GRAFT C S. Qin et al. Eur J Immunol 1987;17:1159 S. Qin et al. J Exp Med 1989;169:779
6 Linked suppression is a feature of this type of tolerance. % Graft Survival 100 (B x C)F 1 50 C (+B) Time (days) 120 A hosts tolerised to B Third party graft C
7 THE GENERAL INTERPRETATION OF LINKED SUPPRESSION SUPPRESSOR T-CELL Anti-B NAIVE T-CELL Anti-C DENDRITIC CELL expressing B and C
8 T-cells from tolerant mice are UNABLE to reject grafts. Tolerant CD4+ T-Cells SUPPRESS rejection by naïve T-cells in an adoptive transfer system Foxp3+CD4+ T-Cells are responsible for mediating the suppression
9 % skin graft survival TGFβ signalling in T-cells is required for therapeutic transplant tolerance WT no antibodies Time (days) WT + anti-cd4/8/40l Antibody Rx dntgfrii no antibodies dntgfrii + anti-cd4/8/40l Antibody Rx Daley et al A Key Role for TGF-b Signaling to T Cells in the Long-Term Acceptance of Allografts. Journal of Immunology 179, 3685
10 TRANSGENIC MICE OFFER REDUCTIONIST OPPORTUNITIES FOR SOLUTIONS OF MECHANISMS Tolerance can be achieved in conventional mice, and in TCR transgenic mice that react with just one single minor transplantation antigen-hy. TCR transgenic mice lack ttreg, and can therefore be used to study the role of ptreg in tolerance.
11 The Foxp3 gene is needed for tolerance in TCR transgenic mice Foxp3 sufficient mice (13) Foxp3 deficient mice (11) Regateiro et al J.Immunol. (2012)
12 Use of knock-in mice with a human CD2-CD52 fusion protein expressed under the FoxP3 promoter- CD2 D2 D1 CD52 9 aa GPi foxp3 IRES-hCD2-hCD52 3
13 hcd2 Foxp3+ ptreg cells develop in tolerised animals Male skin -> Marilyn.RAG1 -/-.Foxp3 hcd2 Kendal, A. R, 2011, JEM 208, Foxp3
14 Foxp3 +ve TGFβ-conditioned cells (itreg) fail to reject grafts but can regulate in vivo Foxp3 +ve or Foxp3 -ve % Graft survival x10 6 Foxp3 +ve 1x10 6 Foxp3 +ve cells / -ve (n=5) mixed cells (n=4) 1x10 6 Foxp3 -ve cells (n=5) empty mouse Days Kendal, A. R, Chen, Y, Regateiro, F.S. Ma, J, Adams, E, Cobbold, S. P, Hori, S, Waldmann, H. 2011, Journal of Experimental Medicine 208,
15 Foxp3 expression is sufficient for suppression of graft rejection. LTR Foxp3 GFP ERT2 IRES 4-hydroxytamoxifen rcd8 LTR Naïve T cell cfoxp3
16 cfoxp3-transduced T cells become anergic and also regulate in vitro anergy suppression Transduced cell 3 H-thymidine (cpm 10-3 ) cfoxp3 Effector T cell 3 H-thymidine (cpm 10-3 ) effector only empty vector cfoxp3 no 4HT 4HT added Ye Chen et al. European Journal of Immunology, , ,
17 Foxp3 expression is sufficient for suppression of graft rejection Day -1 cfoxp3-transduced TCR Transgenic T-cells Day 0 graft Tam only (n=4) 5x10 5 ctregs + 4HT + Tam (n=4) Day 28: tamoxifen stopped 100 TCR Transgenic recipient Daily tamoxifen (1mg) % Graft Survival FoxP3 with Tamoxiphen Tamoxiphen Ye Chen et al. European Journal of Immunology, , , Days
18 Tolerance depends on constant vigilance by FoxP3+ Treg (adoptive transfer of tolerant splenocytes into lymphocyte deficient mice) Kendal, A. R, 2011, JEM 208,
19 Tolerance through co-receptor blockade is dominant and infectious Tolerising antibodies Eliminate the orange lymphocytes Qin et al Infectious Transplantation Tolerance. Science, 259, Kendal, A. R et al. 2011, Journal of Experimental Medicine 208, blue T-cells become tolerant
20 Proposed mechanisms for tolerance Based on ;- Kendal, A. R et al. 2011, Journal of Experimental Medicine 208,
21 Events in the tolerated tissue?
22 THE GENERAL INTERPRETATION OF LINKED SUPPRESSION SUPPRESSOR T-CELL Anti-B NAIVE T-CELL Anti-C DENDRITIC CELL expressing B and C
23 TOLERATED GRAFTS CONTAIN CELLS THAT CAN REJECT BUT THESE CELLS ARE UNDER RESTRAINT Tolerant mouse Transfer skin graft Accepted MST >150 days n=17 Transfer accepted grafts after 60 days 1 mg Anti-CD25 Acute MAb to target Treg in the graft Rejection MST< 20 days n=17 LYMPHOCYTE DEFICIENT RECIPIENTS
24 Tolerated grafts are still retained after treatment with:- Anti-IL2 Anti-IL4 Anti-IL10R Anti-IFNg Anti-PDL1 TNFR-Ig anti-vegf
25 Percent survival male grafts Anti-CTLA4 Rx exposes rejection of tolerated male grafts in female TCR transgenic mice. Isotype control (n=16) Anti-CTLA4 (n=11) Days
26 % graft survival TGFb is also needed in the tissue microenvironment to ensure local tolerance/privilege. Control Male skin + anti-tgfb (n=9) Isotype control (n=10) Anti-TGFb (n=11).
27 Percent graft survival Anti-IL9 antibody Rx exposes rejection in the TCR transgenic model PBS control (n=9) Data pooled from TIG3045+TIG726 Anti-IL9 (n=15) Days
28 Percent graft survival 1-Me-Tryptophan in drinking water exposes graft rejection:- IDO, Nutrient (tryptophan) sensing and mtor inhibition Water control n=12) p< Me tryptophan (n=14) Days
29 Catabolism of essential amino acids? mtor inhibition. Stephen P. Cobbold, Elizabeth Adams, Claire A. Farquhar, Kathleen F. Nolan, Duncan Howie, Kathy O. Lui, Paul J. Fairchild, Andrew L. Mellor, David Ron, and Herman Waldmann(2009). Infectious tolerance by the consumption of essential amino-acids and mtor signalling. Proc. Nat. Acad. Sci 106,
30 itreg CTLA4 TGFb Indoleamine DeOxygenase TryptoPhan Hydroxylase Arginase ++ L-nitric oxide synthase Histidine Ammonia Lyase ++ Histidine DeCarboxylase ++ L-amino acid oxidase ++ Threonine DeHydrogenase
31 Local Microenvironment Infectious tolerance via the consumption of amino acids and mtor signalling mtor is inhibited when insufficient amino acids are available TGFb TCR signalling and mtor inhibition synergise with TGFb to induce foxp3 and new Tregs (with GCN2 needed for survival) Essential amino acids Additional enzymes are Induced by wound healing/innate immunity IDO, Arg1, inos, IL4i1, Hdc etc. Bcat1, Tdh Antigen presenting cell in target tissue or lymph node CTLA-4 IL-10, TGFb Tregs cause the induction of multiple enzymes that consume essential amino acids Local Microenvironment
32 TGFb may also control of availability of extracellular adenosine ATP CD39 AMP CD73 Adenosine Extracellular ATP is pro-inflammatory VS Extracellular adenosine is anti-inflammatory Kobie et al. J. Immunol. (2006); 177: Ohta, A and Sitkovsky, M. Nature, (2001) 414:
33 Induction of CD73 by TGF-b, and its suppression by Th1, Th2 & Th17 cytokines geometric mean CD *** *** *** *** 13C4 IL4 IL6 IL9 IL10 IL12 IL21 IL23 IFNg 1D11 IL4 IL6 IL9 IL10 IL12 IL21 IL23 IFNg TGFb IL4 IL6 IL9 IL10 IL12 IL21 IL23 IFNg *** *** *** 13C4 1D11 TGF-b Regateiro et al. European Journal of Immunology, 2011
34 TGF-b itregs can suppress by converting AMP to adenosine H incorporation no AMP AMP1 AMP0.5 AMP0.1 AMP0.05 CD73KO responders no AMP AMP1 AMP0.5 AMP0.1 AMP0.05 CD73KO responders + Foxp3KO notgfb MMC no AMP AMP1 AMP0.5 AMP0.1 AMP0.05 CD73KO responders + Foxp3KO +TGFb MMC Foxp3KOnoTGF MMC Foxp3KO+TGF MMC Regateiro et al. European Journal of Immunology, 2011
35 ACQUIRED TISSUE PRIVILEGE Tr? tfoxp3 pfoxp3 CHANGES REDUCED INNATE ACTIVATION, IL-10, TGFb, CATABOLISM OF ESSENTIAL AMINO ACIDS, ADENOSINE, CTLA4 IL-9 IL-2R GM-CMSF DECOMISSIONED APC Tissue
36 Contributors Dunn School of Pathology, Oxford. Stephen Cobbold Elizabeth Adams Jianbo Ma Adrian Kendal Frederico Regateiro Giovanni Piotti Duncan Howie Robert Hilbrands
37 Foxp3+ itreg cells prevent graft rejection by naive CD4 T cells, and enable conversion of further naïve T-cells to ptreg.. Infectious induction of FoxP3+ T-cells. Kendal, A. R et al. 2011, Journal of Experimental Medicine 208, l.
38 Antigen TGF-b-mediated Foxp3 gene expression TGF-b IL-2 p p TCR/CD3 Smad3 p Smad4 Stat5 JAK SOCS3 p NFAT p NFAT Foxp3 promoter NFAT Smad3 Enhancer1 Downregulation of SOCS3 expression Stat5 p AP-1 Creb Enhancer 2 CpG demethylation Foxp3 gene Tone et al. (2008) Nat Immunol. 9, Ogawa et al. (2014). J Immunol 192:
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