Download presentation
Presentation is loading. Please wait.
Published bySuzan York Modified over 9 years ago
2
Therapeutic approaches for MG studied in animal models Miriam Souroujon Open University of Israel Weizmann Institute of Science International Conference on Myasthenia Gravis Paris, December 2009
3
Experimental animal models for Myasthenia Gravis Active immunization Torpedo AChR EAMG Passive transfer Anti-AChR Abs Animal models for MuSK+ MG Humanized SCID/NOD mouse model for MG
4
Treatment modalities tested in EAMG Targeting AChR-specific T and B cell responses Apheresis of pathogenic anti-AChR antibodies - immunoadsorption on ECDs Anti-TCR (Vb5.1) antibodies Targeting the antigen-binding site of HLA-restricting alleles Anti-idiotypes (IVIG) Antigen (AChR)- specific Immunization by AChR recombinant fragments or synthetic peptides Denatured AChR Synthetic AChR peptides: Altered peptides, Dominant T cell epitopes AChR recombinant fragments (mucosal tolerance) Xenogeneic, Syngeneic Pathogenic B-cell epitope free
5
Cell based Dendritic cells Mesenchymal stem cells T regulatory (Treg) cells Non-cell based targets Cytokine networks (IFN-, IL-18, TNF-, IL-1) Costimulatory signaling (CD40L) Complement pathways Fc receptor Cholinergic balance at the neuromuscular junction AChR-associated anchor protein, rapsyn Chemokines and chemokine receptors (IP-10/CXCR3) Phosphodiesterases Treatment modalities tested in EAMG Immunomodulatory approaches
6
Cell based Dendritic cells Mesenchymal stem cells T regulatory (Treg) cells Non-cell based targets Cytokine networks (IFN-, IL-18, TNF-, IL-1) Costimulatory signaling (CD40L) Complement pathways Fc receptor Cholinergic balance at the neuromuscular junction AChR-associated anchor protein, rapsyn Chemokines and chemokine receptors (IP-10/CXCR3) Phosphodiesterases Treatment modalities tested in EAMG Immunomodulatory approaches
7
Following PTX treatment PDE 4 TNF- , IL-18, IL-12 IL-10 Foxp3 T cell proliferation Anti-AChR Ab PDE 1, 4, 7 TNF- Cathepsin-l PDE 2,3,4,7 Cathepsin-l In EAMG PDE 1,3,4,7 Immune systemMuscle
8
Following PTX treatment PDE 4 TNF- , IL-18, IL-12 IL-10 Foxp3 T cell proliferation Anti-AChR Ab PDE 1, 4, 7 TNF- Cathepsin-l PDE 2,3,4,7 Cathepsin-l In EAMG PDE 1,3,4,7 Immune systemMuscle
9
PTX acts as a steroid-sparing agent
10
PDE expression in thymus of MG patients
11
PDE expression in PBL of MG patients
12
Are phosphodiesterase (PDE) levels altered in other autoimmune diseases? Experimental models ? Human diseases ?
13
*** ** LNC *** ** * 0 50 100 150 200 250 PDE1PDE2PDE3PDE4PDE7 TNF- Gene/Actin (%) CFA EAE 0 50 100 150 200 250 PDE1PDE2PDE3PDE4PDE7 TNF- Gene/Actin (%) CFA EAE CD4 + cells * * * ***
14
PDE expression in PBL of Multiple Sclerosis patients
15
The expression levels of selective PDE subtypes are upregulated in EAMG and MG. The general PDE inhibitor PTX acts as a steroid sparing agent in EAMG. The expression levels of selective PDE subtypes are upregulated also in multiple sclerosis (MS) and its animal model, EAE. PDEs may be potential therapeutic targets in various autoimmune diseases. Summary I PDE
16
Cell based Dendritic cells Mesenchymal stem cells T regulatory (Treg) cells Non-cell based targets Cytokine networks (IFN-, IL-18, TNF-, IL-1) Costimulatory signaling (CD40L) Complement pathways Fc receptor Cholinergic balance at the neuromuscular junction AChR-associated anchor protein, rapsyn Chemokines and chemokine receptors (IP-10/CXCR3) Phosphodiesterases Treatment modalities tested in EAMG Immunomodulatory approaches
17
Treg abnormalities are observed in MG Functional impairments were found in thymic Treg cells of MG patients Decreased CD4 + CD25 high cell numbers were found in PBL of MG patients Successful treatments or thymectomy result in elevated numbers of CD4 + CD25 high cells CD4 + CD25 + cells are involved in the suppressive action of various effective therapies in EAMG
18
EAMG rats have reduced levels of Treg cell s
19
Treg-based treatments Cancer Infectious disease Autoimmune Inflammatory disease Administration of Exogenous Treg Administration of Exogenous Treg Modulation of endogenous Treg Modulation of endogenous Treg Treg
20
Ex-vivo generation of CD4+CD25+ regulatory T cells Spleen from healthy or EAMG donor rat Negative selection of CD4+ cells using magnetic beads YY YY Y Y YY Y Y Y Y Y Y Y Y Y Y Y 90% CD4 + TGF- IL-2 culture cells on anti-CD3 and anti-CD28 coated plates
21
Characterization of ex vivo generated CD4+CD25+ Treg cells 5% CD4 CD25 EAMG Splenocytes + + + + Co-culture with - evCD4+CD25+ nCD4+CD25+ nCD4+CD25 - * * 96% DAY 0DAY 3 Foxp3 0 0.1 0.2 0.3 0.4 0.5 evCD4+CD25+ nCD4+CD25 - Relative expression levels CTLA-4 0 0.5 1 1.5 2 2.5 3 3.5 evCD4+CD25+ nCD4+CD25 - Relative expression levels TGF- 0 0.5 1 1.5 evCD4+CD25+ nCD4+CD25 - Relative expression levels
22
Treg generated ex vivo from healthy donors suppress EAMG 012345678 0.0 0.5 1.0 1.5 2.0 2.5 PBS evCD4+CD25+ nCD4+CD25- Weeks
23
CD25 Healthy EAMG 0 0.5 1 1.5 2 2.5 3 3.5 4 0123456789101112 Weeks Clinical score evCD4 + CD25 + from EAMG donors CONTROL (PBS) evCD4 + CD25 + from healthy donors Treg from myasthenic rats exacerbate EAMG
24
Revisiting the Th1-Th2 Paradigm Naive T cell Dendritic cell TGF- IFN IL-4 + IL-6 - IL-6 Th1 Tbet Th2 Gata 3 Th17 ROR T Treg Foxp3 IL-12R IL-12 IL-23R IL-23 Adapted from Reiner et al., Cell, 2007 Autoimmunity Inflammation Cancer Extracellular bacteria Allergy and asthma Systemic pathology Harmful role Counter regulation Parasitic worms Intracellular pathogens Protective role
25
3 Weeks 7 Weeks Expression of Foxp3
26
3 Weeks7 Weeks Expression of Th17-related genes
27
3 Weeks7 Weeks Expression of regulatory cytokines
28
Treatment by anti-IL-6 Abs starting at the acute phase of EAMG 0 0.5 1 1.5 2 2.5 3 3.5 4 012345678910 weeks clinical score PBS anti IL-6
29
0 0.5 1 1.5 2 2.5 3 3.5 4 01234567891011 weeks clinical score anti IgG anti IL-6 Treatment by anti-IL-6 Abs starting at the chronic phase of EAMG
30
* Total anti-AChR IgG controlanti IL-6 0.0 0.1 0.2 0.3 controlanti IL-6 0 10 20 30 40 % of splenic B cells *
31
Expression following anti-IL-6 treatment
32
Cytokines expression following anti IL-6 treatment
33
Serum IL-17 in anti-IL-6 treated rats controlAnti-IL-6 0 1 2 3 4 5 6
34
Revisiting the Th1-Th2 Paradigm Naive T cell Dendritic cell TGF- IFN IL-4 + IL-6 - IL-6 Th1 Tbet Th2 Gata 3 Th17 ROR T Treg Foxp3 IL-12R IL-12 IL-23R IL-23 Adapted from Reiner et al., Cell, 2007 Autoimmunity Inflammation Cancer Extracellular bacteria Allergy and asthma Systemic pathology Harmful role Counter regulation Parasitic worms Intracellular pathogens Protective role
35
Summary II Treg Suppression of EAMG can be achieved by: Administration of exogenous Treg from healthy donors Shifting the balance between endogenous Treg and Th17 in favor of Treg
36
Hopefully, the vast repertoire of therapeutic approaches studied in experimental models of MG will pave the way to clinical studies that will eventually improve the management of MG
37
Thanks !! Sara Fuchs Revital Aricha Tali Feferman Keren Mizrachi Sonia Berrih-Aknin Ariel Miller (MS) Avi Ben-Nun (EAE) Sara Fuchs Revital Aricha Tali Feferman Keren Mizrachi Sonia Berrih-Aknin Ariel Miller (MS) Avi Ben-Nun (EAE)
38
Recipients of Treg have elevated CD4 + CD25 + FoxP3 + cells FoxP3+ PBS treated 31% FoxP3+ 54% evCD4+CD25+ treated 0 1 2 3 4 PBSnCD4+CD25-evCD4+CD25+ % of CD25+among CD4+ cells * 0 1 2 3 PBSnCD4+CD25-evCD4+CD25+ % of CD25+FoxP3+among CD4+ cells % FoxP3+ among CD4+CD25+ cells of recipients
Similar presentations
© 2025 SlidePlayer.com. Inc.
All rights reserved.