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b-Glycosphingolipids as immune modulators for oral immune therapy Yaron Ilan, M.D. Liver and Gastroenterology Units, Department of Medicine Hebrew University-Hadassah Medical Center Jerusalem, Israel
6/2012 EWGGD
Disclosure I have financial relationships with the companies below and the content of my presentation does include a discussion of the investigative use of Imm124, anti-CD3, and glucosylceramide. Medical Director: Accelmed; Immuron; Exalenz Biosciences, Adjuvan Pharma Board member: Exalenz Biosciences, Plantylight, WAYS. Consultant: Abbott, Teva Pharmaceuticals, ENZO Biochem, Chiasma Pharma, Plantylight, Nasvax, Alcobra, One Day.
b-Glucosylceramide (GC)
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b-Glucosylceramide (GC) • Oral immune therapy • GC in oral immune therapy • GC in animal models • GC in clinical trials
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Oral Immune therapy • An approach to treat autoimmune, infectious, malignant and inflammatory diseases. • An active process that uses the inherent ability of the GI tract's immune system to control unwanted systemic immune responses, by inducing regulatory T cells in an antigen-specific manner.
Antigen / Antibody / adjuvant
Presented to the Gut associated lymphoid tissue /dendritic cells
Target organs • Bowel • Pancreas • Adipose tissue • Liver • Brain
Induction of regulatory T cells (Tregs) in mesenteric lymph nodes
Oral Immune therapy • Platform for a wide range of diseases • No side effects or toxicity • Not associated with general immune suppression • No risks of severe infection or malignancy • Easily tolerated by patients
Hundreds of years ago, sages wrote in the Talmud: “ If one is bitten by a mad dog, he may eat his liver and be cured.”
The immune system of the bowel The gut mucosal immune system is the largest lymphoid organ. It differentiates the antigenic signals against the high “background noise” of food and bacterial antigens. Despite constant antigenic stimulation, suppression of inflammation is the rule. Antigen+adjuvant
M cell
DC
NKT
DC
Macrophage
DC
DC
Interfollicular T cell area
Th2 cell
Tregs
Th3 cell
Tr1
Perifollicular area B cell follicule
Ilan Y, Immunology Cell Biology, 2009
NKT lymphocytes
NKT cells co-express CD3/abTCR and NK markers. Rare in the peripheral blood. Abundant in the liver and bowel. Secrete large amounts of IFNg or IL4. Regulate immune mediated disorders. Antigen+adjuvant
LSEC
NKT
DC M cell
Kupffer cells Lamina Propria
Tregs
DC
NKT
DC
Macrophage
DC
DC
Liver
Interfollicular T cell area
Th2 cell
Tregs
Th3 cell
Tr1
Perifollicular area B cell follicule
NKT - DC cross talk NKT cells recognize exogenous glycosphingolipids anchored by the MHC-like CD1d molecule.
Glycosphingolipid CD1d NKT
DC
Potential ligands for NKT regulatory lymphocytes The endogenous ligands have yet to be identified. Alpha-galactosylceramide is a potent activator for type I NKT. Sulfatides are potential ligands for type II NKT cells.
Doyle, Nature Reviews Immunology, 2007
b-Glucosylceramide (GC) • •
Patients with Gaucher’s disease may have an altered NKT cells number and function. GC may activate dendritic cells and/or NKT cells in the gut.
Dendritic cell
NKT cell
Promotion of the DC-NKT interaction by b-glycosphingolipids b-glycosphingolipids
DC
GC
NKT
Effector T cell
Treg
GC inhibits NKT cell proliferation
STIMULATION INDEX
1.2 1 0.8 0.6 0.4
*
NKT+BSA NKT+GC NKT+DC+BSA NKT+DC+GC
0.2 0 Am J Physiol 2005
NKT - DC cross talk can increase or decrease immune responses
Doyle, Nature Reviews Immunology, 2007
Administration of GC alleviates ConA hepatitis 900
ConA
800 700 600
GC+ConA (2h) ConA+GC (2h) ConA GC Naïve
500 400 300
Naive
GC+ConA
200 100 0 ALT
AST
GC in naive
Am J Physiol 2005
Administration of GC alleviates colitis
TNBS+GC
TNBS
NAÏVE+GC
NAÏVE
Gut 2007
Administration of GC suppresses melanoma tumor growth
Control
GC
Oral administration of GC suppresses hepatocellular carcinoma growth 90 80
*
130
70
110 GC CONTROL
60
90
*
50
70
40
50
30
Survival (%)
Tumor volume (mm3)
Gut 2007
Administration of GC alleviates GVHD in the bowel Control
GC-treated
Semi-allogeneic
Chronic
Transplantation, 2007
Th1: acute GVHD, semi-allogeneic: C57BL/6 F1,C57BL/6 x Balb/c Th2: chronic GVHD : B10.D2 Balb/c
Administration of GC alleviates GVHD in the liver Control
GC-treated
Semi-allogeneic
Chronic
Optimization of b-glycolipid structure b-D-glucosyl-thio-ceramide 14000
aGalCer GCT
12000
AST ALT
HO HO
10000
U/ml
O
OH HN
O S OH
OH
8000 6000 PBS
4000
GC
GCT
aGalCer+GC
2000 0
A
B
C
D
E
F
G
H
Ben Yaakov A, Mol Immunol 2009
Inhibition of STAT1 expression
STAT1
Phospho-STAT1
b-actin
GC
GCT
8.00 6.00 4.00 2.00 0.00
A
B
C
D
E
F
G
Inhibition of NKT lymphocytes 8
PBS
aGalCer
% gated
6 GC
GCT
4
aGalCer+GC
2 0
A
B
C
D
E
F
G
H
Inhibition of apoptosis
PBS PBS
1mg a-GalCer a-GalCer
1.5mg GC,GC, IP IP 1.5mg
1.5mg b-D-thiol GC, IP
15mg GC, 1mg GC, IPIP
15mg b-D-thiol GC, IP
150mg b-D-thiol GC, IP
Oral administration of GC delays liver cell proliferation following partial hepatectomy
Oil-red-O staining 48 hours after partial hepatectomy shows an increase in fat accumulation in the GC treated mice.
Administration of GC reduces BrdU incorporation after partial hepatectomy
p=0.017
The frequency of mitotic bodies is lower in GC vs. PBS treated mice
p=0.047
Oral GC in the metabolic syndrome •
Disruption of the interface between inflammatory and metabolic pathways is central to the pathogenesis of chronic metabolic diseases.
•
Obesity is characterized by chronic activation of inflammatory pathways in peripheral tissues.
Hotamisligil Nature Reviews Immunolo, 2008 8:943
Organs involved in the pathogenesis of the metabolic syndrome
Immune system
Based on: Hotamisligil, Nature, 2006
Non alcoholic fatty liver disease
Non alcoholic steatohepatitis
A. Mae Diehl, EASL NASH, 2009
Non alcoholic fatty liver disease Non alcoholic steatohepatitis
A. Mae Diehl, EASL NASH, 2009
Leptin deficient ObOb mice • Features the metabolic syndrome • Non-alcoholic steatohepatitis, diabetes, obesity, hyperlipidemia • Altered NKT cell function b-Glucosylceramide
GC
GC decreases transaminase levels
GC decreases triglyceride levels 3
700 OB/OB+GC
2.5
600
IU
400
LEAN+ GC
1.5
*
500
*
2
*
OB/OB+PBS
300
LEAN+ PBS
200
1
100 AST
ALT
GC improves glucose tolerance test 400 350 GLUCOSE
300 250 200 150 100 50 0 0
15
30
60
90
120
180
TIME
Lalazar, Am. J. Pathol., 2009
GC decreases hepatic fat accumulation
Control Ob/Ob
GC-treated Ob/Ob
20 OB/OB+PBS
15
LEAN+ GC
10
*
CM 2 x SI INDEX
OB/OB+GC
LEAN+ PBS
5 0
Control Ob/Ob
GC-treated Ob/Ob
Margalit M, J Pharmacol Exp Ther. 2007 Margalit, J. JExp. Therap. Zygnmod Em, Am. Physiology Endo2006 2009
IGL GC
b-Glucosylceramide
LC
b-Lactosylceramide
Psammomys obesus The desert gerbil Psammomys obesus (sand rat) is a model of a nutritionally-induced type II diabetes, characterized by insulin resistance. It is adapted to a low energy diet, the Saltbush. When transferred to a high energy diet, it develops obesity, hyperinsulinemia, hyperglycemia, and steatohepatitis.
Tayer-Shiffman; Hepatology 44:4 (S1) 71A, 2006
IGL decreases insulin and glucose post-prandial levels p
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