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January 29, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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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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