Rationales behind novel therapies for coeliac disease Ludvig M. - - PowerPoint PPT Presentation

Ludvig M. Sollid

Director (CIR), Professor (UiO)

Rationales behind novel therapies for coeliac disease

Coeliac UK Research Conference London, March 11, 2015

CONFLICT OF INTEREST

Ludvig M. Sollid

Ø Regeneron Pharma – Consulting / Funding Ø ImmusanT Inc – Membership on advisory committee / Honoraria Ø Alvine Pharma – Membership on advisory committee / Honoraria Ø Glenmark Pharma – Consulting

Magliocca et al Arch Histol Cytol 1992

l

+ gluten

• gluten

NORMAL MUCOSA CELIAC DISEASE MUCOSA

+ gluten

• gluten

NORMAL MUCOSA CELIAC DISEASE MUCOSA

antibodies to gluten (gliadin) transglutaminase 2 (TG2)

Photo: Per Brandtzaeg

Koblingsanalyse

GENOME WIDE ASSOCIATION STUDIES

Mathew, Nat Rev Genet 2007

S

GWAS and MHC (HLA)

Slide courtesy: TH Karlsen

HLA association in celiac disease

DQ2.5 ¡ DQ2.2 ¡ DQ8 ¡

60-90% 5-30% 1-5% 1-5%

TCR MHC II

T APC T-cell Antigen Presenting Cell Antigen

Ag

B B-cell Plasma cell

BCR

Antibodies

APC

IFN-γ IL-21 Wheat

TG2

Deamidation by TG2

The celiac lesion

CD4 CD4 CD4

APC

CD8 CD8

TCR CD4 HLA-DQ2 (or -DQ8)

CD4 T cell APC CD8 T cell

Enterocyte NKG2D MIC TCR

cyto- lysis Hüe et al Meresse et al Immunity 2004

IL-15

¡ ¡

Gluten ¡pep/de ¡ HLA-­‑DQ2.5 ¡

Stanford ¡& ¡Oslo ¡

A gluten peptide caught in the act

α2-gliadin (AJ133612)

1 MVRV 1 MVRVPVPQLQ PQNPSQQQ QQQPQ E EQVPLV LVQQQQ QQQQ F FPGQQQ QQQPF PFPP PP QQ QQPYPQPQPF F PSQQ QQPYL YLQLQ 61 61 PFPQPQLPYP QPQLPYPQPQ L LPYPQPQPFR FR PQQ QQPYPQSQP QYS YSQPQQ QQPIS IS QQQQQQQQQQ QQQQQQQQQQ 121 121 QQ QQKQQQQQQQ QQQQQQQ QIL ILQQ QQIL ILQQQ QQQ LIPCRDVVL LIPCRDVVLQ QHSIAYGSS HSIAYGSSQ VL VLQQ QQSTY STYQLV LV QQ QQLCC LCCQQ QQLW LWQ 181 I 181 IPEQSRC SRCQAI HNVVHAIILH AI HNVVHAIILH QQQQQQQQQQ QQ QQQQQQQQQQ QQPLS LSQVSF VSFQ QPQQQ QQQYPSG YPSGQ GSF GSFQPSQQ QQNP 241 241 QAQGSV GSVQPQQ QQ L LPQFEEIRNL ALETL FEEIRNL ALETLPAMCN VYI AMCN VYIPP PPYCTIA YCTIA PVGIFGTNYR VGIFGTNYR LQLQ 61 61 PFPQPQLPYP QPQLPYPQPQ L LPYPQPQPF F

digestive enzymes Transglutaminase (QXP)

LQLQ 61 61 PFPQPELPYP QPELPYPQPE L LPYPQPQPF F

after transglutaminase treatment peptide (33 amino acids)

Generation of T-cell epitopes in the gut

PFPQPELPY Y PQPELPYP Q PYP QPELPY Y P QPELPYPQ PYPQPE LPY Y PQPE LPYPQ Q

6 copies of T cell epitopes

Shan et al, Science 2002; Arentz-Hansen et al, Gastroenterology 2002

DQ2.5 DQ8

HLA-DQ2.5 and HLA-DQ8 restricted gluten T-cell epitopes

T cell S-PE

B B B B

HLA-DQ2.5-gluten epitope tetramers

Increased frequency of gluten-specific effector- memory CD4+ T cells in celiac disease

Control TCD UCD EM Christophersen et al., UEG J 2014

T cells (CD3) Plasma cells (CD138)

Photo: Ann-Christin Beitnes

Active celiac disease

bio$n-­‑TG2 ¡ ¡ ¡ ¡ ¡an$-­‑CD138 ¡ ¡ ¡ ¡ ¡merge ¡

Visualization of TG2-specific plasma cells by immunofluorescence on intestinal cryosections

celiac

Di Niro et al., Nat Med 2012

Detection of TG2-specific plasma cells by flow cytometry on intestinal cell suspensions

biotin-TG2

Anti-IgA (gated on CD138+ plasma cells)

3.5 8.3 0.1 0.3 0.4 0.7

Patient with active CD Healthy donor CD patient

• n GFD

Di Niro et al., Nat Med 2012

SA

PE PE

b

TG2

b TG2 b

TG2

b

TG2

APC IFN-γ IL-21

Wheat

TG2

Deamidation by TG2

CD4 CD4

APC

CD8 CD8

B CD4

CD4

APC B CD4 APC

The celiac lesion

Mucosa (effector site) Mesenteric lymph node

• r Peyer’s patch

(priming site)

CD4

via blood via lymph

plasmablast

CD4

Germinal centre

CD8

IL-15

TCR MHCII

Ag

Relationship T-cell epitope and B-cell epitope

T cell help

Accessory molecules Cytokines

T CD4 B

T-cell epitope must be physically linked with B-cell epitope prior to Ag processing

T-cell help to TG2-specific B cells by gluten-specific T cells

Gluten peptide

TG2

TG2-gluten peptide complex

‘Hapten-carrier like’ model

TG2-specific B cell

TCR MHCII

B

T-cell help

APC

Gluten-specific T cell

T CD4

HLA-DQ2

Anti-TG2 antibodies

Activation Proliferation Plasma cell differentiation Activation Proliferation Clonal expansion

T-cell – B-cell interaction: An amplifying loop for the T-cell reponse

Gluten peptide TCR MHCII

B T CD4

TG2 TG2

Gluten peptide TCR MHCII

B T CD4

TG2

TCR MHCII

B T CD4

Deamidated gluten peptide

Transglutaminase (TG2) specific B cell Deamidated gluten specific B cell

Gluten specific T cells can give help to both TG2- specific and deamidated gluten-specific B cells

Anti-TG2 antibodies

TG2

Anti-deamidated gluten antibodies

Key event in the pathogenesis of coeliac disease

Clonal expansion of:

• Gluten specific CD4+ T cells
• TG2 specific B cells
• Gluten specific B cells

The point of T- and B-cell clonal expansions is when the patient is crossing the bridge.

Non-dietary therapies for coeliac disease I

Prevent gluten from stimulating T cells

• Grain modification
• Polymers binding gluten (BioLine Rx)
• Glutenases (Alvine)
• Epithelial barrier (Alba)
• Transglutaminase (TG2) inhibitors (Dr. Falk, Sitari)
• Elafin (prevents gluten deamidation)

Non-dietary therapies for coeliac disease II

Modify immune response

• Cytokine therapy (anti-IL15; Celimmune, Calypso)
• Peptide therapy (ImmusanT)

CONTRIBUTORS

Oslo Roberto Di Niro Øyvind Steinsbø Rasmus Iversen Luka Mesin Shuo-Wang Qiao Asbjørn Christophersen Michael Bodd Elin Bergseng Siri Dørum Jorunn Stamnaes Knut E.A. Lundin Ludvig M. Sollid Chicago Carole Dunand Patric C. Wilson Stanford Chaitan Khosla

ACKNOWLEDGEMENTS