Immunology of Chronic PancreatitisPancreasFest: July 26, 2019

Aida Habtezion

Ballinger-Swindells Scholar

Associate Professor of Medicine

Division of Gastroenterology & Hepatology

Institute for Immunity, Transplantation, and Infection

School of Medicine, Stanford University

Incidence Rates: Pancreatitis and Pancreatic Cancer

yearly incident rates per 100,000 persons

Yadav & Lowenfels, Gastroenterology 2013

Cystic fibrosis

Hereditary pancreatitis

Hypertriglyceridemia

Autoimmune

Tropical (fibrocalcific)

Etiologies

Alcohol abuse/

Cigarette smoking

Idiopathic

Other

Chronic Pancreatitis

AGA slides

• Risk factor for developing pancreas cancer

• Smoking an independent risk factor for developing CP

• How does smoking increase or promote CP progression?

• Are there immune mediated mechanisms?

Chronic Pancreatitis (CP)

Nguyen et al J Exp Pharm 2015

http://www.compoundchem.com/2014/05/01/the-chemicals-in-cigarette-smoke-their-effects/

Th22

AhR ligands in cigarette smoke promote fibrosis in CP

Xue*, Zhao* et al Gastroenterology 2016

Editorial: Kumar & Batra, Gastroenterology 2016

AhR ligands in cigarette smoke promote fibrosis in CP

Xue*, Zhao* et al Gastroenterology 2016

Editorial: Kumar & Batra, Gastroenterology 2016

Figure5. Circulating IL-22 is elevated in CP and associated with cigarette

smoking among CP patients

HC Non Current Ex0

20

40

60

CP

IL-2

2(p

g/m

l)

P<0.001

P<0.001

P<0.05 P<0.01P<0.01

A

B

C

Iso VE BaP 10nM BaP 100nM BaP 100nM+CH223191

TCDD 10nM TCDD 100nM TCDD100nM+CH223191

IL-1

7a

IL-22

IL-22

IL-1

7a

VEBa

P10n

MBa

P100

n

M

BaP1

00nM

+C

HTCD

D10n

MTC

DD10

0n

M

TCDD

100n

M+C

H

0

5

10

15

IL-2

2+ a

ctiv

ate

d T

ce

lls (

%)

P=0.017 P=0.024

P=0.046 P=0.045

Macrophage and PSCs interaction in CP

IL-4Rα

STAT6

M2 genes

IL-4

IL-13Th2 / other cells

Alternatively activated

Macrophages

TGFβ

PDGF

Activated PSCs

Sustained

Activation

Fibrogenesis

Macrophages

TIMPs ECMs

Xue et al Nat Commun 2015

Macrophage and PSCs interaction in CP

IL-4Rα

STAT6

M2 genes

IL-4

IL-13Th2 / other cells

Alternatively activated

Macrophages

TGFβ

PDGF

Activated PSCs

Sustained

Activation

Fibrogenesis

Macrophages

TIMPs ECMs

IL4/IL13 BP

Xue et al Nat Commun 2015

Con IL4/13BP

H&

ET

rich

rom

e

Acinar-Immune Cell Interaction

Zhao et al, Gastroenterology 2018

STING signaling in CP

STING signaling in CP

Zhao*, Manohar* et al Gut 2019

STING signaling in CP

Zhao*, Manohar* et al Gut 2019

STING signaling in CP

Zhao*, Manohar* et al Gut 2019

STING signaling in CP

Zhao*, Manohar* et al Gut 2019

STING signaling in CP

Zhao*, Manohar* et al Gut 2019

Immune Cell Interactions in Pancreatitis

PSCsAcinar Cells

Leukocytes

AP CP

Nakamichi*, Habtezion* et al. J Clin Invest 2005

Habtezion et al. Gut 2011

Xue et al. Gastroenterology 2012

Xue & Habtezion. J Clin Invest 2014

Zhao et al. Gastroenterology 2018

Xue*, Zhao* et al. Gastroenterology 2016

Xue et al. Nat Commun 2015

Zhao*, Manohar* et al. Gut 2019

Relevance to human disease?

Access to human pancreas tissues from deceased organ donors and CP patients

Bellin D. M. American J Gastroenterology (2018)

CP pancreasfrom patients

(UMN)

Total Pancreatectomy with Islet Isolation

Control pancreasfrom organ donors

(UCSF)

Exocrine compartment for immune profiling

(Stanford U)

TPIAT (Total Pancreatectomy with Islet Auto-Transplantation)

Thank you!