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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!