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. Author manuscript; available in PMC: 2020 Jul 1.
Published in final edited form as: Pancreas. 2019 Jul;48(6):759–779. doi: 10.1097/MPA.0000000000001335

TABLE 4.

GEMMs With a Spontaneous Pancreatitis Phenotype

GEMM Phenotype References
rEla1;sshIL-1β

  • Pancreatic atrophy, dilation of ducts occurred secondary to proximal fibrotic stenosis, increase acinar proliferation and apoptosis, increased expression of chemokines and cytokines

  • Crossing in a p53 mutation to obtain Elastase sshIL-1β*p53R172H/+ results in the development of PanINs and lesions indicative of acinar to ductal metaplasia

  • Exposure to aqueous extract of cigarette smoke or Snus containing diet results in ductal epithelia flattening and proliferation, and glandular atrophy

  • High penetrance

 76,254
rEla1;mPRSS1R122H (hereditary pancreatitis)

  • 7 wks-acinar damage

  • 12 wks-inflammatory infiltrate

  • 24 wks fibrosis

  • 40% penetrance by 1yr

 63
rEla1;hPRSS1R122H/N29I (hereditary pancreatitis)

  • Fibrosis

  • Pathology consistent with chronic pancreatitis (>9month)

  • 10% penetrance

 64
PACE-try(on)
Ela-creERT;ratPRSSII (hereditary pancreatitis)

  • AP only, rapid caspase-3 activation, apoptosis with delayed necrosis, loss of acinar cells leads to replacement with fatty tissue.

  • Chronic inflammation or fibrosis does not develop.

 65
Ela1-cre;PERK−/−

  • Hyperglycemic by 4 wks

  • Induction of ER stress response, nonapoptotic acinar cells death pronounced inflammation

  • Exocrine and endocrine insufficiency

 255
Ela1-LTab
(Ela1-LTβ)

  • Model of AIP, overexpression of lymphotoxin beta

  • Formation of B and T cell zones (tertiary lymphoid tissues)

  • Systemic autoimmune response

  • Chronic inflammation (in pancreas)

 256
PDX1-cre;IKKα−/−

  • Elevated serum amylase and lipase

  • progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and compensatory proliferation

 257
PDX1-cre;Kif3a−/−

  • By 2 wks. acinar to ductal metaplasia and periductal fibrosis is evident

  • By 12wks, acinar cells are replaced by adipose

  • By 6mo, pancreata composed of enlarging cysts

 258
PDX1-cre;SRF−/−

  • After weaning, mice develop profound morphological alterations of the exocrine pancreas, which were reminiscent of severe pancreatitis.

  • massive acinar injury, Nuclear Factor Kappa B activation and proinflammatory cytokine release leads to complete destruction of the exocrine pancreas and its replacement by adipose tissue

 259
Pft1a-creex1; Atg5−/−

  • Greater penetrance in male

  • Inflammation, necrosis, acinar-to-ductal metaplasia, acinar hypertrophy and degeneration, increased ROS, decreased glutamate metabolism, reduced autophagy, increased p62, ER and mitochondrial stress

 260
Mist1-creERT2;XBP1+/−

  • Activation of the unfolded protein response

  • Extensive apoptosis followed by recovery and regeneration of acini

 114,261
hInsulin;TGFβ

  • Fibrosis and inflammation

 262
bK5; COX-2

  • Overexpression of COX2 under the bovine K5 promotor induces CP (fibrosis and chronic inflammation) by 3 mo.

  • At 5–6 mo pancreatic hypertrophy

  • At 6–8 mo, dysplasia

 263
hK8

  • Overexpression of human keratin 8

  • Exocrine pancreas alterations, includes dysplasia, loss of acinar architecture, redifferentiation of acinar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. 

  • Extra pancreatic epithelial changes also observed

 264,265
CPA1N356K

  • C57Bl/6 mice harbor human p.N256K mutation in exon 7 of mouse Cpa1 locus

  • At 3 mo., pancreata begin to atrophy (decrease weight) with 35–40% decrease @ 6 mo

  • Loss of acini (30% by 12 mo), inflammatory infiltrate, presence of pseudotubular complexes (acinar-to ductal metaplasia), widespread fibrotic changes

  • At 1 mo., elevated circulating amylase that is lost by 3 mo

  • Elevated intrapancreatic trypsin and markers of endoplasmic reticulum stress

 266
SPINK3−/−
(hereditary pancreatitis)

  • Pancreata initially develop normally

  • acinar degeneration starts around E16.5

  • Rapid onset cell death begins within days of birth

  • Mice die by P14.5

 267–269
D23A
(hereditary pancreatitis)

  • T7D23A knock-in mouse carries a heterozygous p.D23A mutation in mouse cationic trypsinogen (isoform T7) on a C57BL/6N background

  • Pancreata are normal for first 2–3 weeks of life, with diminution in size visible by 2 months

  • 4–5 weeks of age
    • 40% exhibit typical AP at 4–5 weeks, characterized by edema, inflammatory infiltrate (dominated by neutrophils and macrophages), and localized necrosis
    • >50% exhibit minimal parenchyma and widespread regeneration including fibrosis and stellate cell activation
    • Elevated amylase in 40% of mice
  • 2–12 months of age
    • Elevated intrapancreatic trypsin activity
    • Adipose replacement dominated, while inflammatory infiltrate decreased
    • Distorted ducts surrounded by prominent fibrosis
    • No calcifications and no loss of islets observed
 66
LXRβ−/−

  • Liver X receptor β was removed using cre-transgenic deleter mouse strain

  • Inflammation, duct dilation, fibrosis

  • Pancreatic exocrine insufficiency

 270
LAMP2−/−

  • Begins with acinar cell vacuolization and progresses to severe damage, macrophage infiltration, and acinar cell death

  • Decreased amylase, increased MPO, Caspase-3

 271
MHCII−/− (aged)

  • At 6 mo, periductal lymphocytic infiltrate observed that progresses to selective acinar cell destruction

  • Significant decrease in amylase and lipase

  • Adoptive transfer of splenic mononuclear cells confers disease upon recipient

 272
E2F1−/−/E2F2 −/−

  • endocrine and exocrine cell dysplasia

  • a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue.

  • Mutant pancreatic cells exhibit increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy

 273
IKK2 CA
constitutively active, inducible
  • CMVrtTA X tetO-IKK2-EE(IKK2) CA
    • Doxycycline induces constitutive IKK2 activity via S177E and S181E mutations
    • only minor damage, leukocyte infiltration, elevated RANTES and TNFα
  • Ela1-rtTA X luciferase-(tetO)7-IKK2CA, Ela-creERT X LSL-IKK2
    • Tamoxifen induces constitutive IKK2 activity in acinar cells
    • Results in edema, immune infiltration, necrosis, elevated lipase, and fibrosis
    • Severity increased by co-expressing p65
 126,127,274
MRL-Mplpr/lpr
(autoimmune pancreatitis, AIP)

  • Express lymphoproliferative gene (lpr)

  • Incidence of pancreatitis is significantly greater in females, with the highest incidence (74%) in mice 34–38 weeks

  • spontaneous inflammatory lesions characterized by mononuclear cell infiltration, acini destruction, and replacement of parenchyma by adipose

  • Treating MRL-Mp mice with repeated injections of polyinosinic-polycytidylic acid drives a Type I AIP, characterized by enhanced levels of IgG4 antibodies which is associated with systemic IgG4-related disease.

 275–277