Skip to main content

Advertisement

SpringerLink
Log in

Immune cells and immune-based therapy in pancreatitis

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

AP:

Acute pancreatitis

ANS:

Anti-neutrophil serum

CP:

Chronic pancreatitis

IL:

Interleukin

MCP:

Monocyte chemotactic protein

PSCs:

Pancreatic stellate cells

Th:

T helper

Treg:

Regulatory T cells

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

References

  1. Apte MV, Wilson JS. Mechanisms of pancreatic fibrosis. Dig Dis. 2004;22:273–9.

    Article  CAS  PubMed  Google Scholar 

  2. Talukdar R, Saikia N, Singal DK, Tandon R. Chronic pancreatitis: evolving paradigms. Pancreatology. 2006;6:440–9.

    Article  CAS  PubMed  Google Scholar 

  3. Talukdar R, Tandon RK. Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol. 2008;23:34–41.

    Article  CAS  PubMed  Google Scholar 

  4. Steer ML. Pathogenesis of acute pancreatitis. Digestion. 1997;58(Suppl 1):46–9.

    Article  PubMed  Google Scholar 

  5. Gukovskaya AS, Vaquero E, Zaninovic V, Gorelick FS, Lusis AJ, Brennan ML, Holland S, Pandol SJ. Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis. Gastroenterology. 2002;122:974–84.

    Article  CAS  PubMed  Google Scholar 

  6. Sandoval D, Gukovskaya A, Reavey P, Gukovsky S, Sisk A, Braquet P, Pandol SJ, Poucell-Hatton S. The role of neutrophils and platelet-activating factor in mediating experimental pancreatitis. Gastroenterology. 1996;111:1081–91.

    Article  CAS  PubMed  Google Scholar 

  7. Bhatia M, Saluja AK, Hofbauer B, Lee HS, Frossard JL, Steer ML. The effects of neutrophil depletion on a completely noninvasive model of acute pancreatitis-associated lung injury. Int J Pancreatol. 1998;24:77–83.

    CAS  PubMed  Google Scholar 

  8. Abdulla A, Awla D, Thorlacius H, Regner S. Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis. J Leukoc Biol. 2011;90:975–82.

    Article  CAS  PubMed  Google Scholar 

  9. Dunay IR, Fuchs A, Sibley LD. Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infect Immun. 2010;78:1564–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Rinderknecht H. Fatal pancreatitis, a consequence of excessive leukocyte stimulation? Int J Pancreatol. 1988;3:105–12.

    CAS  PubMed  Google Scholar 

  11. Zaninovic V, Gukovskaya AS, Gukovsky I, Mouria M, Pandol SJ. Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells. Am J Physiol Gastrointest Liver Physiol. 2000;279:G666–76.

    CAS  PubMed  Google Scholar 

  12. Frossard JL, Saluja A, Bhagat L, Lee HS, Bhatia M, Hofbauer B, Steer ML. The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis-associated lung injury. Gastroenterology. 1999;116:694–701.

    Article  CAS  PubMed  Google Scholar 

  13. Hartman H, Abdulla A, Awla D, Lindkvist B, Jeppsson B, Thorlacius H, Regner S. P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis. Br J Surg. 2012;99:246–55.

    Article  CAS  PubMed  Google Scholar 

  14. Awla D, Abdulla A, Zhang S, Roller J, Menger MD, Regner S, Thorlacius H. Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis. Br J Pharmacol. 2011;163:413–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Makhija R, Kingsnorth AN. Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002;9:401–10.

    Article  PubMed  Google Scholar 

  16. McKay C, Imrie CW, Baxter JN. Mononuclear phagocyte activation and acute pancreatitis. Scand J Gastroenterol Suppl. 1996;219:32–6.

    Article  CAS  PubMed  Google Scholar 

  17. Bhatia M, Ramnath RD, Chevali L, Guglielmotti A. Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1259–65.

    Article  CAS  PubMed  Google Scholar 

  18. Sakai Y, Masamune A, Satoh A, Nishihira J, Yamagiwa T, Shimosegawa T. Macrophage migration inhibitory factor is a critical mediator of severe acute pancreatitis. Gastroenterology. 2003;124:725–36.

    Article  CAS  PubMed  Google Scholar 

  19. Saeki K, Kanai T, Nakano M, Nakamura Y, Miyata N, Sujino T, Yamagishi Y, Ebinuma H, Takaishi H, Ono Y, Takeda K, Hozawa S, Yoshimura A, Hibi T. CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice. Gastroenterology. 2012;142:1010–20.

    Article  CAS  PubMed  Google Scholar 

  20. Shrivastava P, Bhatia M. Essential role of monocytes and macrophages in the progression of acute pancreatitis. World J Gastroenterol. 2010;16:3995–4002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Bedrosian AS, Nguyen AH, Hackman M, Connolly MK, Malhotra A, Ibrahim J, Cieza-Rubio NE, Henning JR, Barilla R, Rehman A, Pachter HL, Medina-Zea MV, Cohen SM, Frey AB, Acehan D, Miller G. Dendritic cells promote pancreatic viability in mice with acute pancreatitis. Gastroenterology. 2011;141(1915–1926):e1911–4.

    Google Scholar 

  22. Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R, Zambirinis CP, Fallon NC, Rehman A, Pylayeva-Gupta Y, Badar S, Hajdu CH, Frey AB, Bar-Sagi D, Miller G. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209:1671–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Dib M, Zhao X, Wang XD, Andersson R. Role of mast cells in the development of pancreatitis-induced multiple organ dysfunction. Br J Surg. 2002;89:172–8.

    Article  CAS  PubMed  Google Scholar 

  24. Yonetci N, Oruc N, Ozutemiz O, Ak Celik H, Yuce G. Effects of mast-cell stabilization in cerulein-induced acute pancreatitis in rats. Int J Gastrointest Cancer. 2001;29:163–72.

    Article  CAS  PubMed  Google Scholar 

  25. Kempuraj D, Twait EC, Williard DE, Yuan Z, Meyerholz DK, Samuel I. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice. PLoS ONE. 2013;8:e56866.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Pezzilli R, Billi P, Gullo L, Beltrandi E, Maldini M, Mancini R, Incorvaia L, Miglioli M. Behavior of serum soluble interleukin-2 receptor, soluble CD8 and soluble CD4 in the early phases of acute pancreatitis. Digestion. 1994;55:268–73.

    Article  CAS  PubMed  Google Scholar 

  27. Demols A, Le Moine O, Desalle F, Quertinmont E, Van Laethem JL, Deviere J. CD4(+)T cells play an important role in acute experimental pancreatitis in mice. Gastroenterology. 2000;118:582–90.

    Article  CAS  PubMed  Google Scholar 

  28. Xue J, Nguyen DT, Habtezion A. Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. Gastroenterology. 2012;143:1670.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Braganza JM, Lee SH, McCloy RF, McMahon MJ. Chronic pancreatitis. Lancet. 2011;377:1184–97.

    Article  CAS  PubMed  Google Scholar 

  30. Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest. 2007;117:50–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43:128–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–32.

    Article  CAS  PubMed  Google Scholar 

  33. Treiber M, Neuhofer P, Anetsberger E, Einwachter H, Lesina M, Rickmann M, Liang S, Kehl T, Nakhai H, Schmid RM, Algul H. Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis. Gastroenterology. 2011;141:1473–85.

    Article  CAS  PubMed  Google Scholar 

  34. Schmid-Kotsas A, Gross HJ, Menke A, Weidenbach H, Adler G, Siech M, Beger H, Grunert A, Bachem MG. Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type I and C-fibronectin in cultured pancreatic stellate cells. Am J Pathol. 1999;155:1749–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Tessem JS, Jensen JN, Pelli H, Dai XM, Zong XH, Stanley ER, Jensen J, DeGregori J. Critical roles for macrophages in islet angiogenesis and maintenance during pancreatic degeneration. Diabetes. 2008;57:1605–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Goecke H, Forssmann U, Uguccioni M, Friess H, Conejo-Garcia JR, Zimmermann A, Baggiolini M, Buchler MW. Macrophages infiltrating the tissue in chronic pancreatitis express the chemokine receptor CCR5. Surgery. 2000;128:806–14.

    Article  CAS  PubMed  Google Scholar 

  37. Esposito I, Friess H, Kappeler A, Shrikhande S, Kleeff J, Ramesh H, Zimmermann A, Buchler MW. Mast cell distribution and activation in chronic pancreatitis. Hum Pathol. 2001;32:1174–83.

    Article  CAS  PubMed  Google Scholar 

  38. Zimnoch L, Szynaka B, Puchalski Z. Mast cells and pancreatic stellate cells in chronic pancreatitis with differently intensified fibrosis. Hepatogastroenterology. 2002;49:1135–8.

    PubMed  Google Scholar 

  39. Hunger RE, Mueller C, Z’Graggen K, Friess H, Buchler MW. Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. Gastroenterology. 1997;112:1656–63.

    Article  CAS  PubMed  Google Scholar 

  40. Grundsten M, Liu GZ, Permert J, Hjelmstrom P, Tsai JA. Increased central memory T cells in patients with chronic pancreatitis. Pancreatology. 2005;5:177–82.

    Article  PubMed  Google Scholar 

  41. Schmitz-Winnenthal H, Pietsch DH, Schimmack S, Bonertz A, Udonta F, Ge Y, Galindo L, Specht S, Volk C, Zgraggen K, Koch M, Buchler MW, Weitz J, Beckhove P. Chronic pancreatitis is associated with disease-specific regulatory T-cell responses. Gastroenterology. 2010;138:1178–88.

    Article  PubMed  Google Scholar 

  42. Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology. 1997;112:960–7.

    Article  CAS  PubMed  Google Scholar 

  43. Van Laethem JL, Marchant A, Delvaux A, Goldman M, Robberecht P, Velu T, Deviere J. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology. 1995;108:1917–22.

    Article  PubMed  Google Scholar 

  44. Malleo G, Mazzon E, Siriwardena AK, Cuzzocrea S. TNF-alpha as a therapeutic target in acute pancreatitis—lessons from experimental models. Sci World J. 2007;7:431–48.

    Article  CAS  Google Scholar 

  45. Werner J, Z’Graggen K, Fernandez-del Castillo C, Lewandrowski KB, Compton CC, Warshaw AL. Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1. Ann Surg. 1999;229:834–40 (discussion 841-832).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Norman JG, Franz MG, Fink GS, Messina J, Fabri PJ, Gower WR, Carey LC. Decreased mortality of severe acute pancreatitis after proximal cytokine blockade. Ann Surg. 1995;221:625–31 (discussion 631-624).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Hofbauer B, Saluja AK, Bhatia M, Frossard JL, Lee HS, Bhagat L, Steer ML. Effect of recombinant platelet-activating factor acetylhydrolase on two models of experimental acute pancreatitis. Gastroenterology. 1998;115:1238–47.

    Article  CAS  PubMed  Google Scholar 

  48. Dumot JA, Conwell DL, Zuccaro G Jr, Vargo JJ, Shay SS, Easley KA, Ponsky JL. A randomized, double blind study of interleukin 10 for the prevention of ERCP-induced pancreatitis. Am J Gastroenterol. 2001;96:2098–102.

    Article  CAS  PubMed  Google Scholar 

  49. Deviere J, Le Moine O, Van Laethem JL, Eisendrath P, Ghilain A, Severs N, Cohard M. Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography. Gastroenterology. 2001;120:498–505.

    Article  CAS  PubMed  Google Scholar 

  50. Johnson CD, Kingsnorth AN, Imrie CW, McMahon MJ, Neoptolemos JP, McKay C, Toh SK, Skaife P, Leeder PC, Wilson P, Larvin M, Curtis LD. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut. 2001;48:62–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Triantafillidis JK, Cheracakis P, Hereti IA, Argyros N, Karra E. Acute idiopathic pancreatitis complicating active Crohn’s disease: favorable response to infliximab treatment. Am J Gastroenterol. 2000;95:3334–6.

    Article  CAS  PubMed  Google Scholar 

  52. Clayton H, Flatz L, Vollenweider-Roten S, Schoepfer A, Gilliet M, Conrad C. Anti-TNF therapy in the treatment of psoriasis in a patient with acute-on-chronic pancreatitis. Dermatology. 2013;227:193–6.

    Article  PubMed  Google Scholar 

  53. Gloor B, Blinman TA, Rigberg DA, Todd KE, Lane JS, Hines OJ, Reber HA. Kupffer cell blockade reduces hepatic and systemic cytokine levels and lung injury in hemorrhagic pancreatitis in rats. Pancreas. 2000;21:414–20.

    Article  CAS  PubMed  Google Scholar 

  54. Gea-Sorli S, Closa D. In vitro, but not in vivo, reversibility of peritoneal macrophages activation during experimental acute pancreatitis. BMC Immunol. 2009;10:42.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Nakamichi I, Habtezion A, Zhong B, Contag CH, Butcher EC, Omary MB. Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest. 2005;115:3007–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Habtezion A, Kwan R, Akhtar E, Wanaski SP, Collins SD, Wong RJ, Stevenson DK, Butcher EC, Omary MB. Panhematin provides a therapeutic benefit in experimental pancreatitis. Gut. 2011;60:671–9.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Xue J, Nguyen DT, Habtezion A. Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. Gastroenterology. 2012;143:1670–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Chen P, Sun B, Chen H, Wang G, Pan S, Kong R, Bai X, Wang S. Effects of carbon monoxide releasing molecule-liberated CO on severe acute pancreatitis in rats. Cytokine. 2010;49:15–23.

    Article  CAS  PubMed  Google Scholar 

  59. Xue J, Habtezion A. Carbon monoxide-based therapy ameliorates acute pancreatitis via TLR4 inhibition. J Clin Invest. 2014;124:437–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Pandol SJ, Saluja AK, Imrie CW, Banks PA. Acute pancreatitis: bench to the bedside. Gastroenterology. 2007;132:1127–51.

    Article  CAS  PubMed  Google Scholar 

  61. Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101:2379–400.

    Article  PubMed  Google Scholar 

  62. Rattner DW. Experimental models of acute pancreatitis and their relevance to human disease. Scand J Gastroenterol Suppl. 1996;219:6–9.

    Article  CAS  PubMed  Google Scholar 

  63. Buchler M, Friess H, Uhl W, Beger HG. Clinical relevance of experimental acute pancreatitis. Eur Surg Res. 1992;24(Suppl 1):85–8.

    PubMed  Google Scholar 

  64. Steinberg WM, Schlesselman SE. Treatment of acute pancreatitis. Comparison of animal and human studies. Gastroenterology. 1987;93:1420–7.

    CAS  PubMed  Google Scholar 

  65. Su KH, Cuthbertson C, Christophi C. Review of experimental animal models of acute pancreatitis. HPB. 2006;8:264–86.

    Article  PubMed  Google Scholar 

  66. Chan YC, Leung PS. Acute pancreatitis: animal models and recent advances in basic research. Pancreas. 2007;34:1–14.

    Article  PubMed  Google Scholar 

  67. Chari ST, Singer MV. The problem of classification and staging of chronic pancreatitis. Proposals based on current knowledge of its natural history. Scand J Gastroenterol. 1994;29:949–60.

    Article  CAS  PubMed  Google Scholar 

  68. Andersen BN, Pedersen NT, Scheel J, Worning H. Incidence of alcoholic chronic pancreatitis in Copenhagen. Scand J Gastroenterol. 1982;17:247–52.

    Article  CAS  PubMed  Google Scholar 

  69. Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology. 2013;144:1180–93.

    Article  PubMed  Google Scholar 

  70. Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. Fibrogenesis Tissue Repair. 2011;4:26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Marrache F, Tu SP, Bhagat G, Pendyala S, Osterreicher CH, Gordon S, Ramanathan V, Penz-Osterreicher M, Betz KS, Song Z, Wang TC. Overexpression of interleukin-1beta in the murine pancreas results in chronic pancreatitis. Gastroenterology. 2008;135:1277–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Vonlaufen A, Phillips PA, Xu Z, Zhang X, Yang L, Pirola RC, Wilson JS, Apte MV. Withdrawal of alcohol promotes regression while continued alcohol intake promotes persistence of LPS-induced pancreatic injury in alcohol-fed rats. Gut. 2011;60:238–46.

    Article  CAS  PubMed  Google Scholar 

  73. Vonlaufen A, Xu Z, Daniel B, Kumar RK, Pirola R, Wilson J, Apte MV. Bacterial endotoxin: a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model. Gastroenterology. 2007;133:1293–303.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Robert Wood Johnson Foundation grant (to A.H.), the National Institutes of Health Grant DK092421 (to A.H.), and Digestive Disease Center Grant DK56339 (to Stanford University).

Conflict of interest

The authors disclose no conflicts.

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA

    Jing Xue, Vishal Sharma & Aida Habtezion

Authors
  1. Jing Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vishal Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aida Habtezion
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aida Habtezion.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xue, J., Sharma, V. & Habtezion, A. Immune cells and immune-based therapy in pancreatitis. Immunol Res 58, 378–386 (2014). https://doi.org/10.1007/s12026-014-8504-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8504-5

Keywords

Search

Navigation