Immune response mechanisms in acute and chronic pancreatitis: strategies for therapeutic intervention

Abstract

Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.

Keywords: acute pancreatitis; chronic pancreatitis; fibrosis; immune response; therapy.

Figure 1

Schematic illustration of the temporal development of pancreatic damage and the local immune response during acute pancreatitis. In three different phases of the disease course, it is shown how cells of the innate and adaptive immune system are involved in the processes of acinar necrosis, the clearance of damaged tissue and the regeneration of pancreatic tissue or it`s fibrotic replacement. Tissue resident macrophages (grey) are the first cells which become activated and differentiate into classical or alternatively activated macrophages, similar to the monocyte derived macrophages. The AP-induced immune response showed similarities to classical wound healing reactions which results in fibrosis and scar formation. Multiple episodes of AP thus result in increased organ fibrosis which characterises the clinical picture of CP.

Figure 2

Development of SIRS/CARS during acute pancreatitis. (A) Illustrates the temporal correlation of SIRS and CARS with the disease progression. While SIRS frequently leads to organ complications and associates with early mortality, infected necrosis frequently occurs during CARS and causes late mortality. Excessive pro-inflammation suppresses the anti-inflammation and results in an immunological disbalance which is associated with serious complications and an increased mortality (dotted lines). However, excessive anti-inflammation also results in a suppressed ability to respond to bacterial infection and leads to colonization of necrosis by commensal intestinal bacteria, which is also associated with a severe disease course and increased mortality (dotted lines). (B) Recent data suggest a simultaneous induction of pro- and anti-inflammatory responses, which keep the balance during the disease progression. (C) An immunotherapeutic approach needs to preserve this balanced immune response and prevent a shift to either SIRS or CARS. Solid lines mark the immune dysbalance and disease severity of surviving patients, whereas dotted lines indicate a lethal course of the disease.

Figure 3

A schematic illustration of the regulation mechanism of cell regeneration vs. fibrogenesis in recurrent acute episodes of chronic pancreatitis patients. Each repetitive episode of pro-inflammation and wound healing or fibrosis is characterized by the release of PSC activating pro-inflammatory cytokines such as TNFα or IL-1β from macrophages and T-cells (Th17, Th22). The anti-inflammatory type 2 immune response (Th2 and ILC2s) in parallel induces the differentiation of alternatively activated macrophages which control the fibrosis/regeneration balance via the release of growth factors like TGF-β and PDGF. Both, pro- and anti-inflammatory signals are involved in the control of the regeneration/fibrosis balance.