Advances in immunomodulatory therapy for severe acute pancreatitis

doi:10.1016/j.imlet.2019.11.002

Immunology Letters

Volume 217, January 2020, Pages 72-76

https://doi.org/10.1016/j.imlet.2019.11.002 Get rights and content

Abstract

Severe acute pancreatitis (SAP) has a complex course and a worse prognosis. Immune response imbalance is an important cause of severe pancreatitis or even death in patients. Immunomodulation therapy can regulate the imbalance of inflammatory response, alleviate SAP-related organ damage and improve the prognosis of patients. There are some problems in early immune regulation measures, such as single target and simple way. In recent years, new treatment methods, such as regulating the maturation and apoptosis of immune cells, the application of mesenchymal stem cells (MSCs) and multifactor combination therapy, have provided new ideas and hope for the future treatment of SAP. This article reviews the development of SAP immunoregulation and its recent progress.

Section snippets

Severe acute pancreatitis

Severe acute pancreatitis (SAP) is a common clinical acute abdominal disease. Its course of disease is complex and its prognosis is lethal. The fatality rate can reach more than 30 % [1,19]. At present, the clinical treatment of SAP is still mainly supportive or integrated traditional Chinese and Western medicine, and there is still no specific treatment for its pathogenesis [12,13,15,48]. Imbalance of immune regulation is an important cause of severe disease or even death in patients with

Immune response imbalance in SAP

The essence of SAP is inflammation. The course of SAP is complex. It is accompanied by systemic inflammatory response syndrome (SIRS) stage and compensatory anti-inflammatory response syndrome (CARS) stage [24,34]. There are also stages of alternating occurrence of SIRS and CARS. In addition, the same immune cell or inflammatory factor also plays an inflammatory and/or anti-inflammatory role in different stages and pathological conditions of SAP. The pro-inflammatory and anti-inflammatory

Development of SAP immunomodulatory therapy

The aim of early SAP immune regulation measures are mainly blocking the inflammatory response in the body. In the 1980s and 1990s, researchers detected a significant increase in cytokines and inflammatory mediators in peripheral blood of SAP patients, and found that they were positively correlated with the severity of SAP [29]. Therefore, they considered the treatment of SAP by antagonizing these cytokines and inflammatory mediators. Some researchers injected TNF-alpha into the abdominal cavity

Regulation of immune cells

Regulating the maturation, apoptosis and differentiation of immune cells is one of the most recent directions in the field of SAP treatment in recent years. Several studies showed that the total number and composition of immune cells in peripheral blood of healthy people, patients with pancreatitis and patients with concurrent infection are different [38,53]. Immunocytes, especially innate immune-related inflammatory cells (including neutrophils, macrophages, etc.), play an important role in

Problems and prospects

Imbalance of inflammatory response regulation in the body is an important cause leading to severe or even death in patients with pancreatitis. Immunomodulation is an important means to improve the prognosis of patients with SAP. At present, the new immunomodulatory therapy pays more attention to the regulation of immune cells themselves. The most popular direction of SAP treatment is to regulate the maturation and apoptosis of immune cells. In addition, the use of MSCs and multi-drug

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowlegment

This work was supported by the National Natural Science Funding of China(Grant no. 81470874) and the Zhejiang Provincial Natural Science Foundation of China (Grant no. LY13H030009).

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Cited by (21)

Optimal timing of free total rhubarb anthraquinones on immune regulation in rats with severe acute pancreatitis
2023, Journal of Ethnopharmacology
Rhubarb is the peeled and dried root of Rheum palmatum L., Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. Free total rhubarb anthraquinones (FTRAs) isolated and extracted from rhubarb display the beneficial effects of anti-inflammation and immunological modulation. The timing of immune regulation is a major problem in the immunotherapy for severe acute pancreatitis (SAP). several studies reported that FTRAs could reduce systemic inflammatory responses by inhibiting early immune overactivity in the gut in rats with SAP. But, the optimal timing of rhubarb and FTRAs administration is not clear in clinical practice. Therefore, the time window for the best efficacy of rhubarb and FTRAs in the treatment of SAP patients should be further elucidated.
The main purpose of the present study was to evaluate the efficacy and optimal timing of immune modulation with FTRAs in the treatment of SAP in rats. Materials and methods: FTRAs (22.5, 45 and 90 mg/kg), Rhubarb (RHU) (900 mg/kg, positive control) or normal saline (vehicle control) were initiated at 0 (immediately), 48 and 72 h every 12 h for three times in total. The therapeutic effects of FTRAs and RHU on pancreas and intestinal tissues injury, secondary infection with pseudomonas aeruginosa (PA), amylase, lipase, D-lactic acid (DLA), endotoxin (ET), proinflammatory and anti-inflammatory cytokines, macrophages, dendritic cells and regulatory T cells (Tregs) in the blood, small intestine and/or mesenteric lymph node (MLN) were determined in rats with SAP after treatment.
The results showed that administration of FTRAs at 0 h was superior to 48 h and 72 h, which significantly protected the injury of pancreas and intestinal tissues, reduced the mortality induced by secondary infection with PA, decreased the levels of amylase, lipase, DLA, ET, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-8, IL-18 and Tregs, and increased the levels of IL-4, sTNF-αR, macrophages and dendritic cells, secretary immunoglobulin A (SIgA) in the blood and/or small intestinal tissues in rats with SAP.
In conclusion, our studies indicate that the treatment window of FTRAs for SAP is within 48 h of development, administration of FTRAs at the early stage (0 h, immune overreaction period) was the optimal time and superior to that of 48 h and 72 h for its therapeutic efficacy. The earlier the administration of FTRAs, the better the therapeutic efficacy. Therefore, our data may provide a scientific rationale for the clinical application and optimal timing of FTRAs in the treatment of SAP.
Macrophages in pancreatitis: Mechanisms and therapeutic potential
2020, Biomedicine and Pharmacotherapy
Citation Excerpt :
Biliary diseases, alcohol, smoking, hyperlipidemia, and heredity are the main pathogenic factors [4,5], which would lead to the sustained increase of Ca2+ in the cytoplasm of pancreatic acinar cells, premature intracellular trypsinogen, and activation of the NF-κB inflammatory signalling pathway and then cause damage to pancreatic acinar cells [6,7]. Particularly, immune dysfunction is a significant cause of severe AP and even death [8]. Macrophages, as innate immune cells located in the pancreatic tissue, liver, lung, and abdominal cavity, mediate and amplify the inflammatory cascade response in the pathological progress of severe AP together with neutrophils, lymphocytes, and other immune cells, which determines the severity of pancreatitis [9–11].
Macrophages play a crucial role in the pathogenesis of pancreatitis that is a common gastrointestinal disease. Particularly, macrophages differentiate into different phenotypes and exert diverse functions in acute pancreatitis (AP) and chronic pancreatitis (CP), respectively. In AP, macrophages in the pancreas and other related organs are mainly activated and differentiated into a pro-inflammatory M1 phenotype, and furthermore secrete inflammatory cytokines and mediators, causing local inflammation of the pancreas, and even intractable systemic inflammatory response or multiple organ failure. In CP, macrophages often exhibit a M2 polarisation and interact with pancreatic stellate cells (PSCs) in an autocrine and paracrine cytokine-dependent manner to promote the progression of pancreatic fibrosis. As the severity of pancreatic fibrosis aggravates, the proportion of M2/M1 macrophage cytokines in the pancreas increases. The discovery of macrophages in the pathogenesis of pancreatitis has promoted the research of targeted drugs, which provides great potential for the effective treatment of pancreatitis. This paper provides an overview of the roles of various macrophages in the pathogenesis of pancreatitis and the current research status of pancreatitis immunotherapy targeting macrophages. The findings addressed in this review are of considerable significance for understanding the pivotal role of macrophages in pancreatitis.
Evaluation of the therapeutic efficiency and efficacy of blood purification in the treatment of severe acute pancreatitis
2024, PLoS ONE
Efficacy and safety of early enteral and intravenous fluid resuscitation in severe acute pancreatitis: a systematic review and meta-analysis
2023, International Journal of Colorectal Disease
Prospect of Mesenchymal Stem-Cell-Conditioned Medium in the Treatment of Acute Pancreatitis: A Systematic Review
2023, Biomedicines
Construction and evaluation of a prognostic model for severe acute pancreatitis based on CT scores and inflammatory factors
2023, Chinese Critical Care Medicine

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ReviewAdvances in immunomodulatory therapy for severe acute pancreatitis

Abstract

Section snippets

Severe acute pancreatitis

Immune response imbalance in SAP

Development of SAP immunomodulatory therapy

Regulation of immune cells

Problems and prospects

Declaration of Competing Interest

Acknowlegment

Immune-modulating therapy in acute pancreatitis: fact or fiction

World J. Gastroenterol.

Acute and chronic inflammation

Fundamentals of Inflammation

Dendritic cells promote pancreatic viability in mice with acute pancreatitis

Gastroenterology

Effect of mesenchymal stem cells on renal injury in rats with severe acute pancreatitis

Exp. Biol. Med.

Transient human gene therapy: a novel cytokine regulatory strategy for experimental pancreatitis

Ann. Surg.

The potential role of therapeutic cytokine manipulation in acute pancreatitis

Surg. Clin. North Am.

Diagnostic strategy and timing of intervention in infected necrotizing pancreatitis: an international expert survey and case vignette study

HPB

Multimodal management - Of value in fulminant acute pancreatitis?

Pancreatology

Progresses of immunomodulatory therapy in sever acute pancreatitis

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue

Complex role for the immune system in initiation and progression of pancreatic cancer

World J. Gastroenterol.

Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe acute pancreatitis compared with delayed enteral nutrition: a prospective pilot study

World J. Surg.

Clinical efficacy of Taohe Chengqi decoction plus ulinastatin for patients with severe acute pancreatitis

World Chinese J. Dig.

The Effect of Plasma Exchange on the Expression of FOXP3 and RORC2 in Relapsed Multiple Sclerosis Patients

Iran. J. Immunol.: IJI

Effects of early enteral nutrition on immune function of severe acute pancreatitis patients

World J. Gastroenterol.

Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats

Gastroenterology

Therapeutic effect of human clonal bone marrow-derived mesenchymal stem cells in severe acute pancreatitis

Arch. Pharm. Res.

Effect of fetal membrane-derived mesenchymal stem cell transplantation in rats with acute and chronic pancreatitis

Pancreas

JPN Guidelines for the management of acute pancreatitis: diagnostic criteria for acute pancreatitis

J. Hepatobiliary. Surg.

The clinical course of acute pancreatitis and the inflammatory mediators that drive it

Int. J. Inflam.

Inflammation and immunosuppression in severe acute pancreatitis

World J. Gastroenterol.

Immunomodulatory therapies for acute pancreatitis

World J. Gastroenterol.

The special relationship in the development and function of T helper 17 and regulatory T cells

Prog. Mol. Biol. Transl. Sci.

Differential roles of inflammatory cells in pancreatitis

J. Gastroenterol. Hepatol. (Australia)

Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis

Gastroenterology

SOCS1, a negative regulator of cytokine signals and TLR responses, in human liver diseases

Gastroenterol. Res. Pract.

Review
Advances in immunomodulatory therapy for severe acute pancreatitis