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Alternatives to steroids?! Beneficial effects of immunosuppressant drugs in autoimmune pancreatitis
  1. Gitta Seleznik,
  2. Rolf Graf
  1. Division of Visceral & Transplantation Surgery, Swiss HPB (Hepato-pancreato-biliary) Center, Zürich, Switzerland
  1. Correspondence to Dr Rolf Graf, Division of Visceral & Transplantation Surgery, Swiss HPB (Hepato-pancreato-biliary) Center, Rämistrasse 100, Zürich 8091, Switzerland; Rolf.graf{at}usz.ch

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Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis. AIP is a relatively new disease entity, which has become a new evolving field in gastroenterology. Its importance and relevance are increasing, especially due to being one important differential diagnosis of pancreatic cancer.

Based on an international consensus, AIP is classified into two distinct types: (1) Type 1 AIP appears to be part of a systemic immunoglobulin IgG4-positive disease with lobular, interlobular inflammation, prominent lymphoplasmacytic inflammation and vasculitis, and intense fibrosis affecting multiple other organs (bile duct, kidney, salivary gland). (2) Type 2 AIP presents as a fibro-inflammatory duct-centric type with granulocyte epithelial pancreatic lesions and destruction of the pancreatic duct without IgG4-positive cells or systemic involvement.1

The only therapy that has been established and accepted so far is corticosteroids, but the relapse rate is significant (15%–60%).2 Limited data suggest that immune suppressive agents (like azathioprine) are recommended in patients who fail steroid therapy, exhibit relapse or cannot be weaned from steroids. A comparative study by Hart and colleagues3 tested immunomodulatory (IM) drugs, such as azathioprine, 6-mercaptopurine or mycophenolate mofetil for prevention of relapses in AIP. However, the authors concluded that relapse-free survival was similar in patients treated with steroids alone versus steroids plus IM maintenance treatment.

As the aetiology of AIP is still completely in the dark, development of clinically meaningful therapeutic approaches at least requires an understanding of the underlying disease pathophysiology. As suggested by its name, the immune system—with cellular and humoral components—is involved in the pathophysiology of AIP; however, it is still not completely understood whether the immune system induces or only maintains the processes of AIP.

As in other autoimmune diseases, like Sjögrens syndrome, CD4 T cells are predominantly involved in the development of AIP; however, it is still under debate whether a Th1 or Th2 type immune response is induced. According to the latest concept the pathogenesis of AIP is based on a biphasic mechanism. Th1 cytokines are essential in the induction of AIP, while Th2 cytokines could be involved in the progression of the disease.4 ,5 Recently, an important role has been attributed to regulatory T cells (Tregs) in IgG4 related diseases. Besides preventing autoimmune disease by suppressing self-reactive T cells, they are able to promote the shift of B cells toward IgG4 producing plasma cells via IL-10 production.6 In line with this, several human and animal studies showed that the number of Tregs is characteristically increased in tissue-resident lymphocytes and whole blood of patients with type 1 AIP and mouse model, respectively.5 ,7

In the current report of Schwaiger et al,8 the authors nicely describe the different T cell subpopulations and their roles, supporting the hypothesis of AIP being a T cell mediated disease. Two independent mouse models are used to investigate the immunosuppression of T cells. (1) The established mouse model of type 1 AIP, MRL/Mp mice stimulated with poly I:C and (2) mice with genetic deletion of CTLA-4 which showed an identical pattern of tissue destruction. Mutations in CTLA-4 gene have been associated with human AIP, which makes it a relevant candidate to study its pathophysiological role in AIP. CTLA-4 is expressed on T lymphocytes and its physiological role is binding to costimulatory molecules on antigen presenting cells (APCs) in order to attenuate T cell response and to influence Treg activity. Along this line, blocking CTLA-4 in the MRL/Mp model led to increased severity of AIP, via enhancing the frequency of activated effector (CD4, CD3, CD69) T cells (Teffs). In parallel, a slight increase in non-suppressive Tregs was also detected.

The above results suggest that an imbalance between Tregs and activated Teffs is responsible for the progression of the disease, making them attractive therapeutic targets. Therefore, the authors set out to test the effectiveness of clinically established immunosuppressant drugs, such as cyclosporine A and rapamycin in comparison with azathioprine.

Azathioprine is a well-established immunosuppressant in various autoimmune diseases. It has already been used in AIP, however, with different outcomes.3 ,9 ,10 So far, treatment with cyclosporin A or rapamycin has not been studied in the setting of AIP either in human or animal models. The results of Schwaiger et al8 now suggest that the last two treatment options are superior to azathioprine. Azathioprine did not reduce the severity of AIP; the pancreatic inflammatory infiltrates remained unchanged. Although a slight increase in Tregs was observed, it did not have a meaningful beneficial effect since most likely those Tregs are non-suppressive (CD25 low); besides, overall number and the activation status of Teffs remained unchanged. On the other hand, treatment with both cyclosporine A and rapamycin significantly reduced the inflammatory infiltrates in the pancreas of MRL/Mp mice, preserved tissue architecture and reduced fibrosis. Assessing different T cell populations in the spleen (summarised in table 1) sheds light on the potential mechanisms related to the beneficial effects. Cyclosporine A, a calcineurin inhibitor, acted via decreasing the activated Teff cell population (CD4, CD69 high, CD62L low), while the frequency of regulatory T cells remained unaffected. On the contrary, the mTOR inhibitor rapamycin significantly expanded the suppressing Treg population in parallel by a decrease in activated Teff cells.

Table 1

Effect of cyclosporine A, rapamycin and azathioprine on different T cell population isolated from the spleen of MRL/mp mice

This paper8 offers a good alternative to the currently used azathioprine, giving additional insight into the underlying mechanisms. Since both cyclosporine A and rapamycin are widely used in clinical routine, they can both be considered to be directly tested in human AIP in an off-label scenario. However, the question remains whether it should or could substitute corticosteroids and be suitable for a long term administration despite the known side effects of immunosuppressant treatments. Alternatively, they could be applied after steroids to prevent disease relapse.

Interestingly, none of the treatment regimens applied in this experimental AIP model affected the B cell population or had an impact on the autoantibody levels. In the current paper,8 the authors do not attribute a prominent role to B cells in the pancreas, based on a higher proportion of T cells, on Immunohistochemistry (IHC). Nevertheless, even if the autoimmune destruction of the pancreas is mediated by Teffs, B cells likely also contribute to the disease. B cells could serve as a subset of APCs, which efficiently support the expansion of pathogenic T cell responses.11 Supporting this, recently, B cell depletion with the monoclonal antibody rituximab was reported to be a promising therapeutic agent in treating patients with relapsing AIP, comparable with corticosteroids and other IM agents. In 10/12 patients with steroid intolerance or IM resistance, treatment with rituximab achieved complete remission, making it a promising alternative in the difficult-to-treat patients.3 Therefore, rituximab should be tested in experimental models of AIP to gain additional insight on the mode of action of benefits upon B cell depletion.

Conclusions

This report8 serves as an excellent example of how an experimental animal model can complement clinical observations and help to identify new potential therapeutic strategies. Even though IM drugs have been successfully used in treating autoimmune diseases, in case of AIP a change in treatment regimens to the mTOR inhibitor rapamycin appears as an attractive new approach.

References

Footnotes

  • GS and RG contributed equally

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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