Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice

Ravichandran, Gevitha; Neumann, Katrin; Berkhout, L; Weidemann, Sören; Langeneckert, Annika E.; Schwinge, Dorothee; Poch, T; Huber, Samuel; Schiller, Birgit; Hess, Leonard U.; Ziegler, Annerose E.; Oldhafer, Karl J.; Barikbin, R; Schramm, Christoph; Altfeld, Marcus; Tiegs, Gisa

doi:10.1016/j.jhep.2019.05.023

Cited by 39 publications

(43 citation statements)

References 38 publications

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“…Previous studies have shown a predictive value in PSC of biomarkers of inflammation like soluble CD14 and interleukin-8 [25,26]. Furthermore, IFNÇ signaling has been shown to be an important mediator in the progression of the PSC-relevant mouse Mdr2 knockout model, [10] and inhibition of macrophage recruitment in an acute model of sclerosing cholangitis attenuated liver injury, [5] both supporting the potential relevance of neopterin and KT-ratio as biomarkers of disease severity in PSC. An important question is whether increased neopterin and KT-ratio reflect increased disease activity or later disease stage.…”

Section: Discussionmentioning

confidence: 90%

“…Also, neopterin has been observed to be increased in multiple chronic liver diseases, including autoimmune etiologies, but no PSC patients were investigated [8,17]. Both neopterin and KT-ratio increase with IFNc signaling, and the data are therefore supported by the observations of increased IFNcand the IFNc-driven chemokines CXCL10 and CXCL11 found in serum in small cohorts of PSC patients [10,18]. IFNc concentration was also increased in PSC bile, [19] increased IFNc mRNA expression has been found in PSC explants, [20] and more IFNc-producing T cells were found in colons of ulcerative colitis patients with concomitant PSC compared with ulcerative colitis patients without PSC [21].…”

Section: Discussionmentioning

confidence: 97%

“…One early study reports higher levels of neopterin in patients with liver disease compared to healthy controls, and also in patients with liver cirrhosis compared to non-cirrhotic patients [8]. Increased IFNÇ activity has also recently been reported in PSC and relevant mouse models [10]. Notably, another event occurring during IFNÇ stimulation is activation of indoleamine 2,3-dioxygenase, which is a first-step of the kynurenine pathway of tryptophan catabolism.…”

Section: Introductionmentioning

confidence: 98%

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Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis

Dhillon

Rupp

Bergquist

et al. 2021

Scandinavian Journal of Gastroenterology

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Background and aims: Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine-tryptophanratio (KT-ratio) in PSC. Methods: Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. Results: Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50-0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23-0.42) in all cohorts. Conclusions: Neopterin and KT-ratio were elevated in PSC and associated with liver transplantationfree survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

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Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis

Dhillon

Rupp

Bergquist

et al. 2021

Scandinavian Journal of Gastroenterology

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“…For example, in the setting of viral infection, type II interferon stimulates the proliferation of activated CD8+ T-cells through direct interaction with its receptor on their surface [71]. Moreover, it increases their cytotoxicity via upregulation of granzyme B and TNFrelated apoptosis-inducing ligand (TRAIL), which are key proteins involved in the process of apoptosis [72]. However, there are also evidences that IFN-γ can negatively impact the proliferation of Teffs [73] or limit their responses [74].…”

Section: Ifn-γ and T Cellsmentioning

confidence: 99%

Roles of IFN-γ in tumor progression and regression: a review

et al. 2020

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Background Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-γ in the tumor microenvironment (TME) may be misleading in terms of its clinical application. Main body Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-γ in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. Conclusion Significant research efforts are required to decipher IFN-γ-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-γ in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-γ responsive patients to improve their sensitivity to immuno-therapies.

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“…While PD-1/L-1 inhibitors causes in ammation with a high rate of CD8 + /CD4 + cells, which is a pathological feature of immune-related adverse event in the hepatobiliary system [24]. The CD8 + cells associate with sclerosing cholangitis by producing interferon gamma [25]. The invasion of the CD8 + in ammation cells may have in uenced its association with the immune-related cholangitis.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Clinical Features between Immune-Related Sclerosing Cholangitis and Hepatitis

Takinami

Ono

Kawabata

et al. 2021

Preprint

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Background Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis.Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness.Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P <0.001). A ≥grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively.Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020)

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Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice

Cited by 39 publications

References 38 publications

Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis

Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis

Roles of IFN-γ in tumor progression and regression: a review

Comparison of Clinical Features between Immune-Related Sclerosing Cholangitis and Hepatitis

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