Altered Thymic Function during Interferon Therapy in HCV-Infected Patients

Beq, Stéphanie; Rozlan, Sandra; Pelletier, Sandy; Willems, Bernard; Bruneau, Julie; Lelièvre, Jean‐Daniel; Lévy, Yves; Shoukry, Naglaa H.; Cheynier, Rémi

doi:10.1371/journal.pone.0034326

Cited by 10 publications

(13 citation statements)

References 54 publications

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“…In contrast, interferon-a does not seem to affect the proportion of T cells expressing IL-7Ra. Thus, we found no effect of PEG/ R AE 1.PI treatment on the proportion of IL-7Ra+ T cells and a decrease in the proportion of IL-7Ra+ T cells post SVR which is in agreement with previous studies (23,25). Furthermore, the reduced proportion of IL-7Ra+ T cells post SVR is consistent with our previous study demonstrating higher proportions of IL-7Ra+ CD4+ T cells in chronic HCV patients with fibrosis compared to healthy controls (16).…”

Section: Discussionsupporting

confidence: 93%

“…Interferon-a modulates both innate and adaptive immune responses (20,21), and interferon-a is related to a variety of adverse events including anemia, neutropenia, and lymphopenia (22). The mechanisms causing lymphopenia are complex and not completely understood, but interferon-a affects both hematopoiesis at an early stage and lymphoid differentiation at a later stage including direct impairment of thymic output (23,24). Furthermore, decreased interleukin (IL)-7 plasma levels has been documented during interferon-a treatment (23).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms causing lymphopenia are complex and not completely understood, but interferon-a affects both hematopoiesis at an early stage and lymphoid differentiation at a later stage including direct impairment of thymic output (23,24). Furthermore, decreased interleukin (IL)-7 plasma levels has been documented during interferon-a treatment (23). In contrast, interferon-a does not seem to affect the proportion of T cells expressing IL-7Ra.…”

Section: Discussionmentioning

confidence: 99%

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T‐cell homeostasis in chronic HCV‐infected patients treated with interferon and ribavirin or an interferon‐free regimen

Hartling

Birch

Gaardbo

et al. 2015

APMIS

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Direct-acting antiviral has replaced pegylated interferon-α and ribavirin-based treatment in the treatment of chronic hepatitis C virus (HCV) infection. While interferon-α is immune modulating and causes lymphopenia, interferon-free regimens seem to be well-tolerated. This study aimed to compare T-cell homeostasis before, during, and after HCV treatment with or without interferon-α in patients with chronic HCV infection. A total of 20 patients with chronic HCV infection were treated with pegylated interferon-α and ribavirin, and six patients were treated with an interferon-free regimen. All patients were treated for a minimum of 12 weeks. Interferon-α treatment caused an increase in the density of the receptor for IL-7 (IL-7Rα) during treatment, while interferon-free regimens caused a decrease in IL-7Rα density. After a sustained viral response, proportions of IL-7Rα+ T cells and IL-7Rα density decreased compared to prior treatment values. Finally, a proportion of CD8+ effector memory was lower while proportion of apoptotic T cells was higher after sustained virologic response compared to prior treatment. Despite lymphopenia during interferon, alterations in T-cell homeostasis during treatment were relatively similar in patients receiving interferon-based treatment and in patients receiving interferon-free treatment, and alterations during and after treatment seem to illustrate a reduced need for high levels of T cells aimed at controlling infection.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

T‐cell homeostasis in chronic HCV‐infected patients treated with interferon and ribavirin or an interferon‐free regimen

Hartling

Birch

Gaardbo

et al. 2015

APMIS

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“…Indeed, studies have underscored the role of type I interferons in thymic development and T-cell selection (33). Moreover, it was shown that fetal thymocytes are susceptible to viral infections (34), and IFNα treatment in patients with HCV infection is associated with inhibition of intrathymic precursor Tcell proliferation (35). Thus, our data support the concept that genetic-epigenetic regulation of intrathymic self-antigen expression (e.g., TSHR) is key to self-tolerance, and that alterations in these mechanisms can decrease autoantigen expression in the thymus, leading to escape of self-reactive T cells.…”

Section: Discussionmentioning

confidence: 99%

Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Stefan

Wei²,

Lombardi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Graves disease (GD) is an autoimmune disease caused by interactions between genetic, epigenetic, and environmental factors. The thyrotropin receptor ( TSHR ) is the major autoantigen in GD and is a key GD susceptibility gene. SNPs in intron 1 of the TSHR are associated with GD, but the causative variant and the mechanisms are unknown. By mapping epigenetic modifications induced by IFNα, a viral-induced cytokine triggering GD, we pinpointed the causative variant in intron 1 of the TSHR . We demonstrate that the disease-associated variant interacts epigenetically with a transcriptional repressor, promyelocytic leukemia zinc finger protein, and reduces thymic TSHR expression, leading to escape from tolerance and autoimmunity to the TSHR. These genetic–epigenetic interactions leading to decreased thymic self-antigen expression reveal a universal mechanism in autoimmunity.

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“…Early ID was seen during or within 6 weeks of discontinuation of PEG-IFN/RBV therapy and often resulted in premature termination of PEG-IFN/RBV; it may reflect unmasking or exacerbation of autoimmune hepatitis by PEG-IFN, a phenomenon that is also seen in the non-transplant setting [23–27]. Late ID was seen ≥6 months after discontinuation of PEG-IFN/RBV therapy with no other precipitating cause.…”

Section: Discussionmentioning

confidence: 99%

Immunological dysfunction during or after antiviral therapy for recurrent hepatitis C reduces graft survival

et al. 2013

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Introduction Pegylated interferon and ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after liver transplantation (LT) is associated with a lower sustained virological response (SVR) rate as well as more frequent side effects compared to non-transplant patients. We aimed to determine the incidence and clinical characteristics of LT recipients with recurrent hepatitis C who developed immunological dysfunction (ID) during or after PEG-IFN/RBV therapy and to assess its impact on patient and graft survival. Methods Seventy-four deceased donor LT recipients with histological recurrence of hepatitis C were treated with PEG-IFN/RBV from 1/00 to 12/08. ID was defined as biopsy-proven rejection or moderate plasma cell hepatitis. Patients were followed up until death, re-LT or 30 September 2011. Results Twelve patients (16 %) had ID, 8 (10.7 %) had cholestasis without ID, while 54 had no ID/cholestasis during or after discontinuation of PEG-IFN/RBV therapy. Biopsy-proven acute cellular rejection prior to (hazard ratio = 4.87, p = 0.009) and type of immunosuppression at the time of initiation of PEG-IFN/RBV were the only independent predictors of ID. Patients who were on tacrolimus at the time of initiation of PEG-IFN/RBV had a significantly lower risk of ID compared to those who were on cyclosporine (HR 0.254, p = 0.023). Patients with ID had a trend toward a lower SVR rate (25 vs. 54 %, p = 0.18) and a significantly higher rate of graft failure (33 vs. 4 %, p = 0.004) compared to patients with no ID/cholestasis. Conclusions ID is common during or after PEG-IFN/RBV therapy for recurrent hepatitis C and frequently associated with decreased graft survival, trending toward low rates of SVR. Careful monitoring of liver biochemistries during or after PEG-IFN/RBV therapy with a low threshold to biopsy patients and particularly those receiving cyclosporine-based immunosuppression may improve outcomes in these patients.

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Altered Thymic Function during Interferon Therapy in HCV-Infected Patients

Cited by 10 publications

References 54 publications

T‐cell homeostasis in chronic HCV‐infected patients treated with interferon and ribavirin or an interferon‐free regimen

T‐cell homeostasis in chronic HCV‐infected patients treated with interferon and ribavirin or an interferon‐free regimen

Genetic–epigenetic dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity

Immunological dysfunction during or after antiviral therapy for recurrent hepatitis C reduces graft survival

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