M. Basso

Sustained virological response to pegylated interferon and ribavirin is maintained during long-term follow-up of chronic hepatitis C patients

Aliment Pharmacol Ther 31, 502–508

Non‐Antigen‐Specific CD8+ T Suppressor Lymphocytes in Diseases Characterized by Chronic Immune Responses and Inflammation

Abstract: Recent studies on regulatory lymphocytes demonstrate that CD8+ T suppressor (Ts) cells may have great relevance in controlling immune system homeostasis and avoiding development of chronic inflammatory diseases. Among the three subpopulations of CD8+ Ts cells so far recognized in humans, the type 2 (non‐antigen‐specific) cell is characterized by the capacity to inhibit both T cell proliferation and cytotoxic T lymphocyte activity through secretion of soluble factors. Previous work has shown the impairment of in vitro generation of type 2 CD8+ Ts cells from the peripheral blood of relapsed patients with multiple sclerosis, systemic lupus erythematosus, or systemic sclerosis. Here, similar findings are demonstrated for patients with human immunodeficiency virus or chronic hepatitis C virus infection. Furthermore, the presence of type 2 CD8+ Ts cells infiltrating diseased tissues in patients with autoimmune thyroiditis or cancer is shown. Collectively, these findings suggest that type 2 CD8+ Ts cells may be involved in the control of pathologic chronic immune responses, contributing in some cases to the pathogenesis of the disease.

Predictive value of on-treatment response during full-dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension.

Objective.  Therapy with full‐dose pegylated interferon (PEG‐IFN) and weight‐based ribavirin has been evaluated in limited series of patients with hepatitis C virus (HCV) and advanced disease. In this study, we evaluated the efficacy and tolerability of full‐dose antiviral therapy in patients with compensated, fully developed cirrhosis, and assessed the predictive value of on‐treatment virological response.

Kinetics of soluble tumour necrosis factor (TNF)‐α receptors and cytokines in the early phase of treatment for chronic hepatitis C: comparison between interferon (IFN)‐α alone, IFN‐α plus amantadine or plus ribavirin

We have previously studied the effect of three different treatment regimens with interferon (IFN)‐α alone or in combination with amantadine or ribavirin on viral kinetics in the first month of therapy. To understand the regulation of cytokine immune response during early inhibition of HCV replication, we analysed the longitudinal profile of proinflammatory markers (soluble TNFRs), of type 1 cytokines [IFN‐γ and interleukin (IL‐12)], and of a type 2 cytokine (IL‐10). Twenty‐two chronic hepatitis C patients received daily therapy for 6 months. Sera were collected at baseline, at 6, 12, 24, 30 and 48 h and at the 3rd, 7th, 15th and 30th days of treatment. All cytokines and receptors were evaluated by enzyme linked immunosorbent assay (ELISA). At baseline, a correlation was found between the two soluble TNFRs (P < 0·0001) and between the soluble TNFRs and ALT levels (P < 0·003), as shown previously. Regardless of the type of treatment, lower levels of soluble TNFR‐p75 were present from day 3 in patients who had significant virus decay at day 30 (P < 0·01). Baseline IL‐10 levels correlated with TNFR‐p75 (P < 0·01) and with treatment response (P < 0·05) and a significant IL‐10 reduction from baseline was observed from day 3 among responders, irrespective of the type of treatments (P < 0·05). IL‐12 and IFN‐γ levels did not differ according to treatment or outcome. These findings suggest a pivotal role for IL‐10 in orchestrating the antiviral immune response. Its early decline can favour the shift from a Th2 to a Th1 immune response, which has been shown to be associated with a long‐term virological response to treatment.

Elevations in alanine aminotransferase levels late in the course of antiviral therapy in hepatitis C virus RNA–negative patients are associated with virological relapse

The incidence and clinical meaning of elevated alanine aminotransferase (ALT) in chronic hepatitis C patients who are hepatitis C virus (HCV)‐RNA negative during pegylated interferon (PEG‐IFN) and ribavirin therapy have not been completely characterized. In this study our aim was to assess the incidence, pattern, predictive factors, and clinical meaning of elevated ALT in a cohort of 173 chronic hepatitis C patients who obtained viral clearance during either PEG‐IFNα2a or α2b and weight‐based ribavirin therapy. Patients were defined sustained viral responders (SVRs) or relapser responders (RRs) on the basis of a serum HCV‐RNA result at 24‐week follow‐up. SVR and RR were obtained in 141 (58%) and 32 patients (13%), respectively. Among the 173 study patients, 57 patients (33%) had undetectable serum HCV‐RNA and elevated ALT in at least one evaluation (weeks 2, 4, 12, 24 in all genotypes, and week 48 in HCV genotype 1 and 4 alone), and this phenomenon was not differently distributed between SVRs and RRs. No pretreatment demographic (age, gender), clinical (ALT levels, histological grade and stage, body mass index) and viral (load, genotype) parameter was associated with this phenomenon. The incidence of elevated ALT levels was not associated with type of PEG‐IFN and ribavirin dose. Elevated ALT levels showed a different longitudinal pattern, occurring more frequently between week 12 and the end of treatment in RR as compared to SVR patients (90% versus 9%, P = 0.000001). Conclusion: The occurrence of elevated ALT levels in HCV‐RNA‐negative patients during PEG‐IFN and ribavirin therapy is a fairly frequent and unpredictable phenomenon. Although ALT elevation per se is not associated with a greater risk of relapse, its occurrence in the later phases of therapy is more common in relapsing patients. (HEPATOLOGY 2009.)

The induction of distinct cytokine cascades correlates with different effects of granulocyte-colony stimulating factor and granulocyte/macrophage-colony-stimulating factor on the lymphocyte compartment in the course of high-dose chemotherapy for breast cancer.

Abstract The availability of the myeloid hemopoietic growth factors (HGF) granulocyte- and granulocyte/macrophage-colony stimulating factor (G-CSF and GM-CSF) has enhanced the therapeutic index of high-dose chemotherapeutic antitumoral regimens (HDCT), as well as the rate of severe damage to immune competence. We investigated some immune functions before, during and after one course of HDCT for poor-risk breast cancer and compared the effects of G-CSF and GM-CSF on the immune recovery. They exerted different influences on the functions we examined and showed distinctive patterns of both qualitative and quantitative in vivo activities on the immune system. The main findings were that (a) granulocyte and lymphocyte recovery rates were faster in the patients receiving G-CSF; (b) looking at the lymphocyte compartment, this difference was restricted to the CD3+/CD8+ and CD56+ lymphocyte subsets; (c) the reconstitution rate of CD19+ lymphocytes was slow in both groups; (d) at the end of follow-up HLA-DR expression by CD3+ lymphocytes was higher in the GM-CSF group; (e) the lymphocyte proliferative capacity was restored at a faster rate in the GM-CSF group, whereas cytotoxic activities recovered better in the G-CSF group; (f) the early repopulating phase was characterized by higher interleukin-6 serum levels in the GM-CSF group. Overall, GM-CSF seemed to exert an earlier effect on all T lymphocyte subsets, preventing them from a complete drop during the long-lasting “nadir” of the cell count, whereas G-CSF appeared to boost them strongly, though a few days later, hastening their final recovery. The distinct pattern of the cytokine cascade induced by each factor, consistent with the different functional changes, seemed to account for the peculiarities of their immune modulations.

Peripheral blood serum markers for apoptosis and liver fibrosis: are they trustworthy indicators of liver realness?

BACKGROUND/AIMS No reliable serum markers for liver inflammation, apoptosis and fibrosis have been established yet, although a large number have been evaluated. Moreover, it is not clear if a molecule detected and quantified in peripheral vein blood is a really trustworthy marker of the liver condition. To answer to this question, we had the opportunity to study paired serum samples drawn simultaneously during haemodynamic study from the right hepatic vein and from a peripheral vein from patients with hepatitis C virus related cirrhosis. METHODS The serum levels of transforming growth factor beta-1, tumour necrosis factor-alpha, hyaluronic acid, soluble (s)human leukocyte class I antigens, soluble FAS ligand, and stumour necrosis factor related ligand were assessed in a consecutive series of 15 patients with hepatitis C virus related cirrhosis. RESULTS No statistically significant differences were found between hepatic vein and peripheral vein levels for the cytokines, substance or soluble molecules evaluated, excepted for shuman leukocyte class I antigens. Instead a strong correlation between hepatic vein and peripheral vein levels was present for: hepatic vein, shuman leukocyte class I antigens, tumour necrosis factor-alpha, soluble FAS ligand and stumour necrosis factor related ligand, but not for transforming growth factor beta-1. CONCLUSIONS Our results show that peripheral vein measurements seem to reflect the liver compartment in a large majority of cases, but not for all molecules and probably for any liver diseases. Further studies on this line are warranted in particular for new molecules.