Véronique Godot

Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists.

Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohns disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-γ-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.

Resistance/susceptibility to Echinococcus multilocularis infection and cytokine profile in humans. I. Comparison of patients with progressive and abortive lesions

To clarify the role of Th1‐ and Th2‐type cytokines in the various outcomes of human alveolar echinococcosis (AE), the cytokine immune response of self‐cured patients was studied and compared with those of progressive AE patients and healthy subjects. Self‐cured patients were divided into two groups according to the following clinical features: subjects who had positive Echinococcus multilocularis serologies and hepatic calcifications typical of AE were classified as ‘abortive AE’ patients, and those who had positive E. multilocularis serologies but no hepatic lesions or calcifications detectable by ultrasonography were classified as ‘positive serology’ subjects. Secretions of IL‐5, IL‐10 and interferon‐gamma, and expression of IL‐5 mRNA were evaluated in peripheral blood mononuclear cells (PBMC) stimulated in vitro with the mitogen phytohaemagglutinin‐C or specific E. multilocularis antigenic preparations. The cytokine profile of abortive AE patients was the opposite of that observed in progressive AE patients. An intermediate profile was observed in positive serology subjects. PBMC from abortive AE patients, whether non‐stimulated or stimulated with PHA and antigenic preparations, secreted significantly lower levels of IL‐10 than those isolated from progressive AE patients. Our observations seem to confirm the regulatory role of IL‐10 in the immunopathology of human AE.

Dexamethasone and IL-10 stimulate glucocorticoid-induced leucine zipper synthesis by human mast cells

Background:  Glucocorticoids (GCs) decrease tissue mast cell (MC) number and prevent their activation via their high‐affinity IgE receptor. Glucocorticoid‐induced leucine zipper (GILZ) is one of the GC‐induced genes, which inhibits the functions of the transcriptional activators AP‐1 and NF‐κB. GILZ appears to be a critical actor in the anti‐inflammatory and immunosuppressive effects of GCs in human T lymphocytes, macrophages and dendritic cells.

Stimulation of the primary anti-HIV antibody response by IFN-α in patients with acute HIV-1 infection

Type I IFNs are needed for the production of antiviral antibodies in mice; whether they also stimulate primary antibody responses in vivo during human viral infections is unknown. This was assessed in patients acutely infected with HIV‐1 and treated with IFN‐α2b. Patients with acute HIV‐1 infection were randomized to receive antiretroviral therapy alone (Group A, n=60) or combined for 14 weeks with pegylated‐IFN‐α2b (Group B, n=30). Emergence of anti‐HIV antibodies was monitored during 32 weeks by Western blot (WB) analyses of serum samples. IFN‐α2b treatment stimulated the production of anti‐HIV antibodies. On Week 32, 19 weeks after the last IFN‐α2b administration, there were 8.5 (6.5–10.0) HIV WB bands (median, interquartile range) in Group B and 7.0 (5.0–10.0) bands in Group A (P=0.054), and band intensities were stronger in Group B (P<0.05 for p18, p24, p34, p40, and p55 HIV antigens). IFN‐α2b treatment also increased circulating concentrations of the B cell‐activating factor of the TNF family (P<0.001) and ex vivo production of IL‐12 (P<0.05), reflecting its effect on innate immune cells. Withdrawal of antiretroviral treatment on Week 36 resulted in a lower rebound of HIV replication in Group B than in Group A (P<0.05). Therefore, type I IFNs stimulate the emerging anti‐HIV immune response in patients with acute HIV‐1 infection, resulting in an improved control of HIV replication. Type I IFNs are thus critical in the development of efficient antiviral immune responses in humans, including the production of antiviral antibodies.

Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial.

Objectives:The ANRS-112 INTERPRIM trial assessed whether fixed-cycles of antiretroviral treatment interruption (ART-STI) combined or not with pegylated interferon alpha-2b (peg-IFN) could lower viral load and achieve a healthier immune system in patients diagnosed during primary HIV-1-infection (PHI). Design and methods:Patients were randomized to receive either continuous ART (cART) during 72 weeks, or cART during 36 weeks followed by three ART-STIs, or the same ART-STIs associated with peg-IFN during the first 14 weeks and each interruption (ART-STI-IFN). Treatment was stopped at week 72. Final evaluation was based on plasma HIV-RNA level 6 months after the last treatment interruption. Results:Eighty-seven percent of patients achieved undetectable HIV-RNA at week 32, with no deleterious impact of sequential treatment interruptions (STIs). Viral rebounds during interruptions were lower in the ART-STI-IFN than in the ART-STI group and during the second and third interruptions compared with the first one. However, HIV-RNA levels, CD4+ T-cell counts and CD4+ T/CD8+ T ratios were similar between groups after the 6-month interruption, with a persistent effect on CD4+ T cells and total cell-associated HIV-DNA levels. Predictive factors of virological outcome were HIV-RNA and HIV-DNA levels at PHI and HIV-DNA levels at treatment interruption. HIV-specific responses did not differ between strategies and were not associated with outcome. Forty-eight percent of patients experienced treatment resumption during long-term follow-up without difference between groups. Conclusion:When initiated during PHI, STIs associated or not with IFN did not result in a different outcome as compared to cART. All regimens showed a high response rate and a sustained immunological benefit after cessation.

Chemokine receptor expression on allergen‐specific T cells in asthma and allergic bronchopulmonary aspergillosis

Background:  Allergic bronchopulmonary aspergillosis (ABPA) is a rare variant of severe asthma resulting from hypersensitivity to Aspergillus fumigatus (Asp f) present in the airways.