Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis.

BACKGROUND AND AIMS: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has been shown to act as a negative regulator of T cell function and has been implicated in the regulation of T helper 1 (Th1)/Th2 development and the function of regulatory T cells. Tests were carried out to determine whether anti-CTLA-4 treatment would alter the polarisation of naive T cells in vivo. METHODS: Mice were treated with anti-CTLA-4 monoclonal antibody (mAb) (UC10-4F10) at the time of immunisation or colonic instillation of trinitrobenzene sulfonic acid (TNBS). The cytokines produced by lymph node cells after in vitro antigenic stimulation and the role of indoleamine 2,3 dioxygenase (IDO) and of interleukin-10 (IL-10) were tested, and the survival of mice was monitored. RESULTS: Injection of anti-CTLA-4 mAb in mice during priming induced the development of adaptive CD4(+) regulatory T cells which expressed high levels of ICOS (inducible co-stimulator), secreted IL-4 and IL-10. This treatment inhibited Th1 memory responses in vivo and repressed experimental intestinal inflammation. The anti-CTLA-4-induced amelioration of disease correlated with IDO expression and infiltration of ICOS(high) Foxp3(+) T cells in the intestine, suggesting that anti-CTLA-4 acted indirectly through the development of regulatory T cells producing IL-10 and inducing IDO. CONCLUSIONS: These observations emphasise the synergy between IL-10 and IDO as anti-inflammatory agents and highlight anti-CTLA-4 treatment as a potential novel immunotherapeutic approach for inducing adaptive regulatory T cells.

A joined analysis of two European Organization for the Research and Treatment of Cancer (EORTC) studies to evaluate the role of pegylated liposomal doxorubicin (Caelyx) in the treatment of elderly patients with metastatic breast cancer.

We have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx) given at 60 mg/m(2) every 6 weeks (treatment A) or 50 mg/m(2) every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age. In the older cohort of patients, no dependence was found between the incidence of grade 3-4 toxicity or antitumor activity and patients' baseline performance status, number and severity of comorbidities, or number of concomitant medications. The higher therapeutic index of Caelyx 50 mg/m(2) every 4 weeks makes it, of the two dose schedules investigated, the preferred regimen in the elderly.

Latest development of the combinatorial model of nuclear level densities

The combinatorial model of nuclear level densities has now reached a level of accuracy comparable to that of the best global analytical expressions without suffering from the limits imposed by the statistical hypothesis on which the latter expressions rely. In particular, it provides, naturally, non-Gaussian spin distribution as well as non-equipartition of parities which are known to have an impact on cross section predictions at low energies [1, 2, 3]. Our previous global models developed in Refs. [1, 2] suffered from deficiencies, in particular in the way the collective effects - both vibrational and rotational - were treated. We have recently improved this treatment using simultaneously the single-particle levels and collective properties predicted by a newly derived Gogny interaction [4], therefore enabling a microscopic description of energy-dependent shell, pairing and deformation effects. In addition for deformed nuclei, the transition to sphericity is coherently taken into account on the basis of a temperature-dependent Hartree-Fock calculation which provides at each temperature the structure properties needed to build the level densities. This new method is described and shown to give promising results with respect to available experimental data.

Numerical simulation of steady inspiratory flow through a multiply branched model of the human central airways

info:eu-repo/semantics/published

Liver-directed lentiviral gene therapy in a dog model of hemophilia B

We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia.