No abstract

Background: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment. Methods:The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 10 6 /kg b.w. of autologous expanded CD3 Results:The disease progressed and all patients were insulin-dependent 2 years after inclusion. The β-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62L + CD45RA + to memory CD62L + CD45RA − Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes. Conclusions:The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM. Trial registration http://www.controlled-trials.com/ISRCTN06128462; registered retrospectively

Regulatory T cells (Tregs) are responsible for the maintenance of peripheral tolerance. Animal studies have shown that administration of Tregs can prevent type 1 diabetes (DM1). Several clinical trials attempted to induce Tregs with various agents, and thus provide long-term tolerance of β cells in DM1. Nevertheless, most of these studies have focused on clinical parameters (e.g. C-peptide) and not Treg numbers nor their function after treatment. Therefore, it is not possible to conclude if the majority of these therapies failed because the drugs did not induce Tregs, or if they failed despite Treg expansion. The current knowledge regarding Tregs, along with our experience in Treg therapy of patients with graft versus host disease, prompted us to use ex vivo expanded Tregs in 10 children with recent-onset DM1. No adverse effects in the treated individuals were observed. There was a significant increase in Treg number in peripheral blood immediately after the treatment administration, while the first clinical differences between treated and control patients were observed 4 months after Treg injection. Treated individuals had higher C-peptide levels and lower insulin requirements than non-treated children. Eleven months after diagnosis of DM1, there are still 2 individuals who are independent of exogenous insulin. These results indicate that autologous Tregs are a safe and well-tolerated therapy in children with DM1, which can inhibit or delay the destruction of pancreatic β cells. Additionally, Tregs can be a useful tool for local protection of transplanted pancreatic islets. Isolation and expansion of antigen-specific Tregs is one of the directions for future studies on cellular therapy of DM1.

Recently, inflammation has been considered as a risk factor of postoperative atrial fibrillation (PAF). The main purpose of this study was to estimate the connections between occurrence of PAF and cytokine release. Thirty-three patients who qualified for cardiopulmonary bypass graft (CABG) were included in the study. Blood was taken from all of them before CABG, then 3 h, 24 h, and 72 h afterwards. Cytokine (IL-6, IL-2, IL-4, IL-10, IFN-gamma, TNF-alpha) concentration was measured at every time point. Eleven patients developed atrial fibrillation after the CABG. Five of them developed PAF until 1 day post-CABG and six of them after 1 day post-CABG. Patients who developed PAF before 1 day post-CABG were characterized by a higher level of IL-2 in sera before 24 h and 72 h post-CABG compared with patients without PAF. Moreover, the PAF before 1 day post-CABG group was also characterized by the higher level of IFN-gamma and IL-10 at 24 h after intervention. Analysis of patients who developed PAF after 1 day post-CABG revealed a higher level of IL-10 and IFN-gamma at 24 h post-CABG compared with patients without PAF. In this study, we have shown for the first time a straightforward connection between IL-2 sera levels and the development of PAF shortly after CABG.

(1) Atrial fibrillation is a common postoperative complication after myocardial revascularization procedures which prolongs ICU stay. (2) The study did not show that the incidence of postoperative AF is influenced by the technique of coronary artery bypass grafting: with or without CPB. (3) The prevalence of postoperative AF increase when CABG is combined with valve replacement.