No abstract

Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.

A 2-h T-tube trial of spontaneous breathing was used in selecting patients ready for extubation and discontinuation of mechanical ventilation. However, some doubt remains as to whether it is the most appropriate method of performing a spontaneous breathing trial. We carried out a prospective, randomized, multicenter study involving patients who had received mechanical ventilation for more than 48 h and who were considered by their physicians to be ready for weaning according to clinical criteria and standard weaning parameters. Patients were randomly assigned to undergo a 2-h trial of spontaneous breathing in one of two ways: with a T-tube system or with pressure support ventilation of 7 cm H2O. If a patient had signs of poor tolerance at any time during the trial, mechanical ventilation was reinstituted. Patients without these features at the end of the trial were extubated. Of the 246 patients assigned to the T-tube group, 192 successfully completed the trial and were extubated; 36 of them required reintubation. Of the 238 patients in the group receiving pressure support ventilation, 205 were extubated and 38 of them required reintubation. The percentage of patients who remained extubated after 48 h was not different between the two groups (63% T-tube, 70% pressure support ventilation, p = 0.14). The percentage of patients falling the trial was significantly higher when the T-tube was used (22 versus 14%, p = 0.03). Clinical evolution during the trial was not different in patients reintubated and successfully extubated. ICU mortality among reintubated patients was significantly higher than in successfully extubated patients (27 versus 2.6%, p < 0.001). Spontaneous breathing trials with pressure support or T-tube are suitable methods for successful discontinuation of ventilator support in patients without problems to resume spontaneous breathing.