Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients

CD4+CD25+FOXP3+ T regulatory cells (Tregs) are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. Rapamycin has been shown to promote tolerance in experimental models and to favor CD4+CD25+ Treg-dependent suppression. We recently reported that rapamycin allows in vitro expansion of murine CD4+CD25+FoxP3+ Tregs, which preserve their suppressive function. In the current study, we show that activation of human CD4+ T cells from healthy subjects in the presence of rapamycin leads to growth of CD4+CD25+FOXP3+ Tregs and to selective depletion of CD4+CD25- T effector cells, which are highly sensitive to the antiproliferative effect of the compound. The rapamycin-expanded Tregs suppress proliferation of both syngeneic and allogeneic CD4+ and CD8+ T cells. Interestingly, rapamycin promotes expansion of functional CD4+CD25+FOXP3+ Tregs also in type 1 diabetic patients, in whom a defect in freshly isolated CD4+CD25+ Tregs has been reported. The capacity of rapamycin to allow growth of functional CD4+CD25+FOXP3+ Tregs, but also to deplete T effector cells, can be exploited for the design of novel and safe in vitro protocols for cellular immunotherapy in T cell-mediated diseases.     

Rapamycin combined with anti-CD45RB mAb and IL-10 or with G-CSF induces tolerance in a stringent mouse model of islet transplantation

Background

A large pool of preexisting alloreactive effector T cells can cause allogeneic graft rejection following transplantation. However, it is possible to induce transplant tolerance by altering the balance between effector and regulatory T (Treg) cells. Among the various Treg-cell types, Foxp3⁺Treg and IL-10–producing T regulatory type 1 (Tr1) cells have frequently been associated with tolerance following transplantation in both mice and humans. Previously, we demonstrated that rapamycin+IL-10 promotes Tr1-cell–associated tolerance in Balb/c mice transplanted with C57BL/6 pancreatic islets. However, this same treatment was unsuccessful in C57BL/6 mice transplanted with Balb/c islets (classified as a stringent transplant model). We accordingly designed a protocol that would be effective in the latter transplant model by simultaneously depleting effector T cells and fostering production of Treg cells. We additionally developed and tested a clinically translatable protocol that used no depleting agent.

Methodology/Principal Findings

Diabetic C57BL/6 mice were transplanted with Balb/c pancreatic islets. Recipient mice transiently treated with anti-CD45RB mAb+rapamycin+IL-10 developed antigen-specific tolerance. During treatment, Foxp3⁺Treg cells were momentarily enriched in the blood, followed by accumulation in the graft and draining lymph node, whereas CD4⁺IL-10⁺IL-4⁻ T (i.e., Tr1) cells localized in the spleen. In long-term tolerant mice, only CD4⁺IL-10⁺IL-4⁻ T cells remained enriched in the spleen and IL-10 was key in the maintenance of tolerance. Alternatively, recipient mice were treated with two compounds routinely used in the clinic (namely, rapamycin and G-CSF); this drug combination promoted tolerance associated with CD4⁺IL-10⁺IL-4⁻ T cells.

Conclusions/Significance

The anti-CD45RB mAb+rapamycin+IL-10 combined protocol promotes a state of tolerance that is IL-10 dependent. Moreover, the combination of rapamycin+G-CSF induces tolerance and such treatment could be readily translatable into the clinic.     

Comparison and multi-model inference of excess risks models for radiation-related solid cancer

In assessments of detrimental health risks from exposures to ionising radiation, many forms of risk to dose–response models are available in the literature. The usual practice is to base risk assessment on one specific model and ignore model uncertainty. The analysis illustrated here considers model uncertainty for the outcome all solid cancer incidence, when modelled as a function of colon organ dose, using the most recent publicly available data from the Life Span Study on atomic bomb survivors of Japan. Seven recent publications reporting all solid cancer risk models currently deemed plausible by the scientific community have been included in a model averaging procedure so that the main conclusions do not depend on just one type of model. The models have been estimated with different baselines and presented for males and females at various attained ages and ages at exposure, to obtain specially computed model-averaged Excess Relative Risks (ERR) and Excess Absolute Risks (EAR). Monte Carlo simulated estimation of uncertainty on excess risks was accounted for by applying realisations including correlations in the risk model parameters. Three models were found to weight the model-averaged risks most strongly depending on the baseline and information criteria used for the weighting. Fitting all excess risk models with the same baseline, one model dominates for both information criteria considered in this study. Based on the analysis presented here, it is generally recommended to take model uncertainty into account in future risk analyses.

     

"Timed Up & Go": A Screening Tool for Predicting 30-Day Morbidity in Onco-Geriatric Surgical Patients? A Multicenter Cohort Study

ObjectiveTo determine the predictive value of the “Timed Up & Go” (TUG), a validated assessment tool, on a prospective cohort study and to compare these findings to the ASA classification, an instrument commonly used for quantifying patients’ physical status and anesthetic risk.BackgroundIn the onco-geriatric surgical population it is important to identify patients at increased risk of adverse post-operative outcome to minimize the risk of over- and under-treatment and improve outcome in this population.Methods280 patients ≥70 years undergoing elective surgery for solid tumors were prospectively recruited. Primary endpoint was 30-day morbidity. Pre-operatively TUG was administered and ASA-classification was registered. Data were analyzed using multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95%-CI). Absolute risks and area under the receiver operating characteristic curves (AUC’s) were calculated.Results180 (64.3%) patients (median age: 76) underwent major surgery. 55 (20.1%) patients experienced major complications. 50.0% of patients with high TUG and 25.6% of patients with ASA≥3 experienced major complications (absolute risks). TUG and ASA were independent predictors of the occurrence of major complications (TUG:OR 3.43; 95%-CI = 1.14–10.35. ASA1 vs. 2:OR 5.91; 95%-CI = 0.93–37.77. ASA1 vs. 3&4:OR 12.77; 95%-CI = 1.84–88.74). AUC_TUG was 0.64 (95%-CI = 0.55–0.73, p = 0.001) and AUC_ASA was 0.59 (95%-CI = 0.51–0.67, p = 0.04).ConclusionsTwice as many onco-geriatric patients at risk of post-operative complications, who might benefit from pre-operative interventions, are identified using TUG than when using ASA.