Background
T cell tolerance of allergic cutaneous contact sensitivity (CS) induced in mice by high doses of reactive hapten is mediated by suppressor cells that release antigen-specific suppressive nanovesicles.
Objective
To determine the mechanism(s) of immune suppression mediated by the nanovesicles.
Methods
T cell tolerance was induced by i.v. injections of hapten conjugated to self antigens of syngeneic erythrocytes and subsequent contact immunization with the same hapten. Lymph node and spleen cells from tolerized or control donors were harvested and cultured to produce a supernatant containing suppressive nanovesicles that were isolated for testing in active and adoptive cell transfer models of CS.
Results
Tolerance was shown due to exosome-like nanovesicles in the supernatant of CD8+ suppressor T cells that were not Treg. Antigen specificity of the suppressive nanovesicles was conferred by a surface coat of antibody light chains, or possibly whole antibody, allowing targeted delivery of selected inhibitory miRNA-150 to CS effector T cells. Nanovesicles also inhibited CS in actively sensitized mice after systemic injection at the peak of the responses. The role of antibody and miRNA-150 was established by tolerizing either panimmunoglobulin deficient JH-/- or miRNA-150-/- mice that produced non-suppressive nanovesicles. These nanovesicles could be made suppressive by adding antigen-specific antibody light chains or miRNA-150, respectively.
Conclusions
This is the first example of T cell regulation via systemic transit of exosome-like nanovesicles delivering a chosen inhibitory miRNA to target effector T cells in an antigen-specific manner by a surface coating of antibody light chains.
To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n ¼ 12) or germline (n ¼ 17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (Po0.001), to occur in predicted transmembrane domains (Po0.001) and were predicted to have damaging effects upon translation (Po0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P ¼ 0.017) and overall survival (OS) (P ¼ 0.021) than ND4 wildtype patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P ¼ 0.052; OS: HR 0.29, CI 0.74-1.20, P ¼ 0.089). Somatic ND4 mutated patients had a higher prevalence of concomitant DNMT3A mutations (P ¼ 0.023) and a higher percentage of the NPM1/FLT3-ITD lowrisk genotype (P ¼ 0.021). Germline affected cases showed higher BAALC (P ¼ 0.036) and MLL5 (P ¼ 0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.
Palliative resection surgery for primary colorectal cancer is associated with a higher median survival rate. Also, the presence of liver metastasis and tumor size are associated with poor survival. Therefore, resection of the primary tumor should be considered in patients with non-curable colon cancer.
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