ABSTRACT
The activation mechanism of chimeric antigen receptor (CAR)-engineered T cells may differ substantially from T cells carrying native T cell receptor, but this difference remains poorly understood. We present the first comprehensive portrait of single-cell level transcriptional and cytokine signatures of anti-CD19/4-1BB/CD28/CD3ζ CAR-T cells upon antigen-specific stimulation. Both CD4 helper T (T) cells and CD8 cytotoxic CAR-T cells are equally effective in directly killing target tumor cells and their cytotoxic activity is associated with the elevation of a range of T1 and T2 signature cytokines, e.g., interferon γ, tumor necrotic factor α, interleukin 5 (IL5), and IL13, as confirmed by the expression of master transcription factor genes TBX21 and GATA3. However, rather than conforming to stringent T1 or T2 subtypes, single-cell analysis reveals that the predominant response is a highly mixed T1/T2 function in the same cell. The regulatory T cell activity, although observed in a small fraction of activated cells, emerges from this hybrid T1/T2 population. Granulocyte-macrophage colony stimulating factor (GM-CSF) is produced from the majority of cells regardless of the polarization states, further contrasting CAR-T to classic T cells. Surprisingly, the cytokine response is minimally associated with differentiation status, although all major differentiation subsets such as naïve, central memory, effector memory, and effector are detected. All these suggest that the activation of CAR-engineered T cells is a canonical process that leads to a highly mixed response combining both type 1 and type 2 cytokines together with GM-CSF, supporting the notion that polyfunctional CAR-T cells correlate with objective response of patients in clinical trials. This work provides new insights into the mechanism of CAR activation and implies the necessity for cellular function assays to characterize the quality of CAR-T infusion products and monitor therapeutic responses in patients.
Subject(s)
Humans , Antigens , Metabolism , CTLA-4 Antigen , Metabolism , Cell Differentiation , Cell Line , Cytokines , Metabolism , Cytotoxicity, Immunologic , Granulocyte-Macrophage Colony-Stimulating Factor , Pharmacology , Lymphocyte Activation , Allergy and Immunology , Lymphocyte Subsets , Metabolism , Phenotype , Proteomics , Receptors, Chimeric Antigen , Metabolism , Single-Cell Analysis , Methods , T-Lymphocytes, Regulatory , Metabolism , Th1 Cells , Cell Biology , Th2 Cells , Cell Biology , Transcription, Genetic , Up-RegulationABSTRACT
This study examined the add-on efficacy of eye movement desensitization and reprocessing (EMDR) therapy among adult civilians with post-traumatic stress disorder (PTSD) who continued to be symptomatic after more than 12 weeks of initial antidepressant treatment. Scores for the Clinician Administered PTSD Scale (CAPS) were rated pre- and post-EMDR and at a 6-month follow-up. After an average of six sessions of EMDR treatment, seven of 14 patients (50%) showed more than a 30% decrease in CAPS score and eight (57%) no longer met the criteria for PTSD. Our results indicate that EMDR could be successfully added after failure of initial pharmacotherapy for PTSD.
Subject(s)
Adult , Humans , Antidepressive Agents , Drug Therapy , Eye Movement Desensitization Reprocessing , Eye Movements , Follow-Up Studies , Stress Disorders, Post-TraumaticABSTRACT
OBJECTIVE: To evaluate the usefulness of power spectral analysis on fetal heart rate variability as a new diagnostic method of fetal distress. STUDY DESIGN: Among 76 pregnant women who underwent computerized electronic fetal monitoring and cord blood gas analysis, we divided them into 3 groups, i.e.; normal fetus group (36), presumed distress group (26) and acidemic distress group (14). In order to perform linear analysis on the raw data of the fetal heart rate, after resampling, we performed Fourier transformation and investigated power distributions among very low frequency (VLF), low frequency (LF), high frequency (HF) bands, and autonomic balance (LF/HF). RESULTS: The results of the spectral analysis showed that in normal fetus group, the difference in the distribution of power spectrums of VLF, LF and HF was significantly higher than in presumed distress group and acidemic distress group. In fetal distress, the LF and VLF value (0.0023, 0.0437) were good predictors (sensitivity 97.5%, 75.0% and specificity 86.1%, 94.4%). The LF value (0.0013) was a good predictor in fetal acidemia (sensitivity 97.5% and specificity 86.1%). CONCLUSIONS: A computerized spectral analysis of fetal heart rate variation is a good predictor of fetal distress, which is made automatically and objectively.