Gamma delta T (γδT) lymphocytes are primed for rapid function, including cytotoxicity toward cancer cells, and are a component of the immediate stress response. Following activation, they can ...function as professional antigen-presenting cells. Chimeric antigen receptors (CARs) work by focusing T cell function on defined cell surface tumor antigens and provide essential costimulation for robust activation. Given the natural tropism of γδT cells for the tumor microenvironment, we hypothesized that their transduction with CARs might enhance cytotoxicity while retaining their ability to migrate to tumor and act as antigen-presenting cells to prolong the intratumoral immune response. Using a GD2-targeting CAR as a model system, we showed that γδT cells of both Vδ1 and Vδ2 subsets could be expanded and transduced to sufficient numbers for clinical studies. The CAR added to the cells’ innate cytotoxicity by enhancing GD2-specific killing of GD2-expressing cancer cell lines. Migration toward tumor cells in vitro was not impaired by the presence of the CAR. Expanded CAR-transduced Vδ2 cells retained the ability to take up tumor antigens and cross presented the processed peptide to responder alpha beta T (αβT) lymphocytes. γδ CAR-T cell products show promise for evaluation in clinical studies of solid tumors.
Chimeric antigen receptors (CARs) have been successfully expressed in human T cells to redirect their cytotoxic effector function against cancer antigens. A rare subset of T cells called gamma delta T cells is shown to be amenable to genetic modification by CARs and to retain the additional functional characteristic of antigen cross presentation.
Objective To investigate the effects of JSH⁃23 combined with Stattic targeting inhibition of nuclear factor⁃κB (NF⁃κB) and signal transducer and activator of transcription factor 3 (STAT3) signaling ...pathways on the proliferation and migration ability of mesenchymal glioblastoma cells and the expressions of NF⁃κB pathway and STAT3 pathway⁃related proteins. Methods The mRNA⁃seq results of 529 glioma patients were downloaded from The Cancer Genome Atlas (TCGA). Bioinformatics was used to analyze the correlation between RelA/P65 and STAT3 and the markers of mesenchymal glioblastoma, as well as the expression of NF⁃κB pathway and STAT3 pathway⁃related proteins in mesenchymal, classical and proneural glioblastoma. The human glioma cell lines U87MG and U251MG in vitro were treated with JSH⁃23, Stattic, JSH⁃23 and Stattic, respectively. The half⁃inhibitory concentration (IC50) of the two drugs was calculated by cytotoxicity assay, and the synergistic effect of the two drugs was observed by drug synergistic assay. CCK
Antibody dynamics on membranes, such as endocytosis and clustering, are vital in determining antibody functions. Yoshiyuki Manabe, Kazuya Kabayama, Koichi Fukase et al. proposed a new approach to ...modulate antibody dynamics and its function. In their Communication (e202304779), the antibody was conjugated with galactose‐containing N‐glycan, and its internalization was suppressed by the interaction with galectin‐3, leading to the enhancement of complement‐dependent cytotoxic (CDC) activity. The glycan–antibody conjugate might provide an alternative strategy for enhancing antibody activity.
Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage ...hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
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•trans-Differentiation of cytotoxic Th17 to Th1 cells promotes liver pathology•CX3CR1+CD8Teff cells inhibit fibrosis by granzyme-mediated killing of fibroblasts•Defective induction of hepatic B cell tolerance promotes autoimmunity in infants•B-cell-modifying therapies promote immune recovery in infants with biliary atresia
Liver immune profiling in infants with biliary atresia suggests B-cell-modifying therapies may alleviate liver pathology
OBJECTIVESThis study aimed to assess antimicrobial efficacy, cytotoxicity, and cytokine release (IL-1b, IL-6, IL-10, TNF-α) from human dental pulp stem cells (hDPSCs) of chitosan (CH) and ...hydroxyapatite (HAp)-modified glass ionomer cements (GIC).METHODSGICs with varied CH and HAp concentrations (0 %, 0.16 %, 2 %, 5 %, 10 %) were tested against S. mutans for 24 h or 7 days. Antimicrobial activity was measured using an MTT test. Cytotoxicity evaluation followed for optimal concentrations, analyzing mitochondrial activity and apoptosis in hDPSCs. Cytokine release was assessed with MAGPIX. Antimicrobial analysis used Shapiro-Wilk, Kruskal-Wallis, and Dunnett tests. Two-way ANOVA, Tukey, and Dunnett tests were applied for hDP metabolism and cytokine release.RESULTSCH 2 % and HAp 5 % significantly enhanced GIC antimicrobial activity, especially after seven days. In immediate analysis, all materials showed reduced mitochondrial activity compared to the control. After 24 h, CH demonstrated mitochondrial metabolism similar to the control. All groups exhibited mild cytotoxicity (∼30 % cell death). Only IL-6 was influenced, with reduced release in experimental groups.SIGNIFICANCECH 2 % and HAp 5 % were most effective for antibacterial effects. GIC-CH 2 % emerged as the most promising formula, displaying significant antibacterial effects with reduced hDPSC toxicity.
BACKGROUNDRV144 is the only preventive HIV vaccine regimen demonstrating efficacy in humans. Attempting to build upon RV144 immune responses, we conducted a phase 1, multicenter, randomized, ...double-blind trial to assess the safety and immunogenicity of regimens substituting the DNA-HIV-PT123 (DNA) vaccine for ALVAC-HIV in different sequences or combinations with AIDSVAX B/E (protein).METHODSOne hundred and four HIV-uninfected participants were randomized to 4 treatment groups (T1, T2, T3, and T4) and received intramuscular injections at 0, 1, 3, and 6 months (M): T1 received protein at M0 and M1 and DNA at M3 and M6; T2 received DNA at M0 and M1 and protein at M3 and M6; T3 received DNA at M0, M1, M3, and M6 with protein coadministered at M3 and M6; and T4 received protein and DNA coadministered at each vaccination visit.RESULTSAll regimens were well tolerated. Antibodies binding to gp120 and V1V2 scaffold were observed in 95%-100% of participants in T3 and T4, two weeks after final vaccination at high magnitude. While IgG3 responses were highest in T3, a lower IgA/IgG ratio was observed in T4. Binding antibodies persisted at 12 months in 35%-100% of participants. Antibody-dependent cell-mediated cytotoxicity and tier 1 neutralizing-antibody responses had higher response rates for T3 and T4, respectively. CD4+ T cell responses were detectable in all treatment groups (32%-64%) without appreciable CD8+ T cell responses.CONCLUSIONThe DNA/protein combination regimens induced high-magnitude and long-lasting HIV V1V2-binding antibody responses, and early coadministration of the 2 vaccines led to a more rapid induction of these potentially protective responses.TRIAL REGISTRATIONClinicalTrials.gov NCT02207920.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069511, UM1 AI069470, UM1 AI069534, P30 AI450008, UM1 AI069439, UM1 AI069481, and UM1 AI069496; the National Center for Advancing Translational Sciences, NIH (grant UL1TR001873); and the Bill & Melinda Gates Foundation (grant OPP52845).
Human influenza is a highly contagious acute respiratory illness that is responsible for significant morbidity and excess mortality worldwide. In addition to neutralizing antibodies, there are ...antibodies that bind to influenza virus–infected cells and mediate lysis of the infected cells by natural killer (NK) cells (antibody-dependent cellular cytotoxicity ADCC) or complement (complement-dependent lysis CDL). We analyzed sera obtained from 16 healthy adults (18-63 years of age), 52 children (2-17 years of age), and 10 infants (0.75-1 year of age) in the United States, who were unlikely to have been exposed to the avian H7N9 subtype of influenza A virus, by ADCC and CDL assays. As expected, none of these sera had detectable levels of hemagglutination-inhibiting antibodies against the H7N9 virus, but we unexpectedly found high titers of ADCC antibodies to the H7N9 subtype virus in all sera from adults and children aged ≥8 years.
Ten novel symmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPs, 1–10) and fourteen dissymmetric BAPs (11–24) were synthesized and evaluated the cytotoxicity. All of the compounds have been ...screened for their anti-inflammatory activity characterized by evaluating their inhibitory effects on LPS-induced IL-6, TNF-α secretion. Among them, BAP 23 exhibits both the highest anti-inflammatory and anti-cancer properties. Western blot analysis showed that BAP 23 markedly reduced the levels of Bcl-2 but increased the levels of cleaved caspase-3and Bax. Moreover, BAP 23 prominently inhibited LPS-induced activation of NF-κB in RAW264.7 cells as well as TNF-α-induced activation of NF-κB in HepG2 cells by blocking phosphorylation of inhibitor IκBα and p65. Consistent with these results, we found that BAP 23 prevented the nuclear translocation of NF-κB induced by LPS or TNF-α. BAP 23 could reasonably bind to the active site of Bcl-2 protein and p65 which is proved by molecular docking modes. These data indicate that BAP 23 is a more potent inhibitor of NF-κB activity which exhibites both anti-inflammatory and anticancer activities.
Twenty four novel symmetric or dissymmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPs) were synthesized. Their cytotoxicity and anti-inflammatory activity were evaluated and BAP 23 could inhibit NF-κB activation both in inflammation and cancer. Display omitted
•Novel symmetric or dissymmetric 3,5-bis(arylidene)-4-piperidones (BAPs) (1–24) were generated and characterized.•23 exhibits both highest anti-inflammatory and anti-cancer properties, and lower cytotoxicity.•23 can promote cell apoptosis by up-regulating cleaved Caspase-3, BAX expression and down-regulating Bcl-2expression.•23 inhibited activation of NF-κB in RAW264.7 cells and HepG2 cells by blocking phosphorylation of inhibitor IκBα and p65.
By fusing the extracellular domain of the natural killer (NK) cell receptor NKG2D to DAP12, we constructed a chimeric antigen receptor (CAR) to improve NK cell tumor responses. An RNA electroporation ...approach that provides transient expression of the CAR was adopted as a risk mitigation strategy. Expression of the NKG2D RNA CAR significantly augmented the cytolytic activity of NK cells against several solid tumor cell lines in vitro and provided a clear therapeutic benefit to mice with established solid tumors. Three patients with metastatic colorectal cancer were then treated with local infusion of the CAR-NK cells. Reduction of ascites generation and a marked decrease in number of tumor cells in ascites samples were observed in the first two patients treated with intraperitoneal infusion of low doses of the CAR-NK cells. The third patient with metastatic tumor sites in the liver was treated with ultrasound-guided percutaneous injection, followed by intraperitoneal infusion of the CAR-NK cells. Rapid tumor regression in the liver region was observed with Doppler ultrasound imaging and complete metabolic response in the treated liver lesions was confirmed by positron emission tomography (PET)- computed tomographic (CT) scanning. Our results highlight a promising therapeutic potential of using RNA CAR-modified NK cells to treat metastatic colorectal cancer.
Xiao et al. have developed a new type of CAR-NK cells specific to NKG2D ligands. Local infusion of these cells into patients with metastatic colorectal cancer shows clinical benefits in controlling malignant ascites and reducing tumor burden, highlighting a promising therapeutic potential of CAR-NK cells to treat solid tumors.
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