BACKGROUND: The efficiency of chimeric antigen receptor (CAR) T-cell-based therapies depends on a sufficient expansion of CAR T cells in vivo and can be weakened by intra-tumoral suppression of CAR T cell functions, leading to a failure of therapy. For example, certain B-cell malignancies such as chronic lymphocytic leukemia are weakly sensitive to treatment with CAR T cells. Co-expression of proinflamatory cytokines such as IL-12 and IL-18 by CAR T cells have been shown to enhance their antitumor function. We similarly engineered CAR T cell to co-express IL-21 and studied the effects of IL-21 on CAR T cells specific to CD19 and prostate-specific membrane antigens using an in vitro co-culture model and NSG mice transplanted with B-cell tumors. RESULTS: IL-21 enhanced the expansion of CAR T cells after antigenic stimulation, reduced the level of apoptosis of CAR T cells during co-culture with tumor cells and prevented differentiation of CAR T cells toward late memory phenotypes. In addition, induced secretion of IL-21 by CAR T cells promoted tumor infiltration by CD19-specific CAR (CAR19) T cells in NSG mice, resulting in reduced tumor growth. By co-culturing CAR19 T cells with bone-marrow fragments infiltrated with CLL cells we demonstrate that IL-21 reduces the immunosupressive activity of CLL cells against CAR19 T cells. CONCLUSIONS: CAR19 T cells armed with IL-21 exhibited enhanced antitumor functions. IL-21 promoted their proliferation and cytotoxicity against chronic lymphocytic leukemia (CLL). The results suggest that arming CAR T cells with IL-21 could boost the effectiveness of CAR T-mediated therapies.
- MeSH
- fenotyp MeSH
- imunosupresivní léčba MeSH
- interleukiny metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádory imunologie terapie MeSH
- proliferace buněk MeSH
- receptory antigenů T-buněk metabolismus MeSH
- T-lymfocyty imunologie MeSH
- transpozibilní elementy DNA genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Peptides ghrelin, obestatin and neuropeptide Y (NPY) play an important role in regulation of energy homeostasis, the imbalance of which is associated with eating disorders anorexia (AN) and bulimia nervosa (BN). The changes in ghrelin, obestatin and NPY plasma levels were investigated in AN and BN patients after administration of a high-carbohydrate breakfast (1604 kJ). Eight AN women (aged 25.4+/-1.9, BMI: 15.8+/-0.5), thirteen BN women (aged 22.0+/-1.05, BMI: 20.1+/-0.41) and eleven healthy women (aged 25.1+/-1.16, BMI: 20.9+/-0.40) were recruited for the study. We demonstrated increased fasting ghrelin in AN, but not in BN patients, while fasting obestatin and NPY were increased in both AN and BN patients compared to the controls. Administration of high-carbohydrate breakfast induced a similar relative decrease in ghrelin and obestatin plasma levels in all groups, while NPY remained increased in postprandial period in both patient groups. Ghrelin/obestatin ratio was lower in AN and BN compared to the controls. In conclusions, increased plasma levels of fasting NPY and its unchanged levels after breakfast indicate that NPY is an important marker of eating disorders AN and BN. Different fasting ghrelin and obestatin levels in AN and BN could demonstrate their diverse functions in appetite and eating suppression.
- MeSH
- bulimia nervosa krev MeSH
- dietní sacharidy aplikace a dávkování MeSH
- financování organizované MeSH
- ghrelin krev MeSH
- index tělesné hmotnosti MeSH
- lidé MeSH
- mentální anorexie krev MeSH
- neuropeptid Y krev MeSH
- postprandiální období fyziologie MeSH
- přijímání potravy fyziologie MeSH
- složení těla MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
