CRISPR-Cas9-Mediated Glucocorticoid Resistance in Virus-Specific T Cells for Adoptive T Cell Therapy Posttransplantation
| Autor: | Tobias Feuchtinger, Larissa Deisenberger, Theresa Kaeuferle, Tanja A. Stief, Semjon Willier, Lena M. Jablonowski, Franziska Blaeschke |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
T cell T-Lymphocytes Drug Resistance Lymphocyte proliferation Lymphocyte Activation Viral Matrix Proteins 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid Drug Discovery Genetics medicine Humans Molecular Biology Cell Engineering Glucocorticoids Cells Cultured 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences business.industry Hematopoietic Stem Cell Transplantation Immunosuppression Adoptive Transfer Transplantation Cytokine medicine.anatomical_structure Virus Diseases 030220 oncology & carcinogenesis Immunology Cyclosporine Molecular Medicine Cytokines Cytokine secretion Tumor necrosis factor alpha Original Article CRISPR-Cas Systems business |
| Zdroj: | Mol Ther |
| Popis: | Immunosuppression posttransplantation exposes patients to an increased risk for refractory viral infections as an important cause of morbidity and mortality. Protective T cell immunity can be restored by adoptive T cell transfer, but ongoing immunosuppression limits efficacy of T cell responses. In order to deliver protection against viral pathogens and allow at the same time necessary steroid therapy, we generated glucocorticoid-resistant T cells by CRISPR-Cas9-mediated knockout of the glucocorticoid receptor in primary human virus-specific T cell products. Characterization of the T cell product revealed high efficiency of glucocorticoid receptor knockout and high purity of virus-specific T cells. This tandem T cell engineering preserved protective T cell functionality, such as cytotoxicity, CD107a degranulation, proliferative capacity, and cytokine release patterns. Virus-specific T cells with glucocorticoid receptor knockout were resistant to the suppressive effect of dexamethasone treatment on lymphocyte proliferation and cytokine secretion (tumor necrosis factor alpha [TNF-α], interleukin-4 [IL-4], IL-6, and sFas). Additionally, glucocorticoid receptor knockout cells remained sensitive to cyclosporine A treatment, thereby providing a rescue approach for patients in case of safety issues. This novel approach provides a therapeutic option for the treatment of patients with viral infections after transplantation who are receiving glucocorticoid therapy. |
| Databáze: | OpenAIRE |
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