A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome
| Autor: | Soëli Charbonnier, Sabrina Lizot, Isabelle André, Emmanuelle Six, Christophe Benoist, Roman Klifa, Steicy Sobrino, Juliette Leon, Juliette Olivré, Armance Marchal, David A. Gross, Hélène Vinçon, Baptiste Lamarthée, Julien Zuber, Alexandrine Garrigue, Marina Cavazzana, Marianne Delville, Mario Amendola, Romane Thouenon, Chantal Lagresle-Peyrou, Florence Bellier, Axel Schambach |
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| Přispěvatelé: | Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Harvard Medical School [Boston] (HMS), Généthon, Hannover Medical School [Hannover] (MHH), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Amendola, Mario, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Interleukin 2 CD4-Positive T-Lymphocytes Male [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology Adoptive cell transfer [SDV.BIO]Life Sciences [q-bio]/Biotechnology Immunology Antineoplastic Agents chemical and pharmacologic phenomena [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology medicine.disease_cause Biochemistry T-Lymphocytes Regulatory Autoimmunity Viral vector Autoimmune Diseases 03 medical and health sciences Mice 0302 clinical medicine In vivo medicine Animals Cyclophosphamide [SDV.BC] Life Sciences [q-bio]/Cellular Biology Autoimmune disease FOXP3 Forkhead Transcription Factors Genetic Diseases X-Linked hemic and immune systems [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Cell Biology Hematology Gene Therapy medicine.disease [SDV.BIO] Life Sciences [q-bio]/Biotechnology Mice Inbred C57BL Haematopoiesis Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Interleukin-2 Drug Therapy Combination Female Immunosuppressive Agents medicine.drug |
| Zdroj: | Blood Blood, 2021, 137 (17), pp.2326-2336. ⟨10.1182/blood.2020009187⟩ Blood, American Society of Hematology, 2021, 137 (17), pp.2326-2336. ⟨10.1182/blood.2020009187⟩ |
| ISSN: | 0006-4971 1528-0020 |
| Popis: | Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in forkhead box P3 (FOXP3), which lead to the loss of function of regulatory T cells (Tregs) and the development of autoimmune manifestations early in life. The selective induction of a Treg program in autologous CD4+ T cells by FOXP3 gene transfer is a promising approach for curing IPEX. We have established a novel in vivo assay of Treg functionality, based on adoptive transfer of these cells into scurfy mice (an animal model of IPEX) and a combination of cyclophosphamide (Cy) conditioning and interleukin-2 (IL-2) treatment. This model highlighted the possibility of rescuing scurfy disease after the latter’s onset. By using this in vivo model and an optimized lentiviral vector expressing human Foxp3 and, as a reporter, a truncated form of the low-affinity nerve growth factor receptor (ΔLNGFR), we demonstrated that the adoptive transfer of FOXP3-transduced scurfy CD4+ T cells enabled the long-term rescue of scurfy autoimmune disease. The efficiency was similar to that seen with wild-type Tregs. After in vivo expansion, the converted CD4FOXP3 cells recapitulated the transcriptomic core signature for Tregs. These findings demonstrate that FOXP3 expression converts CD4+ T cells into functional Tregs capable of controlling severe autoimmune disease. |
| Databáze: | OpenAIRE |
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