A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome.

Autor:	Delville M; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Service de Biothérapie et d'Aphérèse, Hôpital Necker, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.; Centre d'Investigation Clinique Biothérapie, Groupe Hospitalier Universitaire Ouest, AP-HP, Paris, France., Bellier F; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Leon J; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Department of Immunology, Harvard Medical School, Boston, MA., Klifa R; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Service d'Immuno-Hématologie Pédiatrique, Hôpital Necker, AP-HP, Paris, France., Lizot S; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Vinçon H; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Sobrino S; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Thouenon R; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Marchal A; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Garrigue A; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Olivré J; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Charbonnier S; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Lagresle-Peyrou C; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Centre d'Investigation Clinique Biothérapie, Groupe Hospitalier Universitaire Ouest, AP-HP, Paris, France., Amendola M; Genethon, Evry, France., Schambach A; Institute of Experimental Hematology, Hannover Medical School, Hanover, Germany., Gross D; Institut Necker Enfants-Malades, Université de Paris, U1151, INSERM, Paris, France; and., Lamarthée B; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Benoist C; Department of Immunology, Harvard Medical School, Boston, MA., Zuber J; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Service de Néphrologie et Transplantation Rénale, Hôpital Necker, Groupe Hospitalier Universitaire Ouest, AP-HP, Paris, France., André I; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France., Cavazzana M; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.; Service de Biothérapie et d'Aphérèse, Hôpital Necker, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France., Six E; Institut Imagine, Université de Paris, INSERM UMR1163, Laboratory of Human Lymphohematopoiesis, Paris, France.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Apr 29; Vol. 137 (17), pp. 2326-2336.
DOI:	10.1182/blood.2020009187
Abstrakt:	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. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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