Laura Passerini1, Federica Barzaghi2, Rosalia Curto1, Claudia Sartirana1, Graziano Barera3, Francesca Tucci4, Luca Albarello5, Alberto Mariani6, Pier Alberto Testoni6, Elena Bazzigaluppi7, Emanuele Bosi8, Vito Lampasona7, Olaf Neth9, Daniele Zama10, Manfred Hoenig11, Ansgar Schulz11, Markus G Seidel12, Ivana Rabbone13, Sven Olek14, Maria G Roncarolo15, Maria P Cicalese2, Alessandro Aiuti16, Rosa Bacchetta17. 1. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy. 2. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 3. Department of Paediatrics, IRCCS San Raffaele Scientific Institute, Milan, Italy. 4. Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 5. Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. 6. Gastroenterology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. 7. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. 8. Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita Salute San Raffaele University, Milan, Italy. 9. Department of Paediatric Infectious Diseases, Rheumatology and Immunodeficiency, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas/Universidad de Sevilla, Seville, Spain. 10. Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. 11. Clinic of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany. 12. Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria. 13. Department of Pediatrics, University of Turin, Turin, Italy. 14. Epiontis GmbH, Berlin, Germany. 15. Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif. 16. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita Salute San Raffaele University, Milan, Italy. 17. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, Calif. Electronic address: rosab@stanford.edu.
Abstract
BACKGROUND: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS: Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.
BACKGROUND: Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear. OBJECTIVE: We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations. METHODS: Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR. RESULTS: Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor-related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients' Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor-related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells. CONCLUSIONS:Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.
Authors: M Goodwin; E Lee; U Lakshmanan; S Shipp; L Froessl; F Barzaghi; L Passerini; M Narula; A Sheikali; C M Lee; G Bao; C S Bauer; H K Miller; M Garcia-Lloret; M J Butte; A Bertaina; A Shah; M Pavel-Dinu; A Hendel; M Porteus; M G Roncarolo; R Bacchetta Journal: Sci Adv Date: 2020-05-06 Impact factor: 14.136
Authors: María Soledad Caldirola; María Paula Martínez; Liliana Bezrodnik; Norberto Walter Zwirner; María Isabel Gaillard Journal: Front Immunol Date: 2020-10-29 Impact factor: 7.561
Authors: Francesco Rispoli; Erica Valencic; Martina Girardelli; Alessia Pin; Alessandra Tesser; Elisa Piscianz; Valentina Boz; Flavio Faletra; Giovanni Maria Severini; Andrea Taddio; Alberto Tommasini Journal: Diagnostics (Basel) Date: 2021-03-16