RT Journal Article
T1 Treatment with rapamycin can restore regulatory T-cell function in IPEX patients.
A1 Passerini, Laura
A1 Barzaghi, Federica
A1 Curto, Rosalia
A1 Sartirana, Claudia
A1 Barera, Graziano
A1 Tucci, Francesca
A1 Albarello, Luca
A1 Mariani, Alberto
A1 Testoni, Pier Alberto
A1 Bazzigaluppi, Elena
A1 Bosi, Emanuele
A1 Lampasona, Vito
A1 Neth, Olaf
A1 Zama, Daniele
A1 Hoenig, Manfred
A1 Schulz, Ansgar
A1 Seidel, Markus G
A1 Rabbone, Ivana
A1 Olek, Sven
A1 Roncarolo, Maria G
A1 Cicalese, Maria P
A1 Aiuti, Alessandro
A1 Bacchetta, Rosa
K1 Ebi3
K1 FOXP3
K1 GITR
K1 IPEX
K1 autoimmunity
K1 mTOR
K1 rapamycin
K1 regulatory T cells
K1 suppression
AB 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. 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. 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. 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. 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.
YR 2019
FD 2019-12-23
LK http://hdl.handle.net/10668/14874
UL http://hdl.handle.net/10668/14874
LA en
DS RISalud
RD Apr 17, 2025