Treatment with rapamycin can restore regulatory T-cell function in IPEX patients

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Passerini, Laura¹  Barzaghi, Federica^1,2  Curto, Rosalia¹  Sartirana, Claudia¹  Barera, Graziano³  Tucci, Francesca²  Albarello, Luca⁴  Mariani, Alberto⁵  Testoni, Pier Alberto⁵  Bazzigaluppi, Elena⁶  Bosi, Emanuele^6,7  Lampasona, Vito⁶  Neth, Olaf⁸  Zama, Daniele⁹  Hoenig, Manfred¹⁰  Schulz, Ansgar¹⁰  Seidel, Markus G.¹¹  Rabbone, Ivana¹²  Olek, Sven¹³  Roncarolo, Maria G.¹⁴  Cicalese, Maria P.^1,2  Aiuti, Alessandro^1,2,7  Bacchetta, Rosa^1,14 

[1] San Raffaele Telethon Inst Gene Therapy SR Tiget, Milan, Italy

[2] IRCCS San Raffaele Sci Inst, Dept Paediat Immunohematol, Milan, Italy

[3] IRCCS San Raffaele Sci Inst, Dept Paediat, Milan, Italy

[4] IRCCS San Raffaele Sci Inst, Pathol Unit, Milan, Italy

[5] IRCCS San Raffaele Sci Inst, Gastroenterol Unit, Milan, Italy

[6] IRCCS San Raffaele Sci Inst, Diabet Res Inst, Milan, Italy

[7] Univ Vita Salute San Raffaele, Milan, Italy

[8] Univ Seville, CSIC, Inst Biomed Sevilla, Dept Paediat Infect Dis Rheumatol & Immunodeficie, Seville, Spain

[9] Univ Bologna, S Orsola Malpighi Hosp, Dept Pediat, Bologna, Italy

[10] Ulm Univ, Clin Pediat & Adolescent Med, Ulm, Germany

[11] Med Univ Graz, Dept Pediat & Adolescent Med, Div Pediat Hematol Oncol, Graz, Austria

[12] Univ Turin, Dept Pediat, Turin, Italy

[13] Epiontis GmbH, Berlin, Germany

[14] Stanford Univ, Sch Med, Dept Pediat, Div Stem Cell Transplantat & Regenerat Med, Stanford, CA 94305 USA

关键词: autoimmunity;    Ebi3;    FOXP3;    GITR;    IPEX;    mTOR;    rapamycin;    regulatory T cells;    suppression;   

DOI  :  10.1016/j.jaci.2019.11.043

来源: Elsevier

【 摘 要 】

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, glucocorticoidinduced 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.

【 授权许可】

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