Stepwise Reversal of Immune Dysregulation Due to STAT1 Gain-of-Function Mutation Following Ruxolitinib Bridge Therapy and Transplantation

Autor: Busranur Geckin, Arzu Akcay, Elif Karakoc-Aydiner, Ahmet Oğuzhan Özen, Naz Surucu Yilmaz, Louis-Marie Charbonnier, Basak Kayaoglu, Gülyüz Öztürk, Talal A. Chatila, Mayda Gursel, Safa Baris, Sevgi Bilgic Eltan, Nurhan Kasap
Rok vydání: 2021
Předmět:
0301 basic medicine
Oncology
Ruxolitinib
medicine.medical_specialty
Genotype
medicine.medical_treatment
Immunology
Hematopoietic stem cell transplantation
medicine.disease_cause
Immunophenotyping
Diagnosis
Differential
03 medical and health sciences
0302 clinical medicine
Immune system
Internal medicine
Nitriles
medicine
Humans
Janus Kinase Inhibitors
Immunology and Allergy
Phosphorylation
Chronic mucocutaneous candidiasis
Alleles
Immunodeficiency
business.industry
Hematopoietic Stem Cell Transplantation
Immune dysregulation
medicine.disease
Combined Modality Therapy
Transplantation
Phenotype
Pyrimidines
STAT1 Transcription Factor
Treatment Outcome
030104 developmental biology
Immune System Diseases
Child
Preschool
Gain of Function Mutation
Cytokines
Pyrazoles
Female
Autoimmune hemolytic anemia
business
030215 immunology
medicine.drug
Zdroj: Journal of Clinical Immunology. 41:769-779
ISSN: 1573-2592
0271-9142
DOI: 10.1007/s10875-020-00943-y
Popis: Purpose Patients with heterozygous gain-of-function (GOF) mutations in STAT1 frequently exhibit chronic mucocutaneous candidiasis (CMC), immunodeficiency and autoimmune manifestations. Several treatment options including targeted therapies and hematopoietic stem cell transplantation (HSCT) are available for STAT1 GOF patients but modalities and outcomes are not well established. Herein, we aimed to unravel the effect of ruxolitinib as a bridge therapy in a patient with sporadic STAT1 T385M mutation to manage infections and other disease manifestations. Methods Peripheral blood mononuclear cells were isolated from the patient prior to, during ruxolitinib treatment and 6 months after HSCT. IFN-beta-induced STAT1 phosphorylation/dephosphorylation levels and PMA/ionomycin-stimulated intracellular IL-17A/IFN-gamma production in CD4(+) T cells were evaluated. Differentially expressed genes between healthy controls and the patient prior to, during ruxolitinib treatment and post-transplantation were investigated using Nanostring nCounter Profiling Panel. Results Ruxolitinib provided favorable responses by controlling candidiasis and autoimmune hemolytic anemia in the patient. Dysregulation in STAT1 phosphorylation kinetics improved with ruxolitinib treatment and was completely normalized after transplantation. T(H)17 deficiency persisted after ruxolitinib treatment, but normalized following HSCT. Consistent with the impairment in JAK/STAT signaling, multiple immune related pathways were found to be dysregulated in the patient. At baseline, genes related to type I IFN-related pathways, antigen processing, T-cell and B-cell functions were upregulated, while NK-cell function and cytotoxicity related genes were downregulated. Dysregulated gene expression was partially improved with ruxolitinib treatment and normalized after transplantation. Conclusion Our findings suggest that improved disease management and immune dysregulatory profile can be achieved with ruxolitinib treatment before transplantation and this would be beneficial to reduce the risk of adverse outcome of HSCT.
Databáze: OpenAIRE
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