Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Yajnanarayana, SP; Stübig, T; Cornez, I; Alchalby, H; Schönberg, K; Rudolph, J; Triviai, I; Wolschke, C; Heine, A; Brossart, P; Kröger, N; Wolf, D.
JAK1/2 inhibition impairs T cell function invitro and in patients with myeloproliferative neoplasms
BRIT J HAEMATOL. 2015; 169(6): 824-833.
Doi: 10.1111/bjh.13373
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Heine Annkristin
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- Abstract:
- Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT-signalling is known to be involved in the regulation of CD4(+) T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4(+) T cell responses, we undertook an in-depth analysis of CD4(+) T cell function upon ruxolitinib exposure. We observed a decrease in total CD3(+) cells after 3weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro-inflammatory T-helper cell types 1 (Th1) and Th17 were reduced, which were validated by invitro studies. In line with our invitro data, we found that inflammatory cytokines [tumour necrosis factor- (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P<005). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2-dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4(+) T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib-treated patients.
- Find related publications in this database (Keywords)
- myeloproliferative disease
- T cells
- immunotherapy
- ruxolitinib
- Janus kinases inhibitor