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IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling.
- Source :
-
Blood [Blood] 2019 Dec 05; Vol. 134 (23), pp. 2092-2106. - Publication Year :
- 2019
-
Abstract
- Graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT) is characterized by interleukin-6 (IL-6) dysregulation. IL-6 can mediate effects via various pathways, including classical, trans, and cluster signaling. Given the recent availability of agents that differentially inhibit these discrete signaling cascades, understanding the source and signaling and cellular targets of this cytokine is paramount to inform the design of clinical studies. Here we demonstrate that IL-6 secretion from recipient dendritic cells (DCs) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling after targeted IL-6 receptor (IL-6R) deletion in T cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. After engraftment, donor DCs assume the same role, maintaining classical IL-6 signaling-dependent GVHD responses. Surprisingly, cluster signaling was not active after transplantation, whereas inhibition of trans signaling with soluble gp130Fc promoted severe, chronic cutaneous GVHD. The latter was a result of exaggerated polyfunctional Th22-cell expansion that was reversed by IL-22 deletion or IL-6R inhibition. Importantly, inhibition of IL-6 classical signaling did not impair the graft-versus-leukemia effect. Together, these data highlight IL-6 classical signaling and downstream Th17/Th22 differentiation as important therapeutic targets after alloSCT.<br /> (© 2019 by The American Society of Hematology.)
- Subjects :
- Allografts
Animals
Cell Differentiation immunology
Dendritic Cells pathology
Gene Deletion
Graft vs Host Disease genetics
Graft vs Host Disease pathology
Graft vs Leukemia Effect genetics
Graft vs Leukemia Effect immunology
Interleukin-6 genetics
Interleukins genetics
Interleukins immunology
Mice
Mice, Transgenic
Receptors, Interleukin-6 genetics
Receptors, Interleukin-6 immunology
Signal Transduction genetics
Skin Diseases genetics
Skin Diseases pathology
Th17 Cells immunology
Th17 Cells pathology
Interleukin-22
Dendritic Cells immunology
Graft vs Host Disease immunology
Interleukin-6 immunology
Signal Transduction immunology
Skin Diseases immunology
Stem Cell Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 134
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 31578204
- Full Text :
- https://doi.org/10.1182/blood.2019000396