201. IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants.
- Author
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Pan B, Wang D, Li L, Shang L, Xia F, Zhang F, Zhang Y, Gale RP, Xu M, Li Z, and Xu K
- Subjects
- Animals, Cell Line, Chronic Disease, Disease Models, Animal, Humans, Mice, Interleukin-22, Graft vs Host Disease prevention & control, Interleukins therapeutic use, STAT3 Transcription Factor metabolism, Thymus Gland growth & development, Transplantation, Homologous methods
- Abstract
High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs), resulting in poor post-transplant immune recovery. IL-22 mediates recovery of TECs via a proregenerative effect, but the precise mechanism by which this occurs is unknown. In this study, we found IL-22 improved thymus recovery after damage from irradiation in association with increased number of TECs. This effect was blocked by ruxolitinib, a JAK1/JAK2 inhibitor. IL-22 increased the number of TECs via a Stat3-dependent signaling in the mTEC1 murine thymic epithelial cell line. This, in turn, upregulated transcription of myeloid cell leukemia sequence 1 (Mcl1), resulting in increased number of TECs. Similar effects were seen in irradiated mice given IL-22. Defects in IL-22 resulted in delayed thymus recovery in irradiated mice and had an impact on levels of thymus function-related genes such as Foxn1, Aire, and Kgf. In mice, post-transplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intrathymic levels of Aire, and increased the proportion of natural regulatory T cells, resulting in decreased severity of chronic graft-versus-host disease (GVHD). Our data highlight the critical role of the IL-22/Stat3/Mcl-1 pathway in the regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T cell function with IL-22 decreases GVHD after allotransplants., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. All rights reserved.)
- Published
- 2019
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