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High-dose chemotherapy and/or radiation given before an allogeneic hematopoietic cell transplantation severely damage thymic epithelial cells (TECs) resulting in poor posttransplant immune recovery. IL-22 mediates recovery of TECs via a pro-regenerative 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, posttransplant use of IL-22 improved repair of TECs, increased the numbers of thymus T cells, increased the intra-thymic levels of Aire and increased 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 regeneration of TECs after damage from irradiation in mice and highlight circumstances where normalizing thymus T-cell function with IL-22 decreases GVHD post allotransplants.
This article was published in the following journal.
Defect of thymus results in poor posttransplant immune recovery and dysfunction of immune tolerance after allogeneic hematopoietic cell transplants (allo-HCT). Improving thymus regeneration represents...
Interleukin (IL)-6 decreases hepatic expression of numerous transporters. Although IL-6 signaling occurs through STAT3, the extent of the involvement of the STAT3 signaling pathway has not been elucid...
Tmub1 (transmembrane and ubiquitin-like domain-containing 1) plays negative roles in rat hepatocyte proliferation, but its underlying molecular mechanisms in liver regeneration regulation have yet to ...
Psoriasiform chronic graft-versus-host disease (GvHD) is a rare clinical presentation recently described after allogeneic hematopoietic stem cell transplantation. It is characterized by the combinatio...
To assess the potential role of IL-6 in sciatic nerve injury-induced activation of a pro-regenerative state in remote dorsal root ganglia (DRG) neurons, we compared protein levels of SCG-10 and activa...
The purpose of this research study is to determine the safety of IL-2 and the highest dose of this drug that can be given safely to people with chronic graft versus host disease (GVHD). C...
The purpose of this study is to see if a positron emission tomography/computed tomography (PET/CT) scan and a magnetic resonance imaging (MRI) of the chest can assess changes in the thymus...
This phase I trial studies side effects and best dose of recombinant interleukin-7 in promoting immune cell recovery in patients with acute myeloid leukemia, myelodysplastic syndrome, chro...
One purpose of this study is to determine whether the amount of thymus tissue transplanted into DiGeorge syndrome infants has any effect on the immune outcome. Another purpose of this stud...
Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3'...
A signal transducer and activator of transcription that mediates cellular responses to INTERLEUKIN-6 family members. STAT3 is constitutively activated in a variety of TUMORS and is a major downstream transducer for the CYTOKINE RECEPTOR GP130.
An interleukin receptor subunit that was originally discovered as a component of the INTERLEUKIN 2 RECEPTOR. It was subsequently found to be a component of several other receptors including the INTERLEUKIN 4 RECEPTOR, the INTERLEUKIN 7 RECEPTOR, the INTERLEUKIN-9 RECEPTOR, the INTERLEUKIN-15 RECEPTOR, and the INTERLEUKIN-21 RECEPTOR. Mutations in the gene for the interleukin common gamma chain have been associated with X-LINKED COMBINED IMMUNODEFICIENCY DISEASES.
The immune responses of a host to a graft. A specific response is GRAFT REJECTION.
Cell surface receptors for INTERLEUKIN-13. Included under this heading are the INTERLEUKIN-13 RECEPTOR ALPHA2 which is a monomeric receptor and the INTERLEUKIN-4 RECEPTOR TYPE II which has specificity for both INTERLEUKIN-4 and INTERLEUKIN-13.
A cytokine subunit that is a component of both interleukin-12 and interleukin-23. It binds to the INTERLEUKIN-12 SUBUNIT P35 via a disulfide bond to form interleukin-12 and to INTERLEUKIN-23 SUBUNIT P19 to form interleukin-23.
Organ transplantation is the moving of an organ from one body to another or from a donor site to another location on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative ...