Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome
| Autor: | Philip Hugenholtz, Kelli P. A. MacDonald, Andrea S. Henden, Kate H. Gartlan, Kelly R. Locke, Bruce R. Blazar, Chun Y. Lim, Ping Zhang, Rachel D. Kuns, Sumaira Z. Hasnain, Nancy Lachner, Antiopi Varelias, Kate L. Ormerod, Geoffrey R. Hill, Mark D. Bunting, Motoko Koyama, Michael A. McGuckin, Andrew D. Clouston |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Immunology Graft vs Host Disease Biology Biochemistry 03 medical and health sciences Mice 0302 clinical medicine immune system diseases medicine Animals Immunology and Allergy Microbiome Mice Knockout Transplantation Receptors Interleukin-17 Interleukin-17 Cell Biology Hematology Receptors Interleukin medicine.disease Gastrointestinal Microbiome Haematopoiesis Disease Models Animal Intestinal Diseases 030104 developmental biology Graft-versus-host disease Cytokine surgical procedures operative 030220 oncology & carcinogenesis Lymphocyte Transfusion Knockout mouse Acute Disease Dysbiosis Stem cell Cytokine receptor |
| Zdroj: | Publons ResearcherID |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.198.supp.82.8 |
| Popis: | Donor T cell-derived IL-17A can mediate late immunopathology in graft-versus-host disease (GVHD), however protective roles remain unclear. Using multiple cytokine and cytokine receptor subunit knockout mice we demonstrate that stem cell transplant (SCT) recipients lacking the ability to generate or signal IL-17 develop intestinal hyper-acute GVHD. This protective effect is restricted to the molecular interaction of IL-17A and/or IL-17F with the IL-17RA/C receptor. The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and non-hematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we hypothesized a microbiome contribution. Cohousing of WT with IL-17RA and IL-17RC deficient mice, dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted towards that of the IL-17RA/C mice during cohousing prior to transplant, confirming that IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A deletion peri-transplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis. Importantly, this implies that blocking IL-17 in a clinical trial could have adverse effects via dysbiosis, particularly in the early post-transplant setting and raises caution about their potential effects if used long term. |
| Databáze: | OpenAIRE |
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