Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome

Antiopi Varelias, Kate L Ormerod, Mark D Bunting, Motoko Koyama, Kate H Gartlan, Rachel D Kuns, Nancy Lachner, Kelly R Locke, Chun Y Lim, Andrea S Henden, Ping Zhang, Andrew D Clouston, Sumaira Z Hasnain, Michael A McGuckin, Bruce R Blazar, Kelli P A MacDonald, Philip Hugenholtz, Geoffrey R Hill

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Donor T-cell-derived interleukin-17A (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 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-17 receptor A/C (IL-17RA/C). The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and nonhematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we cohoused wild-type (WT) with IL-17RA and IL-17RC-deficient mice, which dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted toward that of the IL-17RA/C mice during cohousing prior to transplant, confirming that an IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A depletion peritransplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis.

LanguageEnglish
Pages2172-2185
Number of pages14
JournalBlood
Volume129
Issue number15
DOIs
Publication statusPublished - 13 Apr 2017
Externally publishedYes

Keywords

  • Acute Disease
  • Animals
  • Disease Models, Animal
  • Dysbiosis/genetics
  • Gastrointestinal Microbiome/immunology
  • Graft vs Host Disease/genetics
  • Interleukin-17/genetics
  • Intestinal Diseases/genetics
  • Lymphocyte Transfusion
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin/genetics
  • Receptors, Interleukin-17/genetics

Cite this

Varelias, A., Ormerod, K. L., Bunting, M. D., Koyama, M., Gartlan, K. H., Kuns, R. D., ... Hill, G. R. (2017). Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. Blood, 129(15), 2172-2185. https://doi.org/10.1182/blood-2016-08-732628
Varelias, Antiopi ; Ormerod, Kate L ; Bunting, Mark D ; Koyama, Motoko ; Gartlan, Kate H ; Kuns, Rachel D ; Lachner, Nancy ; Locke, Kelly R ; Lim, Chun Y ; Henden, Andrea S ; Zhang, Ping ; Clouston, Andrew D ; Hasnain, Sumaira Z ; McGuckin, Michael A ; Blazar, Bruce R ; MacDonald, Kelli P A ; Hugenholtz, Philip ; Hill, Geoffrey R. / Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. In: Blood. 2017 ; Vol. 129, No. 15. pp. 2172-2185.
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abstract = "Donor T-cell-derived interleukin-17A (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 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-17 receptor A/C (IL-17RA/C). The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and nonhematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we cohoused wild-type (WT) with IL-17RA and IL-17RC-deficient mice, which dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted toward that of the IL-17RA/C mice during cohousing prior to transplant, confirming that an IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A depletion peritransplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis.",
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Varelias, A, Ormerod, KL, Bunting, MD, Koyama, M, Gartlan, KH, Kuns, RD, Lachner, N, Locke, KR, Lim, CY, Henden, AS, Zhang, P, Clouston, AD, Hasnain, SZ, McGuckin, MA, Blazar, BR, MacDonald, KPA, Hugenholtz, P & Hill, GR 2017, 'Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome', Blood, vol. 129, no. 15, pp. 2172-2185. https://doi.org/10.1182/blood-2016-08-732628

Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. / Varelias, Antiopi; Ormerod, Kate L; Bunting, Mark D; Koyama, Motoko; Gartlan, Kate H; Kuns, Rachel D; Lachner, Nancy; Locke, Kelly R; Lim, Chun Y; Henden, Andrea S; Zhang, Ping; Clouston, Andrew D; Hasnain, Sumaira Z; McGuckin, Michael A; Blazar, Bruce R; MacDonald, Kelli P A; Hugenholtz, Philip; Hill, Geoffrey R.

In: Blood, Vol. 129, No. 15, 13.04.2017, p. 2172-2185.

Research output: Contribution to journalArticle

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AU - Ormerod, Kate L

AU - Bunting, Mark D

AU - Koyama, Motoko

AU - Gartlan, Kate H

AU - Kuns, Rachel D

AU - Lachner, Nancy

AU - Locke, Kelly R

AU - Lim, Chun Y

AU - Henden, Andrea S

AU - Zhang, Ping

AU - Clouston, Andrew D

AU - Hasnain, Sumaira Z

AU - McGuckin, Michael A

AU - Blazar, Bruce R

AU - MacDonald, Kelli P A

AU - Hugenholtz, Philip

AU - Hill, Geoffrey R

N1 - © 2017 by The American Society of Hematology.

PY - 2017/4/13

Y1 - 2017/4/13

N2 - Donor T-cell-derived interleukin-17A (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 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-17 receptor A/C (IL-17RA/C). The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and nonhematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we cohoused wild-type (WT) with IL-17RA and IL-17RC-deficient mice, which dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted toward that of the IL-17RA/C mice during cohousing prior to transplant, confirming that an IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A depletion peritransplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis.

AB - Donor T-cell-derived interleukin-17A (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 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-17 receptor A/C (IL-17RA/C). The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and nonhematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we cohoused wild-type (WT) with IL-17RA and IL-17RC-deficient mice, which dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted toward that of the IL-17RA/C mice during cohousing prior to transplant, confirming that an IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A depletion peritransplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis.

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KW - Animals

KW - Disease Models, Animal

KW - Dysbiosis/genetics

KW - Gastrointestinal Microbiome/immunology

KW - Graft vs Host Disease/genetics

KW - Interleukin-17/genetics

KW - Intestinal Diseases/genetics

KW - Lymphocyte Transfusion

KW - Mice

KW - Mice, Knockout

KW - Receptors, Interleukin/genetics

KW - Receptors, Interleukin-17/genetics

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T2 - Blood

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Varelias A, Ormerod KL, Bunting MD, Koyama M, Gartlan KH, Kuns RD et al. Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. Blood. 2017 Apr 13;129(15):2172-2185. https://doi.org/10.1182/blood-2016-08-732628