Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease
Danny W. Bruce, … , James M. Coghill, Jonathan S. Serody
Danny W. Bruce, … , James M. Coghill, Jonathan S. Serody
Published April 4, 2017
Citation Information: J Clin Invest. 2017;127(5):1813-1825. https://doi.org/10.1172/JCI91816.
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Research Article Immunology

Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease

Abstract

Acute graft-versus-host disease (aGVHD) is the most common complication for patients undergoing allogeneic stem cell transplantation. Despite extremely aggressive therapy targeting donor T cells, patients with grade III or greater aGVHD of the lower GI tract, who do not respond to therapy with corticosteroids, have a dismal prognosis. Thus, efforts to improve understanding of the function of local immune and non-immune cells in regulating the inflammatory process in the GI tract during aGVHD are needed. Here, we demonstrate, using murine models of allogeneic BMT, that type 2 innate lymphoid cells (ILC2s) in the lower GI tract are sensitive to conditioning therapy and show very limited ability to repopulate from donor bone marrow. Infusion of donor ILC2s was effective in reducing the lethality of aGVHD and in treating lower GI tract disease. ILC2 infusion was associated with reduced donor proinflammatory Th1 and Th17 cells, accumulation of donor myeloid-derived suppressor cells (MDSCs) mediated by ILC2 production of IL-13, improved GI tract barrier function, and a preserved graft-versus-leukemia (GVL) response. Collectively, these findings suggest that infusion of donor ILC2s to restore gastrointestinal tract homeostasis may improve treatment of severe lower GI tract aGVHD.

Authors

Danny W. Bruce, Heather E. Stefanski, Benjamin G. Vincent, Trisha A. Dant, Shannon Reisdorf, Hemamalini Bommiasamy, David A. Serody, Justin E. Wilson, Karen P. McKinnon, Warren D. Shlomchik, Paul M. Armistead, Jenny P.Y. Ting, John T. Woosley, Bruce R. Blazar, Dietmar M.W. Zaiss, Andrew N.J. McKenzie, James M. Coghill, Jonathan S. Serody

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Figure 6

Reduced efficacy of ILC2s in the absence of IL-13.

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Reduced efficacy of ILC2s in the absence of IL-13. B6D2 recipients of B6...
B6D2 recipients of B6 TCD BM (BM only), BM plus splenic T cells (BM + T cells), or BM plus T cells with cultured Il13–/– ILC2s (BM, T cell + Il13–/– ILC2) were evaluated by (A) Kaplan-Meier plot for survival following allo-SCT. Results of 1 representative of 2 combined experiments are shown (n = 8 per group in each experiment). WT ILC2 group shown represents one experiments from Figure 2A. Immune infiltrates were evaluated in GVHD target organs by flow cytometry 12 days after allo-SCT with or without Il13–/– ILC2s. (B) Total number of IFN-γ–producing donor CD4+ and CD8+ T cells and the number of donor CD4+ T cells producing IL-17A in the colon LP. Data represent 2 independent experiments; mean ± SEM (n = 5 each). (C) Frequencies of CD11b+GR-1+Ly-6C+Ly-6G+ MDSCs (gated on donor CD45+cells) in the colon and small bowel of BMT recipients of Il13–/– ILC2s 12 days after transplant. Results represent 2 independent experiments; mean ± SEM. (D) BM-MDSCs were cocultured for 72 hours with WT or Il13–/– ILC2s (1:1), or MDSCs alone or with either IL-13 (80 ng/ml) or IL-7 and IL-33 (10 ng/ml each). BM-MDSC were cocultured with WT or Il13–/– ILC2s (1:1) in Transwell assays, alone or in the presence of IL-13 only. Results represent 2 independent experiments; mean ± SEM. One-way ANOVA with Bonferroni’s correction for multiple comparisons, *P < 0.05, ***P < 0.001.