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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 Transplantation

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

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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 7

ILC2 treatment improves intestinal barrier function and does not abrogate the GVL response.

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ILC2 treatment improves intestinal barrier function and does not abrogat...
Quantification of FITC-dextran in the serum of BMT recipients (A) 6 days, (B) 12 days, and (C) 20 days after transplant. One representative of 2 independent experiments shown; mean ± SEM (n = 5 per group). Statistical analysis by 1-way ANOVA with Bonferroni’s correction for multiple comparisons, *P < 0.05, **P < 0.01, ***P < 0.001. (D) Kaplan-Meier plot of B6D2 recipients of B6 TCD BM (BM only), BM plus splenic T cells (BM + T cells), or BM plus T cells with cultured Areg–/– ILC2s (BM, T cell + Areg–/– ILC2) were evaluated for survival following allo-SCT. One representative of 2 experiments shown (n = 5 per group in each experiment). WT ILC2 group shown represents one experiments from Figure 2A. (E) Quantification of FITC-dextran in the serum of BMT recipients 20 days after transplant. One combined representative of 2 independent experiments is shown; mean ± SEM (n = 5 per group).
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