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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 Article has an altmetric score of 6

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 8

Comparison of ILC2s and other cellular therapies for GVHD.

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Comparison of ILC2s and other cellular therapies for GVHD.
(A) Percentag...
(A) Percentage of GFP+ BC-CML tumor in host spleen 21 days after BMT in the B6-into-B6D2 model. Results represent 2 independent experiments (n = 8 each). Analysis by Student’s t test with Welch’s correction, ***P < 0.001. (B) IVIS imaging of luc-P815 tumor in B6D2 BMT recipients 15 days after transplant comparing recipients of BM and luc-P815 cells (BM only); BM with splenic T cells and luc-P815 cells (BM + T cells); BM, splenic T cells, Tregs, and luc-P815 cells (BM, T cells + Treg); and BM, splenic T cells, WT ILC2s, and luc-P815 cells (BM, T cells + WT ILC2). Results represent 2 independent experiments; n = 5 in each group. (C) Kaplan-Meier plot comparing the survival of the allo-SCT recipients described in B. Log-rank (Mantel-Cox) test, **P < 0.01. (D) Kaplan-Meier plot comparing the survival of recipients of allo-SCT (B6 into B6D2 model) that received BM alone (BM only); BM and splenic T cells (BM + T cells); and those that received BM and splenic T cells at the time of transplant with either WT ILC2s (BM, T cells + WT ILC2) or BM-MDSCs (BM, T cells + MDSC) 7 days after BMT. Results represent 2 combined experiments (n = 10 or more per group). Log-rank (Mantel-Cox) test. (E) Clinical scores of recipients from the survival study in D. **P < 0.01 by 2-way ANOVA, with Bonferroni correction for repeated measures of multiple comparisons. (F) Expansion of human ILC2s (hILC2) from SR-1–stimulated CD34+ cord blood cells in the indicated cytokines. hILC2s were enumerated as CRTH2+CD161–Lin– cells (Supplemental Figure 6F) from days 3 to 21; n = 3.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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