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 May 1, 2017; First 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

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 1

ILC2s are sensitive to radiation and chemotherapy conditioning.

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ILC2s are sensitive to radiation and chemotherapy conditioning. (A) Flow...
(A) Flow cytometry gating scheme used to define ILC2 and ILC3 subsets in MLN. (B) Quantitation by flow cytometry of innate lymphoid and CD4+ T cells in the LP, MLN, or lung in mice without irradiation (filled circles) or 24 hours after receiving radiation (950 cGy) (open circles). Results represent 3 independent experiments; n = 5 for each group. (C) Quantitation of ILC2s in the LP and MLN in mice receiving no therapy (filled circles) or 24 hours after receiving 200 mg/kg of cyclophosphamide (open circles). Results represent 2 independent experiments; n = 4 for each. (D) Quantitation of host and donor-derived ILC2s in the LP and lung 28 days after BMT; mean ± SEM. Results represent 2 independent experiments; n = 5. Statistical analysis by Student’s t test with Welch’s correction, ***P < 0.001, **P < 0.01, *P < 0.05.