Graft-versus-host disease (GvHD) remains the predominant factor limiting the widespread utilization of allogeneic stem cell transplantation (allo-SCT) for the treatment of patients with high-risk or recurrent hematological malignancies. The primary approach to the prevention of acute GvHD is the use of calcineurin inhibitors (CNI) with methotrexate. With this approach, approximately, 30-80% of patients undergoing matched related or unrelated stem cell transplantation will develop acute GvHD. For patients that develop acute GvHD, therapy has not changed in over 30 years and consists of systemic corticosteroids. This approach has substantial side-effects leading to severe long-term complications. Treatment for patients with steroid-refractory acute GvHD is suboptimal with fewer than 15% of patients treated living more than a year after diagnosis. Thus, new forms of therapy are badly needed to improve the outcome of patients undergoing allo-SCT. Aggressive therapy targeting donor T cells in patients with steroid refractory acute GvHD of the lower GI tract, has not improved the long term outcome of patients refractory to corticosteroid therapy. This has led to increased interest in understanding how conditioning therapy and GvHD alter the homeostatic environment of the lower GI tract. Over the past 36 months, my group has evaluated the function of a relatively new population of innate lymphoid cells, termed type 2 innate lymphoid cells (ILC2). These cells are found in the GI tract and generate IL-4, IL-5 and IL-13. The cytokines IL-25 and IL-33 are critical to the generation of ILC2 cells. In the current proposal, we demonstrate that ILC2 cells are radiation and chemotherapy sensitive, and that they poorly reconstitute over a three month period from donor bone marrow cells. We demonstrate that infusion of donor ILC2 cells can prevent and more importantly TREAT ongoing acute GvHD of the lower GI tract. This was associated with significant decreases in donor Th1/Th17 and Tc1 cells in the colon and small bowel and improvement in colonic epithelial cell integrity. The activity of ILC2 cells required the generation of IL-13 and amphiregulin (AREG) by the ILC2 cells. Administration of ILC2 cells had no effect on the GvL response. The goals of the current proposal are to assess the use of ILC2 cells as a novel approach to the treatment of acute GvHD. We will investigate the mechanism by which ILC2 cells treat lower tract GvHD, the function of myeloid derived suppressor cells (MDSCs) and Tregs in this activity, and the roles that IL-13, AREG, dendritic cells and intestinal subepithelial myofibroblasts (ISEMFs) have in the activity of ILC2 cells. We will demonstrate that ILC2 cells function in mice receiving CNI and/or steroids, which will allow us to rapidly translate these findings to patients. Finally, we will evaluate the mechanism for activity of ILC2 cells focusing on signaling downstream of IL-13/IL-13 receptor and NOTCH. Understanding how ILC2 cells function is critical to future clinical trials that will use human ILC2 cells to treat patients with steroid-refractory GvHD of the lower GI tract.

Public Health Relevance

Stem cell or bone marrow transplantation from one individual to another is a standard treatment for patients with high-risk and recurrent leukemia, myelodysplastic syndrome and low-grade lymphoma. The outcome for patients undergoing this treatment is greatly impacted by the development and severity of graft-versus-host disease (GVHD). Lower GI tract GVHD is the most common cause of death due to GVHD. The current proposal will evaluate the use of a new form of cell therapy, innate lymphoid cells, for the treatment/prevention of lower GI tract GVHD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Welniak, Lisbeth A
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Kolupaev, Oleg V; Dant, Trisha A; Bommiasamy, Hemamalini et al. (2018) Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD. Blood Adv 2:2307-2319
Agle, Kimberle; Vincent, Benjamin G; Piper, Clint et al. (2018) Bim regulates the survival and suppressive capability of CD8+ FOXP3+ regulatory T cells during murine GVHD. Blood 132:435-447
Dant, Trisha A; Lin, Kaifeng L; Bruce, Danny W et al. (2017) T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD. Blood 130:348-359
Bruce, Danny W; Stefanski, Heather E; Vincent, Benjamin G et al. (2017) Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease. J Clin Invest 127:1813-1825
Ferrara, James Lm; Smith, Christopher M; Sheets, Julia et al. (2017) Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis. J Clin Invest 127:2441-2451