Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses
ABSTRACT Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transplantation recipients. These studies demonstrate that the selective protection of the colon that occurs as a consequence of inhibition of IL-23 signaling reduces GVHD without loss of the GVL effect. The separation of GVH and GVL reactivity was noted in both acute and chronic hematologic malignancy models, indicating that this approach was not restricted by the kinetic profile of the underlying leukemia. Furthermore, a potent GVL response could be mounted in the colon under conditions where tumor cells migrated to this site, indicating that this organ did not serve as a sanctuary site for subsequent systemic relapse in GVHD-protected animals. These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans.
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ABSTRACT: Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and development of myeloid cells and their precursors in blood and bone marrow. Impressive biologic advances have increased our understanding of leukemogenesis, however, little is known about the pathogenic events which lead to the initiation and progression of AML. T helper type 17 (Th17) cells are a unique subset of CD4+ T cells. They play important roles in the pathogenesis of many diseases, including inflammatory diseases, autoimmune diseases, and cancers. A range of cytokines, such as interleukin (IL)-23, transforming growth factor-beta (TGF-beta), IL-1beta, IL-6, IL-17, IL-22, and IL-21, have been shown related to Th17 cells. Some researchers have reported that the levels of Th17 and its related cytokines were different between normal cells and malignant AML cells, suggesting that Th17 might be involved in AML pathogenesis. In this review, we summarize current progress in the mechanisms of Th17 related cytokines in AML pathogenesis.Frontiers in Bioscience 01/2012; 17:2284-94. · 4.25 Impact Factor
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ABSTRACT: Although major advances have been made in solid organ and hematopoietic stem cell transplantation in the last 50 years, big challenges remain. This review outlines the current immunological limitations for hematopoietic stem cell and solid organ transplantation and discusses new immune-modulating therapies in preclinical development and in clinical trials that may allow these obstacles to be overcome. Copyright © 2015, American Association for the Advancement of Science.Science translational medicine 03/2015; 7(280):280rv2. DOI:10.1126/scitranslmed.aaa6853 · 14.41 Impact Factor
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ABSTRACT: Th17 cells contribute to severe GVHD in murine bone marrow transplantation. Targeted deletion of the RORγt transcription factor or blockade of the JAK2-STAT3 axis suppresses IL-17 production and alloreactivity by Th17 cells. Here, we show that pSTAT3 Y705 is increased significantly in CD4(+) T cells among human recipients of allogeneic HCT before the onset of Grade II-IV acute GVHD. Examination of target-organ tissues at the time of GVHD diagnosis indicates that the amount of RORγt + Th17 cells is significantly higher in severe GVHD. Greater accumulation of tissue-resident Th17 cells also correlates with the use of MTX- compared with Rapa-based GVHD prophylaxis, as well as a poor therapeutic response to glucocorticoids. RORγt is optimally suppressed by concurrent neutralization of TORC1 with Rapa and inhibition of STAT3 activation with S3I-201, supporting that mTOR- and STAT3-dependent pathways converge upon RORγt gene expression. Rapa-resistant T cell proliferation can be totally inhibited by STAT3 blockade during initial allosensitization. We conclude that STAT3 signaling and resultant Th17 tissue accumulation are closely associated with acute GVHD onset, severity, and treatment outcome. Future studies are needed to validate the association of STAT3 activity in acute GVHD. Novel GVHD prevention strategies that incorporate dual STAT3 and mTOR inhibition merit investigation. © Society for Leukocyte Biology.Journal of Leukocyte Biology 02/2015; 97(4). DOI:10.1189/jlb.5A1114-532RR · 4.30 Impact Factor