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  • 1
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 12 April 2019
    Description: Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble membrane-bound ST2 (ST2) are elevated in human and murine aGVHD and correlated to type 1 T cells response. ST2 signals through the adapter protein MyD88. The role of MyD88 in T cells during aGVHD has yet to be elucidated. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of IL-1R and TLR4 signaling in two murine HCT models. This protection was entirely driven by MyD88 CD4 T cells. Transplanting donor MyD88 conventional T cells (Tcons) with wild-type (WT) or MyD88 regulatory T cells (Tregs) lowered aGVHD severity and mortality. Transcriptome analysis of sorted MyD88 CD4 T cells from the intestine 10 d post-HCT showed lower levels of (gene of ST2), , , , and Transplanting donor ST2 Tcons with WT or ST2 Tregs showed a similar phenotype with what we observed when using donor MyD88 Tcons. Decreased ST2 was confirmed at the protein level with less secretion of soluble ST2 and more expression of ST2 compared with WT T cells. Our data suggest that Treg suppression from lack of MyD88 signaling in donor Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways, and ST2 represents a potential aGVHD therapeutic target sparing Tregs.
    ISSN: 00221767
    E-ISSN: 1550-6606
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  • 2
    Language: English
    In: Molecular Phylogenetics and Evolution, April, 2014, Vol.73, p.1(9)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ympev.2014.01.001 Byline: I-Chen Kimberly Chen, Brad Griesenauer, Yuen-Tsu Nicco Yu, Gregory J. Velicer Abstract: Article History: Received 26 August 2013; Revised 30 December 2013; Accepted 2 January 2014 Article Note: (footnote) [star] This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
    Keywords: Rna ; Evolution (Biology)
    ISSN: 1055-7903
    Source: Cengage Learning, Inc.
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  • 3
    Language: English
    In: Biology of Blood and Marrow Transplantation, March 2017, Vol.23(3), pp.1-3
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.bbmt.2016.12.648 Byline: Brad Griesenauer, Abdulraouf Ramadan, Jilu Zhang, Janefrances Egbosiuba, Sophie Paczesny
    Keywords: Medicine
    ISSN: 1083-8791
    E-ISSN: 1523-6536
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  • 4
    Language: English
    In: Frontiers in Immunology, 01 April 2017, Vol.8
    Description: Il1rl1 (also known as ST2) is a member of the IL-1 superfamily, and its only known ligand is IL-33. ST2 exists in two forms as splice variants: a soluble form (sST2), which acts as a decoy receptor, sequesters free IL-33, and does not signal, and a membrane-bound form (ST2), which activates the MyD88/NF-κB signaling pathway to enhance mast cell, Th2, regulatory T cell (Treg), and innate lymphoid cell type 2 functions. sST2 levels are increased in patients with active inflammatory bowel disease, acute cardiac and small bowel transplant allograft rejection, colon and gastric cancers, gut mucosal damage during viral infection, pulmonary disease, heart disease, and graft-versus-host disease. Recently, sST2 has been shown to be secreted by intestinal pro-inflammatory T cells during gut inflammation; on the contrary, protective ST2-expressing Tregs are decreased, implicating that ST2/IL-33 signaling may play an important role in intestinal disease. This review will focus on what is known on its signaling during various inflammatory disease states and highlight potential avenues to intervene in ST2/IL-33 signaling as treatment options.
    Keywords: Il-33 ; St2 ; Il1rl1 ; Graft-Versus-Host Disease ; Cardiac Diseases ; Lung Diseases ; Biology
    E-ISSN: 1664-3224
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  • 5
    In: The Journal of Experimental Medicine, 2018, Vol.215(6), p.1505-1506
    Description: Ma et al. show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL-9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors. In this issue, Ma et al. ( https://doi.org/10.1084/jem.20171576 ) show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL-9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors.
    Keywords: News
    ISSN: 0022-1007
    E-ISSN: 1540-9538
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  • 6
    Language: English
    In: Molecular Phylogenetics and Evolution, April 2014, Vol.73, pp.1-9
    Description: In animals and plants, non-coding small RNAs regulate the expression of many genes at the post-transcriptional level. Recently, many non-coding small RNAs (sRNAs) have also been found to regulate a variety of important biological processes in bacteria, including social traits, but little is known about the phylogenetic or mechanistic origins of such bacterial sRNAs. Here we propose a phylogenetic origin of the myxobacterial sRNA Pxr, which negatively regulates the initiation of fruiting body development in as a function of nutrient level, and also examine its diversification within the Myxococcocales order. Homologs of were found throughout the Cystobacterineae suborder (with a few possible losses) but not outside this clade, suggesting a single origin of the Pxr regulatory system in the basal Cystobacterineae lineage. Rates of sequence evolution varied greatly across Cystobacterineae sub-clades in a manner not predicted by overall genome divergence. A single copy of was found in most species with 17% of nucleotide positions being polymorphic among them. However three tandem paralogs were present within the genus and these alleles together exhibited an elevated rate of divergence. There appears to have been strong selection for maintenance of a predicted stem-loop structure, as polymorphisms accumulated preferentially at loop or bulge regions or as complementary substitutions within predicted stems. All detected homologs are located in the intergenic region between the σ -dependent response regulator and a predicted NADH dehydrogenase gene, but other neighboring gene content has diversified.
    Keywords: Bacterial Development ; Multicellularity ; Myxobacteria ; Non-Coding Small Rnas ; Post-Transcriptional Regulation ; Social Evolution ; Biology
    ISSN: 1055-7903
    E-ISSN: 1095-9513
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  • 7
    In: The Journal of Experimental Medicine, 2017, Vol.214(12), p.3577-3596
    Description: Ramadan et al. demonstrate that triggering the ST2–IL-33 pathway in IL-9–secreting T cells decreases the severity of graft-versus-host disease through AREG upregulation while maintaining graft versus leukemia activity by preserving the central memory phenotype of CD8, increasing CD8α and cytolytic molecule expression. Allogeneic immune cells, particularly T cells in donor grafts, recognize and eliminate leukemic cells via graft-versus-leukemia (GVL) reactivity, and transfer of these cells is often used for high-risk hematological malignancies, including acute myeloid leukemia. Unfortunately, these cells also attack host normal tissues through the often fatal graft-versus-host disease (GVHD). Full separation of GVL activity from GVHD has yet to be achieved. Here, we show that, in mice and humans, a population of interleukin-9 (IL-9)–producing T cells activated via the ST2–IL-33 pathway (T9 IL-33 cells) increases GVL while decreasing GVHD through two opposing mechanisms: protection from fatal immunity by amphiregulin expression and augmentation of antileukemic activity compared with T9, T1, and unmanipulated T cells through CD8α expression. Thus, adoptive transfer of allogeneic T9 IL-33 cells offers an attractive approach for separating GVL activity from GVHD.
    Keywords: Research Articles ; 314
    ISSN: 0022-1007
    E-ISSN: 1540-9538
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  • 8
  • 9
    Language: English
    In: Science translational medicine, 07 October 2015, Vol.7(308), pp.308ra160
    Description: Graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic cell transplantation (HCT). We previously identified high plasma soluble suppression of tumorigenicity 2 (sST2) as a biomarker of the development of GVHD and death. sST2 sequesters interleukin-33 (IL-33), limiting its availability to T cells expressing membrane-bound ST2 (mST2) [T helper 2 (TH2) cells and ST2(+)FoxP3(+) regulatory T cells]. We report that blockade of sST2 in the peritransplant period with a neutralizing monoclonal antibody (anti-ST2 mAb) reduced GVHD severity and mortality. We identified intestinal stromal cells and T cells as major sources of sST2 during GVHD. ST2 blockade decreased systemic interferon-γ, IL-17, and IL-23 but increased IL-10 and IL-33 plasma levels. ST2 blockade also reduced sST2 production by IL-17-producing T cells while maintaining protective mST2-expressing T cells, increasing the frequency of intestinal myeloid-derived suppressor cells, and decreasing the frequency of intestinal CD103 dendritic cells. Finally, ST2 blockade preserved graft-versus-leukemia activity in a model of green fluorescent protein (GFP)-positive MLL-AF9 acute myeloid leukemia. Our findings suggest that ST2 is a therapeutic target for severe GVHD and that the ST2/IL-33 pathway could be investigated in other T cell-mediated immune disorders with loss of tolerance.
    Keywords: Antibodies, Monoclonal -- Therapeutic Use ; Graft Vs Host Disease -- Drug Therapy ; Receptors, Cell Surface -- Antagonists & Inhibitors
    ISSN: 19466234
    E-ISSN: 1946-6242
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  • 10
    Language: English
    In: JCI insight, 26 July 2018, Vol.3(14)
    Description: Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2.
    Keywords: Drug Screens ; Stem Cell Transplantation ; Th2 Response ; Therapeutics ; Transplantation
    E-ISSN: 2379-3708
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