A5037396265- RNA Interference and Gene Delivery
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Autophagy in Disease and Therapy
- Histone Deacetylase Inhibitors Research
- Hematopoietic Stem Cell Transplantation
- Renal Transplantation Outcomes and Treatments
- Acute Lymphoblastic Leukemia research
- Virus-based gene therapy research
- Mycobacterium research and diagnosis
- Cancer-related molecular mechanisms research
- MicroRNA in disease regulation
- Ubiquitin and proteasome pathways
- Immune Response and Inflammation
- NF-κB Signaling Pathways
- Phagocytosis and Immune Regulation
- Cancer Genomics and Diagnostics
- Chromatin Remodeling and Cancer
- Glycosylation and Glycoproteins Research
- Genomics and Phylogenetic Studies
- Adenosine and Purinergic Signaling
- Protein Degradation and Inhibitors
- Cell death mechanisms and regulation
University of Michigan
2015-2021
Sylvester Comprehensive Cancer Center
2019
Michigan Medicine
2017-2019
Michigan United
2016
City University of New York
2014
Abstract Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versus-host disease (GVHD), but the molecular mechanisms remain unknown. Here we show metabolite sensor G-protein-coupled receptor 43 (GPR43) is important for attenuation of gastrointestinal GVHD in multiple clinically relevant murine models. GPR43 critical protective effects short-chain fatty acids (SCFAs), butyrate propionate. Increased severity absence not due to baseline differences endogenous...
DCs undergo metabolic reprogramming from a predominantly oxidative phosphorylation (OXPHOS) to glycolysis mount an immunogenic response. The mechanism underpinning the remains elusive. We demonstrate that miRNA-142 (miR-142) is pivotal for this shift in metabolism, which regulates tolerogenic and responses of DCs. In absence miR-142, fail switch OXPHOS show reduced production proinflammatory cytokines ability activate T cells vitro vivo models sepsis alloimmunity. Mechanistic studies miR-142...
Cross-presentation initiates immune responses against tumors and viral infections by presenting extracellular antigen on MHC I to activate CD8+ T cell-mediated cytotoxicity. In vitro studies in dendritic cells (DCs) established SNARE protein SEC22B as a specific regulator of cross-presentation. However, the vivo contribution cross-presentation has not been tested. To address this, we generated DC-specific Sec22b knockout (CD11c-Cre Sec22bfl/fl) mice. Contrary paradigm, SEC22B-deficient DCs...
The role of negative regulators or suppressors the damage-associated molecular pattern-mediated (DAMP-mediated) stimulation innate immune responses is being increasingly appreciated. However, presence and function DAMP-mediated effects on T cells, whether they can be targeted to mitigate cell-dependent immunopathology remain unknown. Sialic acid-binding immunoglobulin-like lectin G (Siglec-G) a regulator in but its cell-autonomous Utilizing loss-of-function-based (genetic knockout)...
Allogeneic hematopoietic cell transplantation (allo-HCT) through its graft-versus-tumor (GVT) effects is a curative therapy against many hematological malignancies. However, GVT linked to harmful graft-versus-host disease (GVHD) after allo-HCT. Both and GVHD require allogeneic T responses, which an energetically costly process that causes oxidative stress. Sirtuin 3 (SIRT3), mitochondrial histone deacetylase (HDAC), plays important role in cellular processes inhibition of reactive oxygen...
Corticosteroids are the first line therapy for acute graft-versus-host disease (GVHD). However, outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack effective treatments. The development therapies SR-GVHD limited by an incomplete understanding its pathophysiology partly because absence clinically relevant animal models SR-GVHD. Here we addressed need model developing both MHC matched multiple minor histocompatibility antigens (miHAs) mismatched and haploidentical murine We...
Abstract Stool contains DNA shed from cells of the gastrointestinal (GI) tract and has great potential as a bio-specimen for non-invasive, nucleic acid-based detection GI diseases. Whereas methods studying faecal microbiome are plentiful, there is lack well-characterised procedures stabilisation, isolation, quantitative analysis host DNA. We report an optimised pipeline point-of-collection to droplet digital PCR (ddPCR) absolute quantification host-specific gene targets. evaluated multiple...
STAT3 is a master transcriptional regulator that plays an important role in the induction of both immune activation and tolerance dendritic cells (DCs). The targets promoting DC are becoming increasingly understood; however, mechanisms underpinning its causing suppression remain largely unknown. To determine functional gene STAT3, we compared genome-wide binding using ChIP sequencing coupled with expression microarrays to STAT3-dependent regulation DCs after histone deacetylase (HDAC)...
The highly conserved SNARE protein SEC22B mediates diverse and critical functions, including phagocytosis, cell growth, autophagy, secretion. However, these characterizations have thus far been limited to in vitro work. Here, we expand our understanding of the role Sec22b plays vivo. We utilized Cre-Lox mice delete three tissue compartments. With a germline deletion Sec22b, observed embryonic death at E8.5. Hematopoietic/endothelial also resulted utero death. Notably, with CD11c-expressing...
Abstract Autophagy is a vital cellular process whose role in T immune cells poorly understood, specifically, its regulation of allo-immunity. Stimulation wild-type vitro and vivo with allo-antigens enhances autophagy. To assess the relevance autophagy to T-cell allo-immunity, we generated T-cell–specific Atg5 knock-out mice. Deficiency ATG5-dependent reduced proliferation increased apoptosis following allo-stimulation. The absence ATG5 allo-stimulated enhanced their ability release effector...
LncRNAs are differentially expressed by allogeneic antigen-stimulated T cells, and Linc00402 regulates cells.
Key Points Unsupervised machine learning analysis of continuous body temperature data revealed early signals aGVHD in allo-HCT mice. Continuous measurement is promising for prediction human patients.
NLRP6 plays a critical role in regulating innate immune responses and preventing dysbiosis of gut normal microbiota. knock out (NLRP6-/-) mice show greater severity mortality inflammatory bowel diseases (IBD). Given its unique functions GI tract cells, we determined GVHD by testing the hypothesis that absence hosts would enhance GVHD. B6 wild type (WT) NLRP6-/- animals were lethally irradiated (11Gy) transplanted with 5x106 BM 3x106 splenic T-cells from either syngeneic WT-B6 or allogeneic...
The mechanisms governing human allogeneic T-cell responses remain incompletely understood which limits the wider clinical application of BMT. Long non-coding RNAs (lncRNA) are an emerging class that control gene expression with tissue and context specificity. However, their role in alloimmunity is unknown. To determine whether lncRNAs regulate T cell we performed RNA-seq donor T-cells from BMT patients received increasing amounts stimulation. Hierarchical clustering differential analysis...
ABSTRACT Mechanisms governing allogeneic T-cell responses after hematopoietic stem cell (HSC) and solid organ transplantation are incompletely understood. Long non-coding RNAs (lncRNA) do not code for, but control gene expression with tissue specificity. However, their role in alloimmunity is unknown. We performed RNA-seq on donor T-cells from HSCT patients found that increasing strength of stimulation caused greater differential lncRNAs. The was validated an independent patient cohort, also...
IAPs have emerged as novel regulators of innate and adaptive immunity. Clinical development IAP inhibition by SMAC mimetics is underway to treat cancers. However, little known about the role distinct IAPs, namely cellular cIAP 1, 2 X-linked (XIAP), in allo-immunity. We used complementary genetic small molecule approaches determine allo-immunity utilizing well-characterized murine models GVHD. Because pan-IAP inhibitor, mimetic AT-406, regulates TNFα, we hypothesized that it will mitigate...
Members of the sialic acid binding Ig–like lectin (Siglec) family have immunoreceptor tyrosine-based inhibitory motifs (ITIM) or ITIM-like regions in their intracellular domain that negatively regulates damage associated molecular patterns (DAMPs) mediated inflammatory responses. Our previous data suggested Siglec-G-CD24 axis host antigen presenting cells (APCs) plays an important role regulating GVHD. However, T cell autonomous Siglec-G allogeneic responses is not known. In order to examine...
ATG5 is a key protein that regulates autophagy, vital cellular process whose role in immune cells poorly understood. Disruption of autophagy dendritic (DCs) has been reported to cause an increase graft-vs-host disease (GVHD), but its regulating T cell allo-reactivity after bone marrow transplant (BMT) unknown. We first studied the autophagosome marker LC3 unspecific TCR stimulation WT-B6 and demonstrated level that, interestingly, was predominant dividing cells. Next, confirm essential for...