A5026884093- Immune Cell Function and Interaction
- Adenosine and Purinergic Signaling
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Virus-based gene therapy research
- Global Cancer Incidence and Screening
- Herpesvirus Infections and Treatments
- Adolescent and Pediatric Healthcare
- Cell Adhesion Molecules Research
- Cancer Risks and Factors
- RNA Interference and Gene Delivery
- Cancer Immunotherapy and Biomarkers
- Protease and Inhibitor Mechanisms
- Nanoplatforms for cancer theranostics
- Cytokine Signaling Pathways and Interactions
- CRISPR and Genetic Engineering
- Pneumocystis jirovecii pneumonia detection and treatment
- Immune cells in cancer
- Cancer Mechanisms and Therapy
- Epigenetics and DNA Methylation
- Reproductive System and Pregnancy
- Quinazolinone synthesis and applications
- T-cell and Retrovirus Studies
- Macrophage Migration Inhibitory Factor
Washington University in St. Louis
2011-2022
Amgen (United States)
2006-2018
Seattle University
2006-2013
Alvin J. Siteman Cancer Center
2009
Jewish Hospital
2009
Barnes-Jewish Hospital
2009
Saint Louis University
2007
University of Washington
2000-2006
Howard Hughes Medical Institute
2000-2002
National Institutes of Health
2002
A cytokine was identified that stimulated the proliferation of T lymphocytes, and a complementary DNA clone encoding this new cell growth factor isolated. The cytokine, designated interleukin-15 (IL-15), is produced by wide variety cells tissues shares many biological properties with IL-2. Monoclonal antibodies to beta chain IL-2 receptor inhibited activity IL-15, IL-15 competed for binding IL-2, indicating uses components receptor.
We explored the mechanism of action CD39 antibodies that inhibit ectoenzyme conversion extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic humanized tumor models, we contrast potency anti-CD39 mAbs with other agents targeting adenosinergic pathway. demonstrate critical importance an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in antitumor activity mediated by enzyme blockade, rather than simply reducing adenosine as...
Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using murine version virus, we characterized local and systemic antitumor immune responses driving efficacy in syngeneic models.Experimental Design: The activity talimogene laherparepvec was against melanoma cell lines using an vitro viability assay. Efficacy OncoVEXmGM-CSF (talimogene with mouse granulocyte-macrophage colony-stimulating factor transgene) alone or...
Abstract The enzymes that degrade proteins to peptides for presentation on MHC class II molecules are poorly understood. cysteinal lysosomal proteases, cathepsin L (CL) and S (CS), have been shown process invariant chain, thereby facilitating maturation. However, their role in Ag processing is not established. To examine this issue, we generated embryonic fibroblast lines express CL, CS, or neither. Expression of CL CS mediates efficient degradation chain as expected. was evaluated using T...
Abstract We report the development of Translational Science Benefits Model (TSBM), a framework designed to support institutional assessment clinical and translational research outcomes measure community health impacts beyond bibliometric measures. The TSBM includes 30 specific potentially measurable indicators that reflect benefits accrue from science such as products, system characteristics, or activities. Development was based on literature review, modified Delphi method, in‐house expert...
<h3>Background</h3> This open-label, first-in-human, phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and maximum tolerated dose (MTD) of AMG 228, an agonistic human IgG1 monoclonal antibody targeting glucocorticoid-induced tumor necrosis factor receptor−related protein (GITR), in patients with refractory advanced solid tumors. <h3>Methods</h3> 228 was administered intravenously every 3 weeks (Q3W). Dose escalation two stages: single-patient cohorts (3, 9, 30,...
Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits mouse ectoenzyme CD39...
Abstract Fas ligand (FasL/CD95L/APO-1L) is one of a growing number TNF family members whose triggering costimulates maximal proliferation activated T cells. In this study we show that Ag-dependent accumulation transferred TCR-transgenic CD8+ cells requires (CD95/APO-1) expression by the adoptive hosts. Additionally, adoptively FasL+ demonstrate 2-fold advantage in Ag-driven expansion over their FasL−counterparts. This illustrates vivo role TCR-dependent FasL costimulation Ag-specific both...
Interleukin (IL)-15 is a multifunctional cytokine that shares many biological activities with IL-2. This functional overlap, as well receptor binding subunits shared by IL-15 and IL-2, suggests tertiary structural similarities between these two cytokines. In this study, recombinant human was PEGylated via lysine-specific conjugation chemistry in order to extend the circulation half-life of cytokine. Although PEGylation did β-elimination greater than 50-fold, activity polyethylene glycol...
Abstract Epithelial cells at environmental interfaces provide protection from potentially harmful agents, including pathogens. In addition to serving as a physical barrier and producing soluble mediators of immunity, such cytokines or antimicrobial peptides, these are thought function nonprofessional APCs. this regard, intestinal epithelial particularly prominent because they express MHC class II molecules the site massive antigenic exposure. However, unlike bone marrow-derived professional...
Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (Mϕs) are unique that they express both proteases here we sought to determine the relative contribution each enzyme. We observe catL plays no significant role Ii cleavage interferon (IFN)-γ–stimulated Mϕs. In addition, our studies show level activity is significantly decreased Mϕs cultured presence IFN-γ whereas catS increases. The decrease...
We examine the cellular and soluble determinants of coronavirus disease 2019 (COVID-19) relative to aging by performing mass cytometry in parallel with clinical blood testing plasma proteomic profiling ~4,700 proteins from 71 individuals pulmonary 148 healthy donors (25–80 years old). Distinct cell populations were associated age (GZMK+CD8+ T cells CD25low CD4+ cells) COVID-19 (TBET−EOMES− cells, HLA-DR+CD38+ CD8+ CD27+CD38+ B cells). A unique population TBET+EOMES+ was who experienced...
The extracellular ATP/adenosine axis in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), otherwise known CD39, is highly expressed TME, both on infiltrating immune cells and across a broad set of cancer indications. CD39 processes pro-inflammatory ATP to ADP AMP, which then processed by Ecto-5ʹ-nucleotidase/CD73 immunosuppressive adenosine. Directly inhibiting enzymatic function via antibody...
Abstract Thymocyte development is a tightly regulated process. CD4+CD8+ double-positive (DP) immature thymocytes exhibit distinct phenotypic features from mature T cells; they express only 10% of surface TCR that are found on cells and do not proliferate produce IL-2 in response to stimulation. In this report we show transgenic expression the orphan nuclear receptor RORγt down-regulates their expression. The transgene inhibits production by cells, inhibition may be partially due inhibitory...
Loading of antigenic peptide fragments on major histocompatibility complex class II molecules is essential for generation CD4+ T cell responses and occurs after cathepsin-mediated degradation the invariant chain chaperone molecule. Cathepsins are expressed differentially in antigen presenting cells, mice deficient cathepsin S or L exhibit severely impaired presentation peripheral lymphoid organs thymus, respectively. To determine whether these defects due solely to block cleavage, we used...
The Joanne Knight Breast Health Cohort was established to link breast cancer risk factors, mammographic density, benign biopsies and associated tissue markers, blood markers in a diverse population of women undergoing routine screening study factors validate models for prediction.
If T cells require specific interactions with MHC-bound peptides during positive selection, then the specificities of selected by one peptide should be distinct from those another. We have examined selection CD4 in four strains mice, each overexpressing a different peptide–1-A b (A ) complex. show that subset is overexpressed and cells, as measured reactivity to wild-type antigen-presenting vary greatly depending on which overexpressed. These differences specificity are mediated through not...
Abstract The ATP/Adenosine pathway in the tumor microenvironment (TME) has emerged as an important immune-regulatory pathway. ATPase CD39 is highly expressed TME, both on infiltrating immune cells and across a broad set of cancer indications. processes pro-inflammatory extracellular ATP to ADP AMP, which then processed by CD73, immunosuppressive adenosine. Inhibiting enzymatic function potential shift milieu TME 2-pronged fashion: 1) Enhancement immunostimulatory released damaged and/or...