A5038273067- CAR-T cell therapy research
- Multiple Myeloma Research and Treatments
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- T-cell and B-cell Immunology
- Viral Infectious Diseases and Gene Expression in Insects
- Virus-based gene therapy research
- Chronic Lymphocytic Leukemia Research
- Immunodeficiency and Autoimmune Disorders
- RNA Interference and Gene Delivery
- Biosimilars and Bioanalytical Methods
- Synthesis and Biological Evaluation
- Peptidase Inhibition and Analysis
- Diabetes and associated disorders
- Insect Resistance and Genetics
- Cell Adhesion Molecules Research
- Cutaneous lymphoproliferative disorders research
- Protein Degradation and Inhibitors
- Galectins and Cancer Biology
- Pancreatic function and diabetes
- HIV Research and Treatment
- Genetic and phenotypic traits in livestock
- Single-cell and spatial transcriptomics
Lyell Immunopharma (United States)
2019-2022
Editas Medicine (United States)
2019
Seattle Children's Hospital
2009-2016
University of Washington
2001-2013
Benaroya Research Institute
2006-2010
Virginia Mason Medical Center
2007
Seattle University
2006
Norwegian University of Science and Technology
2004
CD4+Foxp3+ regulatory T cells (T reg) are essential for maintaining self-tolerance, but their functional mechanisms and sites of action in vivo poorly defined. We examined the homing receptor expression tissue distribution reg steady state determined whether altering by removal a single chemokine impairs ability to maintain tissue-specific peripheral tolerance. found that distributed throughout all nonlymphoid tissues tested, particularly prevalent skin, where they express unique...
Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B maturation (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification additional targets. The orphan G protein-coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as by mRNA marrow aspirates from patients MM,...
Therapeutic coding sequences can be targeted to the CCR5 locus of primary human T cells with high efficiency by using megaTAL nuclease and an AAV donor template.
Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxical observations. While WASp-deficient (WASp(-/-)) mice exhibited normal thymic generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage forkhead box P3-positive (Foxp3(+)) among...
Patients with the immunodeficiency Wiskott-Aldrich syndrome (WAS) frequently develop systemic autoimmunity. Here, we demonstrate that mutation of WAS gene results in B cells are hyperresponsive to cell receptor and Toll-like (TLR) signals vitro, thereby promoting a cell–intrinsic break tolerance. Whereas this defect leads autoantibody production protein–deficient (WASp−/−) mice without overt disease, chimeric which only lineage lacks WASp exhibit severe autoimmunity characterized by...
Abstract Anti–B-cell maturation antigen (BCMA) chimeric receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine anti-BCMA CAR to enhance function. Using T, we demonstrated that lenalidomide enhances function a concentration-dependent manner....
CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle generating responses tumor-associated antigens. We have made a receptor (TCR) transgenic mouse specific for tumor antigen and crossed TCR-TG mice expressing the in hepatocytes (gag-TG). TCRxgag showed no signs of despite persistence high avidity cells periphery. Peripheral expressed phenotypic markers consistent with encounter vivo had upregulated antiapoptotic molecule Bcl-2. failed proliferate response...
Abstract Clearance of solid tumors by Chimeric Antigen Receptor (CAR) T cells demands greater antitumor potency and persistence than liquid tumors. Using CRISPR/Cas9 library screens we have shown that targeted deletion the Mediator complex subunit 12 (MED12) in human primary CAR boosts their potency, cytokine secretion proliferation (Freitas, Science 2022). Translation CRISPR/Cas9-based enhancements to clinic requires thorough validation extensive analysis specificity genomic integrity over...
Sustained, targeted, high-level transgene expression in primary B lymphocytes may be useful for gene therapy cell disorders. We developed several candidate B-lineage predominant self-inactivating lentiviral vectors (LV) containing alternative enhancer/promoter elements including: the immunoglobulin β (Igβ) (B29) promoter combined with µ enhancer (EµB29); and endogenous BTK or without Eµ (EµBtkp Btkp). LV-driven enhanced green fluorescent protein (eGFP) reporter was evaluated lines cells...
Abstract The pathogenesis of multiple sclerosis involves a breakdown in T cell tolerance to myelin proteins like basic protein (MBP). Most MBP-specific cells are eliminated by central adult mice, however, the developmentally regulated expression MBP allows thymocytes young mice escape negative selection. It is not known how these that encounter for first time periphery regulated. We show naive transferred into cell-deficient induce severe autoimmunity. Regulatory prevent disease, suppression...
A naturally occurring 32-base pair deletion of the HIV-1 co-receptor CCR5 has demonstrated protection against HIV infection human CD4+ T cells. Recent genetic engineering approaches using engineered nucleases to disrupt gene and mimic this mutation show promise for therapy. We developed a megaTAL nuclease targeting third extracellular loop that we delivered primary cells by mRNA transfection. The established resistance in cell lines disrupted expression on with high efficiency, achieving up...
Abstract Type 1 diabetes (T1D) results from the immune-mediated destruction of insulin-producing β-islet cells in pancreas. The genetic and environmental mechanisms promoting development this disease remain poorly understood. We have explored cellular requirements for T1D DO11.10xRIPmOVA (DORmO) mice, which carry a TCR transgene specific an MHC class II-restricted epitope OVA express membrane-bound pancreas under control rat insulin promoter. found that DORmO.RAG2−/− mice do not develop...