scholarly journals Surmounting limited gene delivery into primary immune cell populations: Efficient cell type-specific adenoviral transduction by CAR

2015 ◽  
Vol 45 (6) ◽  
pp. 1596-1599 ◽  
Author(s):  
Björn E. Clausen ◽  
Anna Brand ◽  
Khalad Karram
Keyword(s):  
Gene Delivery ◽  
Immune Cell ◽  
Cell Populations ◽  
Cell Type ◽  
Cell Type Specific ◽  
Adenoviral Transduction

scholarly journals Germline deletion of CIN85 in humans with X chromosome–linked antibody deficiency

2018 ◽  
Vol 215 (5) ◽  
pp. 1327-1336 ◽  
Author(s):  
Baerbel Keller ◽  
Moneef Shoukier ◽  
Kathrin Schulz ◽  
Arshiya Bhatt ◽  
Ines Heine ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
X Chromosome ◽  
Immune Cell ◽  
Antibody Deficiency ◽  
Limited Information ◽  
Cell Type ◽  
Interacting Protein ◽  
Mouse Mutants ◽  
Cell Type Specific

Ubiquitously expressed Cbl-interacting protein of 85 kD (CIN85) is a multifunctional adapter molecule supposed to regulate numerous cellular processes that are critical for housekeeping as well as cell type–specific functions. However, limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type–specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans. Here, we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome. In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface. These results reveal nonredundant functions of CIN85 for humoral immune responses.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals Autocrine, Not Paracrine, Interferon-Gamma Gene Delivery Enhances Ex Vivo Antigen-Specific Cytotoxic T Lymphocyte Stimulation and Killing

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Dazhi Zhang ◽  
Yong Liu ◽  
Min Shi ◽  
Chang Xuan You ◽  
Maohua Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Delivery ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Ex Vivo ◽  
Cell Populations ◽  
Adeno Associated Virus ◽  
Th1 Response ◽  
Compare And Contrast

The adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTL) shows promise in the treatment of cancer and infectious diseases. We utilize adeno-associated virus-(AAV-) based antigen gene-loaded dendritic cells (DCs) to stimulate such antigen-specific CTL. Yet further improvements in CTL stimulation and killing may result by gene delivery of various Th1-response interferons/cytokines, such as interferonγ(IFN-γ), as the delivered gene can continuously produce that interferon. However which immune cell type should optimally express IFN-γis unclear as the phenotypes of both DC and T cells are enhanced by it. Here, we used AAV to compare and contrast IFN-γgene delivery into DC or T cells, and versus the addition of exogenous IFN-γ, for stimulating carcinoembryonic antigen-(CEA-) specific CTL. It was found that AAV/IFN-γdelivery into T cells (autocrine) resulted in T cell populations with the highest CD8(+)/CD4(+) ratio, highest IFN-γ(+)/IL-4(+) ratio, highest CD69(+),CD8(+) levels, and lowest CD4(+)/CD25(+) levels, all consistent with the strongest Th1 response. Most importantly, AAV/IFN-γtransduction of T cells resulted in antigen-specific T cell populations with the highest killing capabilities, 49% above other treatments. These data strongly suggest that AAV/IFN-γautocrine gene delivery into T cells is worthy of further study towards maximizing the generation of antigen-specific anticancer CTL killers.

scholarly journals COMP-16. COMPREHENSIVE TRANSCRIPTOMIC ANALYSIS OF SINGLE CELLS FROM RECURRENT AND PRIMARY GLIOBLASTOMA TO PREDICT CELL-TYPE SPECIFIC THERAPEUTICS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Robert Suter ◽  
Vasileios Stathias ◽  
Anna Jermakowicz ◽  
Alexa Semonche ◽  
Michael Ivan ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Tumor Heterogeneity ◽  
Drug Response ◽  
Adult Brain ◽  
Cell Populations ◽  
Cell Type ◽  
Single Cell Rna Sequencing ◽  
Cell Type Specific ◽  
Recurrent Gbm

Abstract Glioblastoma (GBM) remains the most common adult brain tumor, with poor survival expectations, and no new therapeutic modalities approved in the last decade. Our laboratories have recently demonstrated that the integration of a transcriptional disease signature obtained from The Cancer Genome Atlas’ GBM dataset with transcriptional cell drug-response signatures in the LINCS L1000 dataset yields possible combinatorial therapeutics. Considering the extreme intra-tumor heterogeneity associated with the disease, we hypothesize that the utilization of single-cell RNA-sequencing (scRNA-seq) of patient tumors will further strengthen our predictive model by providing insight on the unique transcriptomes of the cellular niches present within these tumors, and into the transcriptional dynamics of these same cellular niches. By sequencing single-cell transcriptomes from recurrent GBM tumors resected from patients at the University of Miami, and integrating our datasets with previously published scRNA-seq data from primary GBM tumors, we are able to gain additional insight into the differences between these clinical distinctions. We have analyzed the differential expression of kinases both across and within distinct cell populations of primary and recurrent GBM tumors. This transcriptional map of kinase expression represents the heterogeneity of potential targets within individual tumors and between recurrent and primary GBM. Additionally, by generating disease signatures unique to each cellular population, and integrating these with transcriptional drug-response signatures from LINCS, we are able to predict compounds to target specific cell populations within GMB tumors. Additional computational techniques such as RNA velocity analysis and cell cycle scoring elucidate temporal insights to further prioritize these cell-type specific therapeutics, and reveal the intra-cellular dynamics present within these tumors. Collectively, our studies suggest that we have developed a novel omics pipeline based on the single cell RNA-sequencing of individual GBM cells that addresses intra-tumor heterogeneity, and may lead to novel therapeutic combinations for the treatment of this incurable disease.

scholarly journals Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Victor Farutin ◽  
Thomas Prod’homme ◽  
Kevin McConnell ◽  
Nathaniel Washburn ◽  
Patrick Halvey ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cell ◽  
Clinical Laboratory ◽  
Cell Types ◽  
Molecular Profiling ◽  
Response To Treatment ◽  
Cell Type ◽  
Inflammatory Conditions ◽  
Cell Type Specific ◽  
High Level

Abstract Background The goal of this study is to use comprehensive molecular profiling to characterize clinical response to anti-TNF therapy in a real-world setting and identify reproducible markers differentiating good responders and non-responders in rheumatoid arthritis (RA). Methods Whole-blood mRNA, plasma proteins, and glycopeptides were measured in two cohorts of biologic-naïve RA patients (n = 40 and n = 36) from the Corrona CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) registry at baseline and after 3 months of anti-TNF treatment. Response to treatment was categorized by EULAR criteria. A cell type-specific data analysis was conducted to evaluate the involvement of the most common immune cell sub-populations. Findings concordant between the two cohorts were further assessed for reproducibility using selected NCBI-GEO datasets and clinical laboratory measurements available in the CERTAIN database. Results A treatment-related signature suggesting a reduction in neutrophils, independent of the status of response, was indicated by a high level of correlation (ρ = 0.62; p < 0.01) between the two cohorts. A baseline, response signature of increased innate cell types in responders compared to increased adaptive cell types in non-responders was identified in both cohorts. This result was further assessed by applying the cell type-specific analysis to five other publicly available RA datasets. Evaluation of the neutrophil-to-lymphocyte ratio at baseline in the remaining patients (n = 1962) from the CERTAIN database confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03–1.41, p = 0.02]). Conclusion Differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

scholarly journals Cell-Type Specific Expression of the Vasopressin Gene Analyzed by AAV Mediated Gene Delivery of Promoter Deletion Constructs into the Rat SON In Vivo

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e48860 ◽  
Author(s):  
Todd A. Ponzio ◽  
Raymond L. Fields ◽  
Omar M. Rashid ◽  
Yasmmyn D. Salinas ◽  
Daniel Lubelski ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Cell Type ◽  
Specific Expression ◽  
Promoter Deletion ◽  
Cell Type Specific Expression ◽  
Cell Type Specific ◽  
Vasopressin Gene

scholarly journals Bioinformatics Approaches to Profile the Tumor Microenvironment for Immunotherapeutic Discovery

2017 ◽  
Vol 23 (32) ◽  
pp. 4716-4725 ◽  
Author(s):  
Trevor Clancy ◽  
Ruth Dannenfelser ◽  
Olga Troyanskaya ◽  
Karl Johan Malmberg ◽  
Eivind Hovig ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
Cell Types ◽  
Specific Information ◽  
Cell Type ◽  
Signaling Systems ◽  
Important Challenge ◽  
Cell Type Specific ◽  
Tissue Systems ◽  
Heterogeneous Tumor

In the microenvironment of a malignancy, tumor cells do not exist in isolation, but rather in a diverse ecosystem consisting not only of heterogeneous tumor-cell clones, but also normal cell types such as fibroblasts, vasculature, and an extensive pool of immune cells at numerous possible stages of activation and differentiation. This results in a complex interplay of diverse cellular signaling systems, where the immune cell component is now established to influence cancer progression and therapeutic response. It is experimentally difficult and laborious to comprehensively and systematically profile these distinct cell types from heterogeneous tumor samples in order to capitalize on potential therapeutic and biomarker discoveries. One emerging solution to address this challenge is to computationally extract cell-type specific information directly from bulk tumors. Such in silico approaches are advantageous because they can capture both the cell-type specific profiles and the tissue systems level of cell-cell interactions. Accurately and comprehensively predicting these patterns in tumors is an important challenge to overcome, not least given the success of immunotherapeutic drug treatment of several human cancers. This is especially challenging for subsets of closely related immune cell phenotypes with relatively small gene expression differences, which have critical functional distinctions. Here, we outline the existing and emerging novel bioinformatics strategies that can be used to profile the tumor immune landscape.

Targeted delivery of Chil3/Chil4 siRNA to alveolar macrophages using ternary complexes composed of HMG and oligoarginine micelles

Nanoscale ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 933-943 ◽  
Author(s):  
Moonhwan Choi ◽  
Haeyoon Jeong ◽  
Sol Kim ◽  
Minkyung Kim ◽  
Minhyung Lee ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Delivery System ◽  
Alveolar Macrophages ◽  
Targeted Delivery ◽  
Ternary Complexes ◽  
Specific Gene ◽  
Gene Delivery System ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

Cell-type-specific genes involved in disease can be effective therapeutic targets; therefore, the development of a cell-type-specific gene delivery system is essential.

Monoclonal antibody–polyethyleneimine conjugates targeting Her-2/neu or CD90 allow cell type-specific nonviral gene delivery

2005 ◽  
Vol 102 (3) ◽  
pp. 737-747 ◽  
Author(s):  
Claudia Strehblow ◽  
Maj Schuster ◽  
Thomas Moritz ◽  
Hans-Christoph Kirch ◽  
Bertram Opalka ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Gene Delivery ◽  
Nonviral Gene Delivery ◽  
Cell Type ◽  
Cell Type Specific ◽  
Her 2
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