15 results on '"Moffett, Howell F."'
Search Results
2. Not miR-ly small RNAs: Big potential for microRNAs in therapy
- Author
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Love, Tara M., Moffett, Howell F., and Novina, Carl D.
- Published
- 2008
3. B cells engineered to express pathogen-specific antibodies protect against infection.
- Author
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Moffett, Howell F., Harms, Carson K., Fitzpatrick, Kristin S., Tooley, Marti R., Boonyaratanakornkit, Jim, and Taylor, Justin J.
- Abstract
Effective vaccines inducing lifelong protection against many important infections such as respiratory syncytial virus (RSV), HIV, influenza virus, and Epstein-Barr virus (EBV) are not yet available despite decades of research. As an alternative to a protective vaccine, we developed a genetic engineering strategy in which CRISPR-Cas9 was used to replace endogenously encoded antibodies with antibodies targeting RSV, HIV, influenza virus, or EBV in primary human B cells. The engineered antibodies were expressed efficiently in primary B cells under the control of endogenous regulatory elements, which maintained normal antibody expression and secretion. Using engineered mouse B cells, we demonstrated that a single transfer of B cells engineered to express an antibody against RSV resulted in potent and durable protection against RSV infection in RAG1-deficient mice. This approach offers the opportunity to achieve sterilizing immunity against pathogens for which traditional vaccination has failed to induce or maintain protective antibody responses. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
4. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors.
- Author
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Smith, Tyrel T., Moffett, Howell F., Stephan, Sirkka B., Opel, Cary F., Dumigan, Amy G., Xiuyun Jiang, Pillarisetty, Venu G., Pillai, Smitha P. S., Wittrup, K. Dane, Stephan, Matthias T., and Jiang, Xiuyun
- Subjects
- *
BIOPOLYMERS , *T cells , *CHIMERIC antigen receptors , *IMMUNE system , *CYCLIC nucleotides - Abstract
Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting. Here, we have tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors, thereby exposing them to high concentrations of immune cells for a substantial time period. In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells. We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes. Thus, these devices may improve the effectiveness of CAR T cell therapy in solid tumors and help protect against the emergence of escape variants. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
5. MicroRNA Expression Profiling Identifies Activated B Cell Status in Chronic Lymphocytic Leukemia Cells.
- Author
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Shuqiang Li, Moffett, Howell F., Jun Lu, Werner, Lillian, Hao Zhang, Ritz, Jerome, Neuberg, Donna, Wucherpfennig, Kai W., Brown, Jennifer R., and Novina, Carl D.
- Subjects
- *
CHRONIC lymphocytic leukemia , *LEUCOCYTOSIS , *CHRONIC diseases , *LYMPHOCYTES , *PRELEUKEMIA - Abstract
Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70+ and IgVH unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
6. Beyond Help: Direct Effector Functions of Human Immunodeficiency Virus Type 1-Specific CD4+ T Cells.
- Author
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Norris, Philip J., Moffett, Howell F., Yang, Otto O., Kaufmann, Daniel E., Clark, Margaret J., Addo, Marylyn M., and Rosenberg, Eric S.
- Subjects
- *
HIV , *CD4 antigen , *T cells , *VIRAL replication , *ANTIVIRAL agents , *ANTIGENS - Abstract
The immune correlates of protection in human immunodeficiency virus type 1 (HIV-1) infection remain poorly defined, particularly the contribution of CD4+ T cells. Here we explore the effector functions of HIV-1-specific CD4 T cells. We demonstrate HIV-1 p24-specific CD4 -T-cell cytolytic activity in peripheral blood mononuclear cells directly ex vivo and after enrichment by antigen-specific stimulation. We further show that in a rare long-term nonprogressor, both an HIV-1-specific CD4+ T-cell clone and CD4+ T cells directly ex vivo exert potent suppression of HIV-1 replication. Suppression of viral replication was dependent on cell-cell contact between the effector CD4+ T cells and the target cells. While the antiviral effector activity of CD8+ T cells has been well documented, these results strongly suggest that HIV-1-specific CD4+ T cells are capable of directly contributing to antiviral immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
7. Safety switch optimization enhances antibody-mediated elimination of CAR T cells.
- Author
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Shabaneh TB, Moffett HF, Stull SM, Derezes T, Tait LJ, Park S, Riddell SR, and Lajoie MJ
- Abstract
Activation of a conditional safety switch has the potential to reverse serious toxicities arising from the administration of engineered cellular therapies, including chimeric antigen receptor (CAR) T cells. The functionally inert, non-immunogenic cell surface marker derived from human epidermal growth factor receptor (EGFRt) is a promising safety switch that has been used in multiple clinical constructs and can be targeted by cetuximab, a clinically available monoclonal antibody. However, this approach requires high and persistent cell surface expression of EGFRt to ensure that antibody-mediated depletion of engineered cells is rapid and complete. Here we show that incorporating a short juxtamembrane sequence into the EGFRt polypeptide enhances its expression on the surface of T cells and their susceptibility to antibody-dependent cellular cytotoxicity (ADCC). Incorporating this optimized variant (EGFRopt) into bicistronic and tricistronic CAR designs results in more rapid in vivo elimination of CAR T cells and robust termination of their effector activity compared to EGFRt. These studies establish EGFRopt as a superior safety switch for the development of next-generation cell-based therapeutics., Competing Interests: SR is a co-founder of Lyell Immunopharma, Inc. and has received grant funding from Lyell Immunopharma,Inc. SR was a cofounder Juno Therapeutics, a Bristol Myers Squibb company and has served as a scientific advisor to Juno Therapeutics and Adaptive Biotechnologies. SP is an employee of Lyell Immunopharma, Inc. ML is a co-founder of Lyell Immunopharma, Inc., and Outpace Bio. HM andML are listed as inventors on patent applications related to this work.HM, LT, andMLare employees of Outpace Bio, a licensee of patent rights owned by Lyell Immunopharma, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shabaneh, Moffett, Stull, Derezes, Tait, Park, Riddell and Lajoie.)
- Published
- 2022
- Full Text
- View/download PDF
8. Erratum: The microRNA miR-31 inhibits CD8 + T cell function in chronic viral infection.
- Author
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Moffett HF, Cartwright ANR, Kim HJ, Godec J, Pyrdol J, Äijö T, Martinez GJ, Rao A, Lu J, Golub TR, Cantor H, Sharpe AH, Novina CD, and Wucherpfennig KW
- Published
- 2017
- Full Text
- View/download PDF
9. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers.
- Author
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Smith TT, Stephan SB, Moffett HF, McKnight LE, Ji W, Reiman D, Bonagofski E, Wohlfahrt ME, Pillai SPS, and Stephan MT
- Subjects
- Animals, Cell Line, Tumor, Immunity, Cellular genetics, Leukemia genetics, Leukemia immunology, Leukemia pathology, Mice, DNA chemistry, Drug Carriers chemistry, Drug Carriers pharmacology, Gene Transfer Techniques, Immunity, Cellular drug effects, Leukemia therapy, Nanoparticles chemistry, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology, T-Lymphocytes immunology
- Abstract
An emerging approach for treating cancer involves programming patient-derived T cells with genes encoding disease-specific chimeric antigen receptors (CARs), so that they can combat tumour cells once they are reinfused. Although trials of this therapy have produced impressive results, the in vitro methods they require to generate large numbers of tumour-specific T cells are too elaborate for widespread application to treat cancer patients. Here, we describe a method to quickly program circulating T cells with tumour-recognizing capabilities, thus avoiding these complications. Specifically, we demonstrate that DNA-carrying nanoparticles can efficiently introduce leukaemia-targeting CAR genes into T-cell nuclei, thereby bringing about long-term disease remission. These polymer nanoparticles are easy to manufacture in a stable form, which simplifies storage and reduces cost. Our technology may therefore provide a practical, broadly applicable treatment that can generate anti-tumour immunity 'on demand' for oncologists in a variety of settings.
- Published
- 2017
- Full Text
- View/download PDF
10. The microRNA miR-31 inhibits CD8 + T cell function in chronic viral infection.
- Author
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Moffett HF, Cartwright ANR, Kim HJ, Godec J, Pyrdol J, Äijö T, Martinez GJ, Rao A, Lu J, Golub TR, Cantor H, Sharpe AH, Novina CD, and Wucherpfennig KW
- Subjects
- Animals, Antibodies, Viral immunology, Arenaviridae Infections genetics, CD8-Positive T-Lymphocytes drug effects, Calcium metabolism, Chromatin Immunoprecipitation, Dendritic Cells immunology, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression Profiling, Immunoblotting, Interferon Type I pharmacology, Lymphocytic choriomeningitis virus immunology, Mice, Mice, Knockout, MicroRNAs genetics, NFATC Transcription Factors metabolism, Real-Time Polymerase Chain Reaction, Arenaviridae Infections immunology, CD8-Positive T-Lymphocytes immunology, Cytokines immunology, MicroRNAs immunology, Receptors, Antigen, T-Cell immunology
- Abstract
During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8
+ T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection.- Published
- 2017
- Full Text
- View/download PDF
11. MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells.
- Author
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Li S, Moffett HF, Lu J, Werner L, Zhang H, Ritz J, Neuberg D, Wucherpfennig KW, Brown JR, and Novina CD
- Subjects
- B-Lymphocytes pathology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell therapy, MicroRNAs metabolism, Phenotype, Reproducibility of Results, Time Factors, B-Lymphocytes immunology, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocyte Activation genetics, MicroRNAs genetics
- Abstract
Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70(+) and IgV(H) unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL.
- Published
- 2011
- Full Text
- View/download PDF
12. A small RNA makes a Bic difference.
- Author
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Moffett HF and Novina CD
- Subjects
- Animals, Mice, Mice, Knockout, Gene Expression Regulation, Immunity genetics, MicroRNAs genetics
- Abstract
The first highly specific knockouts of a microRNA, miR155, in mice result in multiple defects in adaptive immunity, and also show the feasibility of investigating at least some microRNAs by gene knockout.
- Published
- 2007
- Full Text
- View/download PDF
13. Beyond help: direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells.
- Author
-
Norris PJ, Moffett HF, Yang OO, Kaufmann DE, Clark MJ, Addo MM, and Rosenberg ES
- Subjects
- CD4-Positive T-Lymphocytes virology, Cytotoxicity, Immunologic, HIV Core Protein p24 immunology, Humans, Leukocytes, Mononuclear immunology, Virus Replication immunology, CD4-Positive T-Lymphocytes immunology, HIV-1 immunology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Regulatory immunology
- Abstract
The immune correlates of protection in human immunodeficiency virus type 1 (HIV-1) infection remain poorly defined, particularly the contribution of CD4(+) T cells. Here we explore the effector functions of HIV-1-specific CD4(+) T cells. We demonstrate HIV-1 p24-specific CD4(+)-T-cell cytolytic activity in peripheral blood mononuclear cells directly ex vivo and after enrichment by antigen-specific stimulation. We further show that in a rare long-term nonprogressor, both an HIV-1-specific CD4(+)-T-cell clone and CD4(+) T cells directly ex vivo exert potent suppression of HIV-1 replication. Suppression of viral replication was dependent on cell-cell contact between the effector CD4(+) T cells and the target cells. While the antiviral effector activity of CD8(+) T cells has been well documented, these results strongly suggest that HIV-1-specific CD4(+) T cells are capable of directly contributing to antiviral immunity.
- Published
- 2004
- Full Text
- View/download PDF
14. Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II.
- Author
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SenGupta D, Norris PJ, Suscovich TJ, Hassan-Zahraee M, Moffett HF, Trocha A, Draenert R, Goulder PJ, Binder RJ, Levey DL, Walker BD, Srivastava PK, and Brander C
- Subjects
- AIDS Vaccines immunology, Amino Acid Sequence, Antigens, CD analysis, B-Lymphocytes immunology, Brefeldin A pharmacology, CD8-Positive T-Lymphocytes immunology, Cell Line, Transformed, Dendritic Cells immunology, Epitopes, B-Lymphocyte chemistry, Epitopes, B-Lymphocyte immunology, Epitopes, T-Lymphocyte chemistry, Epitopes, T-Lymphocyte immunology, HIV Core Protein p24 chemistry, HLA-B Antigens immunology, HLA-DQ Antigens immunology, Herpesvirus 4, Human, Humans, Low Density Lipoprotein Receptor-Related Protein-1, Molecular Sequence Data, Peptide Fragments chemistry, Antigen Presentation, Antigens, Neoplasm immunology, HIV Antigens immunology, HIV Core Protein p24 immunology, HIV-1 immunology, Histocompatibility Antigens Class I immunology, Histocompatibility Antigens Class II immunology, Peptide Fragments immunology
- Abstract
Strong CD4(+) and CD8(+) T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4(+) and CD8(+) T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p24 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8(+) T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.
- Published
- 2004
- Full Text
- View/download PDF
15. Fine specificity and cross-clade reactivity of HIV type 1 Gag-specific CD4+ T cells.
- Author
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Norris PJ, Moffett HF, Brander C, Allen TM, O'Sullivan KM, Cosimi LA, Kaufmann DE, Walker BD, and Rosenberg ES
- Subjects
- Amino Acid Sequence, Clone Cells, Cross Reactions, Epitopes, T-Lymphocyte chemistry, HIV Core Protein p24 chemistry, HIV Core Protein p24 genetics, HIV Infections immunology, HIV Infections virology, HIV-1 chemistry, HIV-1 genetics, Humans, Interferon-gamma metabolism, Lymphocyte Activation, Molecular Sequence Data, Peptides chemistry, Peptides pharmacology, CD4-Positive T-Lymphocytes immunology, Epitope Mapping, Epitopes, T-Lymphocyte immunology, HIV Core Protein p24 immunology, HIV-1 immunology
- Abstract
Despite growing evidence that HIV-1-specific CD4(+) T helper (Th) cells may play a role in the control of viremia, discrete Th cell epitopes remain poorly defined. Furthermore, it is not known whether Th cell responses generated using vaccines based on clade B virus sequences will elicit immune responses that are effective in regions of the world where non-clade B viruses predominate. To address these issues we isolated CD4(+) T cell clones from individuals with vigorous HIV-1-specific Th cell responses and identified the minimum epitopes recognized. The minimum peptide length required for induction of CD4(+) T cell proliferation, IFN-gamma secretion, and cytolytic activity ranged from 9 to 16 amino acids in the five epitopes studied. Cross-clade recognition of the defined epitopes was examined for variant peptides from clades A, B, C, D, and AE. Over half the variant epitopes (17 of 32) exhibited impaired recognition, defined as less than 50% of the IFN-gamma secretion elicited by B clade consensus sequence. There was no evidence for antagonistic activity mediated by the variant peptides, and despite strong responses there was no escape of autologous virus from Th responses in the epitopes we studied. Abrogated recognition of variant CD4(+) T cell epitopes presents a potential obstacle to vaccine development.
- Published
- 2004
- Full Text
- View/download PDF
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