DR15 DataRelease
Release Date: 09/16/2015
| SDY80: Cellular and molecular characterization of the immune response in healthy NIH employees at baseline and after immunization with the H1N1 or seasonal influenza vaccines | |||||||||||
| Status: | New | ||||||||||
| Description: | The Center for Human Immunology, Autoimmunity, and Inflammatory Diseases proposes this protocol designed to obtain blood from healthy adult subjects (NIH employees) prior to vaccination and then at various time points after receiving the FDA-licensed seasonal and H1N1 influenza vaccine. These samples will be used to perform a comprehensive and detailed analysis of the immune system at baseline and in response to vaccination. To our knowledge, this protocol will be the first study to characterize the human cellular and molecular immune system parameters, or immunome, in a large number of healthy adults (NIH employees). This information may be useful in designing newer, more effective vaccines to prevent the spread of H1N1 influenza. | ||||||||||
| Program/Contract: |
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| DOI: | 10.21430/M3STAI2V6T | ||||||||||
| Subjects: | 64 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY226: Heterosubtypic Influenza infection antagonizes elicitation of immunological reactivity to hemagglutinin | |||||||||
| Status: | New | ||||||||
| Description: | Influenza-specific immunity in humans is unique because there are repeated exposures to viral strains containing genetically conserved epitopes recruiting memory CD4 T cells and novel epitopes stimulating naive CD4 T cells, possibly resulting in competition between memory and naive lymphocytes. In this study, we evaluated the effect of this competition on CD4 T cell and B cell response specificity using a murine model of sequential influenza infection. We found striking and selective decreases in CD4 T cell reactivity to nonconserved hemagglutinin (HA) epitopes following secondary influenza infection. Surprisingly, this shift in CD4 T cell specificity was associated with dramatic decreases in HA-specific Ab. These results suggest that repeated exposure to influenza viruses and vaccines containing conserved internal proteins may have unintended and negative consequences on the ability to induce HA-specific Ab to novel pandemic strains of influenza. These finding could have important implications on pandemic influenza preparedness strategies. | ||||||||
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| DOI: | 10.21430/M3NWMDUZ08 | ||||||||
| Subjects: | 208 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY268: Programming the magnitude and persistence of antibody responses with innate immunity | |||||||
| Status: | New | ||||||
| Description: | NOTE: only data provided here is from Fig. 15-16. Abstract of entire study: Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence suggests that they activate dendritic cells (DCs) via Toll-like receptors (TLRs)1,2. For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed3, activates DCs via multiple TLRs to stimulate pro-inflammatory cytokines4,5. Triggering specific combinations of TLRs in DCs can induce synergistic production of cytokines6, which results in enhanced T cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that programs such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus Toll-like receptor (TLR) ligands 4 + 7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. Consistent with this there was enhanced persistence of germinal centers (GCs), and of plasma cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma cell response, relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated early programming towards B cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells (DCs), as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques. (PubMed ID: 21350488 ) | ||||||
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| DOI: | 10.21430/M3RE95AC35 | ||||||
| Subjects: | 8 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY295: HLA Homozygous Cell Haplotype Sequencing | |||||||
| Status: | New | ||||||
| Description: | Assay development for HLA homozygous cell haplotype sequencing | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SIG93POM | ||||||
| Subjects: | 109 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY420: Immunobiology of Aging | |||||||||||
| Status: | New | ||||||||||
| Description: | Overriding aim: To develop and make available to other investigators a comprehensive immune phenotype and functional database of a cohort of at least 700 normal healthy individuals. The dataset will comprise a cross-sectional analysis of the general population between the ages of 40 and 90+ (representing equal gender and representative ethnic population, and equal distribution by decade of life). The registry will contain demographic data, race/ethnicity, prescribed medications, over the counter medications, vitamins, alternative therapies, physical function questionnaire, alternative contact person, and HIPPA release. Fasting blood will be obtained for immune phenotyping and functional analyses. The immune profile will contain the results of both conventional and novel immune profiling assays to profile immune related phenotypic and functional changes associated with aging (using PBMC subset analysis, cytokines, and activation induced signaling of PBMCs for phosphoepitope and gene expression analyses). Data from these analyses will be useful in identifying biomarkers associated with aging, gender and/or chronic infection as well as correlation with phenotypic and functional aspects of aging such as sarcopenia and disability. The immune profile (as well as normal blood chemistries and demographic data) of these subjects will be made available to serve as the basis for future longitudinal study of change in the immune profile over time in association with the development of co-morbidities associated with aging. The primary deliverable for this proposal will be a unique open access electronic data repository that has phenotypic and functional information in multiple scales (epidemiological, and clinical, and, at the cell and molecular level, of immune phenotype) and genetic and proteomic information (gene and protein expression of resting and activated PBCs) on over 700 healthy individuals at different ages from 40 to 90 years. This resource will enable a systems-based approach to the immunology of aging. | ||||||||||
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| DOI: | 10.21430/M3WHM08QLC | ||||||||||
| Subjects: | 753 | ||||||||||
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| SDY471: Treatment of MS with Copaxone and Albuterol | |||||||
| Status: | New | ||||||
| Description: | MS is a chronic inflammatory disease of the central nervous system characterized by focal T cell and macrophage infiltrates that lead to demyelination and loss of neurologic function. Four therapies are currently approved for the treatment of MS. Three of these are approved for the treatment of patients with the relapsing-remitting (RR) form of MS, in which patients have clinical exacerbations followed by partial or complete recovery of function. These treatments are only modestly effective and are associated with significant toxicity, often causing patients to delay therapy for significant lengths of time. Thus, there is a need to find therapies with low toxicities that can be administered early during the disease course with the potential for arresting the disease. | ||||||
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| DOI: | 10.21430/M3QEDB55A6 | ||||||
| Subjects: | 44 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY473: Lovastatin Therapy in Rheumatoid Arthritis | |||||||
| Status: | New | ||||||
| Description: | This is a double-blind, placebo-controlled, randomized trial determining whether treatment with a statin reduces the serum CRP in subjects with mildly active RA. After obtaining informed consent, subjects will complete a screening visit (visit 0) to determine whether inclusion and exclusion entry criteria are fulfilled. Eligible subjects will return within 7 days for visit 1 to receive study medication (lovastatin 80 mg/day vs. placebo). Under certain circumstances, the dose may be adjusted. Subjects will return for evaluation every 4 weeks for the duration of this 12-week study. In addition, subjects will have a blood sample drawn at Day 14 to assess CPK and transaminase levels for safety monitoring. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M37QDD1EQF | ||||||
| Subjects: | 64 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY474: Vitamin D3 in Systemic Lupus Erythematosus | |||||||
| Status: | New | ||||||
| Description: | This is a double-blind, multi-center, placebo controlled, Phase II study designed to assess biologic effects of 12 weeks of vitamin D3 supplementation on patients with well-controlled stable systemic lupus erythematosus who have low serum levels of 25-OH vitamin D and an IFN alpha signature. | ||||||
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| DOI: | 10.21430/M30T59MPBU | ||||||
| Subjects: | 57 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY644: Effect of Influenza A (H5N1) Vaccine Prepandemic Priming on CD4+ T-Cell Responses | |||||||
| Status: | New | ||||||
| Description: | Previous priming with avian influenza vaccines results in more rapid and more robust neutralizing antibody responses upon revaccination, but the role CD4+ T cells play in this process is not currently known. | ||||||
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| DOI: | 10.21430/M3T5PSBA22 | ||||||
| Subjects: | 94 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY646: Repeated In Vivo Stimulation of T and B Cell Responses | |||||||
| Status: | New | ||||||
| Description: | Older adults exhibit higher morbidity and mortality from infectious diseases compared with those of the general population. The | ||||||
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| DOI: | 10.21430/M30LVXYFB2 | ||||||
| Subjects: | 8 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY647: Age-associated alterations in CD8a+ dendritic cells impair CD8 | |||||||
| Status: | New | ||||||
| Description: | Age-associated decline in immunity to infection has been documented | ||||||
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| DOI: | 10.21430/M3J0S60RL6 | ||||||
| Subjects: | 6 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY649: Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. | |||||||
| Status: | New | ||||||
| Description: | Naive T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ? 70% of Ag-specific CD8 T cell precursors and that many of the remaining precursors acquire a virtual (central) memory (VM; CD44(hi)CD62L(hi)) phenotype. In this study, we demonstrate that unimmunized TCR transgenic (TCRTg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended on replacement of the original TCRTg specificity by endogenous TCR? rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild-type and old TCRTg mice; that is, old VM, but not old true naive, T cells exhibited blunted TCR-mediated, but not IL-15-mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 and IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and they demonstrate that two separate age-related defects--drastic reduction in true naive T cell precursors and impaired proliferative capacity of their VM cousins--combine to reduce naive T cell responses with aging. | ||||||
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| DOI: | 10.21430/M337H2FFFJ | ||||||
| Subjects: | 5 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY651: WNV induces pro-apoptotic miRNA | |||||||
| Status: | New | ||||||
| Description: | MicroRNAs (miRNAs) are a class of noncoding small RNAs that regulate multiple cellular processes, as well as the replication and pathogenesis of many DNA viruses and some RNA viruses. Examination of cellular miRNA profiles in West Nile virus (WNV)-infected HEK293 and SK-N-MC cells revealed increased expression of multiple miRNA species. One of these miRNAs, Hs_154, was significantly induced not only in WNV-infected neuronal cells in culture but also in the central nervous system tis- sues of infected mice and, upon transfection, caused a significant reduction in viral replication. Analysis of mRNA transcripts enriched through immunoprecipitation of the RNA-induced silencing complex identified several transcripts that contain seed sequence matches to Hs_154 in their 3= untranslated regions (UTRs). Two of these targets, the CCCTC-binding factor (CTCF) and the epidermal growth factor receptor (EGFR)-coamplified and overexpressed protein (ECOP/VOPP1) proteins display re- duced expression in WNV-infected cells, and the 3= UTRs of these transcripts were sufficient to cause downregulation of expres- sion in infected cells or in cells transfected with Hs_154, findings consistent with miRNA targeting of these transcripts. CTCF and ECOP have been shown to be associated with cell survival, implicating miRNA-directed repression of these targets in WNV- induced cell death. Consistent with this hypothesis, expression of these genes in WNV-infected cells results in a reduction in the number of cells undergoing apoptosis. These observations suggest that induction of Hs_154 expression after WNV infection modulates the apoptotic response to WNV and that cellular miRNA expression can be quickly altered during WNV infection to control aspects of the host response. | ||||||
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| DOI: | 10.21430/M3X7K6T1M6 | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY652: Mouse recombination path counting on a gpu | |||||||
| Status: | New | ||||||
| Description: | The goal of the experiment is to test whether convergent recombination predicts TCRb in vivo frequency, by combining high throughput TCRb sequencing on the Roche 454 platform and highthrougput comprehensive TCRb in silico recombination path counting on a graphical processing unit. | ||||||
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| DOI: | 10.21430/M3LVYI9ULI | ||||||
| Subjects: | 2 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY653: Immune Memory Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections | |||||||
| Status: | New | ||||||
| Description: | Direct mammalian target of rapamycin (Rapa) complex 1 inhibition by short-term low-dose Rapa treatment has recently been shown to improve CD8 T cell immunological memory. Whereas these studies focused on memory development, the impact of low-dose Rapa on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. In this study, we investigated the impact of acute Rapa treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naive cells and the reduced formation of short-lived effector cells. Therefore, more than one cell type required for a protective effector immune response is impaired by Rapa in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of Rapa treatment as means to improve immune memory. | ||||||
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| DOI: | 10.21430/M3IY2GJYV6 | ||||||
| Subjects: | 2 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY654: Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. | |||||||
| Status: | New | ||||||
| Description: | Aging of the world population and a concomitant increase in age-related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age-related decline of the immune system, infectious diseases remain among the top 5-10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan. | ||||||
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| DOI: | 10.21430/M33E7TCYXT | ||||||
| Subjects: | 10 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY656: Histone deacetylation critically determines T cell subset radiosensitivity. | |||||||
| Status: | New | ||||||
| Description: | Lymphocytes are sensitive to ionizing radiation and naive lymphocytes are more radiosensitive than their memory counterparts. Less is known about radiosensitivity of memory cell subsets. We examined the radiosensitivity of naive (TN), effector memory (TEM), and central memory (TCM) T cell subsets in C57BL/6 mice and found TEM to be more resistant to radiation-induced apoptosis than either TN or TCM. Surprisingly, we found no correlation between the extent of radiation-induced apoptosis in T cell subsets and 1) levels of pro- and antiapoptotic Bcl-2 family members or 2) the H2AX content and maximal ?H2AX fold change. Rather, TEM cell survival correlated with higher levels of immediate ?H2AX marking, immediate break binding and genome-wide open chromatin structure. T cells were able to mark DNA damage seemingly instantly (30 s), even if kept on ice. Relaxing chromatin with the histone deacetylase inhibitor valproic acid following radiation or etoposide treatment improved the survival of TCM and TN cells up to levels seen in the resistant TEM cells but did not improve survival from caspase-mediated apoptosis. We conclude that an open genome-wide chromatin state is the key determinant of efficient immediate repair of DNA damage in T cells, explaining the observed T cell subset radiosensitivity differences. | ||||||
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| DOI: | 10.21430/M3RLFCF61C | ||||||
| Subjects: | 1 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY659: Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice | |||||||
| Status: | New | ||||||
| Description: | The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span. | ||||||
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| DOI: | 10.21430/M310W5KAMB | ||||||
| Subjects: | 3 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY663: Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice | |||||||
| Status: | New | ||||||
| Description: | T-cell recognition of self and foreign peptide antigens presented in MHC molecules (pMHC) is essential for life-long immunity. How the ability of the CD4+ T-cell compartment to bind self- and foreign-pMHC changes over the lifespan remains a fundamental aspect of T-cell biology that is largely unexplored. We report that, while old mice (18-22 months) contain fewer CD4+ T-cells compared with adults (8-12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. Old mice also have more cells that bind individual or multiple distinct foreign-pMHCs, and the fold increase in pMHC-binding populations is directly related to their CD5 levels. These data demonstrate that the CD4+ T-cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T-cell receptor interactions with self-pMHC. | ||||||
| Program/Contract: |
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| DOI: | 10.21430/M3SR2T3WZF | ||||||
| Subjects: | 6 | ||||||
| Study PI, contact: |
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||