DR34 DataRelease
Release Date: 04/16/2020
| SDY1369: Immune signatures of responses to infection with Dengue and Zika virus | ||||||||||
| Status: | New | |||||||||
| Description: | Peripheral blood immune cell samples were acquired from a cohort of DENV-exposed individuals from the NIMHANS hospital in Bangalore, India. We compared immune mechanisms prevailing in DENV-patients and virus-exposed healthy subjects to define critical elements of anti-viral immunity. | |||||||||
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| DOI: | 10.21430/M3ZND7ZKX0 | |||||||||
| Subjects: | 45 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1381: Host Determinants Of Protection Against Tuberculosis In Adolescents | |||||||||||
| Status: | New | ||||||||||
| Description: | The bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis (M.tb), has infected one quarter of the world's population. Infection occurs when the pathogen is inhaled, following exposure to a patient with lung TB. 10% of infected persons progress to disease, while 90% never do. We don't understand why some people develop disease, while others do not: this is the focus of this application. To address protection against TB, we have established a cohort of 6,363 South African adolescents. 53% were infected with M.tb at baseline. During 2 years of follow-up, 76 of these participants developed TB disease. As blood was collected and stored every 6 months, we have a unique opportunity to compare host responses between adolescents who developed disease and those who have remained healthy. We will have two approaches to defining protection. Our first focus will be on T cells, which are immune cells shown to be critical for protection against TB. Current assays focus on limited aspects of the T cell response, but have not been successful in defining protection. We have devised a new paradigm - we hypothesize that a model including multiple T cell functional attributes plus their regulation by multiple immune cells will define protection. We propose that relative "immune quiescence", i.e., an optimal but relatively silent immune response, is associated with protection. We and others have preliminary data to suggest that too much inflammation, or too much activation of the immune system, may be detrimental. The rationale for our second focus is that our knowledge of host control of M.tb infection remains incomplete - we therefore propose an unbiased approach that will facilitate discovery of novel pathways involved in protection. We will assess genome-wide gene expression in blood cells, including purified immune cell populations, to delineate new pathways involved in protection. Our preliminary studies of protection against TB in infants have shown the incredible power of this approach. The longitudinal nature of the adolescent cohort, and state-of-the-art bioinformatic approaches, afford unique muscle for uncovering host determinants of protection. We will immediately validate findings by studying further groups of adolescents, from the same cohort. This will be followed by mechanistic studies aimed at understanding how newly described markers may act to protect us against TB. Knowledge of host determinants of protection against TB disease could impact TB control in many ways. For example, targeted prophylactic therapy for infected persons could be implemented, as well as rapid clinical testing of novel TB vaccines. Knowledge gained will also stimulate development of new vaccines and drugs against TB. | ||||||||||
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| DOI: | 10.21430/M3E5CED0HU | ||||||||||
| Subjects: | 150 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1403: PROGENI-LI (CTOT-14) | |||||||
| Status: | New | ||||||
| Description: | The main focus of this study is to develop blood and/or urine tests that will help to detect early signs of rejection in people who have had a liver transplant. Researchers will examine blood, urine, and tissue samples and try to identify markers for certain conditions such as rejection, response to therapy, and scarring of the liver. Additionally, researchers would like to identify biomarkers that can detect damage to the native kidneys before blood levels of creatinine rises. By studying gene expression, researchers hope to be able to diagnose these conditions earlier and improve liver survival. | ||||||
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| DOI: | 10.21430/M304ZDGVQ2 | ||||||
| Subjects: | 203 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1433: Optimization of NULOJIX (Belatacept) Usage as a Means of Minimizing CNI Exposure in Simultaneous Pancreas and Kidney Transplantation (CTOT-15) | |||||||
| Status: | New | ||||||
| Description: | Transplant recipients have to take anti-rejection medications to prevent their immune systems (the body's natural defense system against illness) from rejecting their new organs. Most patients who receive a transplanted organ must take these anti-rejection medications for the rest of their lives, or for as long as the transplanted organ continues to work. Taking standard anti-rejection medications for a long time can cause serious side effects, including pancreas and kidney damage. There would be a benefit to finding new anti-rejection medications that work just as well, but could lessen the amount of anti-rejection medications that are taken long term. | ||||||
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| DOI: | 10.21430/M3CEH2A7ZF | ||||||
| Subjects: | 44 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1536: Unconventional ST2- and CD127-negative lung ILC2 populations are induced by the fungal allergen Alternaria | |||||||||||
| Status: | New | ||||||||||
| Description: | Group 2 innate lymphoid cells (ILC2s) have been recognized for their ability to drive type 2 responses in experimental animal models in the absence of T cells. Mice intranasally challenged with Alternaria alternata, a fungal allergen associated with severe asthma and fatal exacerbations in humans, potently activates ILC2s via the IL-33/ST2 (IL-33R) axis to robustly secrete type 2 cytokines. Animal models, including Alternaria-induced lung inflammation in mice, have given us critical insight into pathways of ILC2 regulation that appear to apply to ILC2 responses in human disease.7 Thus, accurate identification of ILC2s in the lungs of mice is critical to future understanding of their biology and contribution to allergic disease. We assessed whether the conventional ILC2 identification markers ST2 and CD127. | ||||||||||
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| DOI: | 10.21430/M3SMNPG422 | ||||||||||
| Subjects: | 6 | ||||||||||
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| Clinical Assessments: | None | ||||||||||
| SDY1555: Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci | |||||||
| Status: | New | ||||||
| Description: | Here we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high depth RNA-seq in healthy individuals. We discovered widespread dynamic allele-specific expression across the genome, where the balance of alleles changes over time, in 356 SNPs spanning 186 genes. These genes were four fold enriched in autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes, particularly for a major autoimmune risk gene, HLA-DQB1. | ||||||
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| DOI: | 10.21430/M379ZLATI0 | ||||||
| Subjects: | 10 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1595: MDR1 expression in hematopeotic cells | |||||||
| Status: | New | ||||||
| Description: | We generated MDR1-reporter (Abcb1aAME /+) mice to quantify steady-state Abcb1a expression in more than 100 immune cell types and developmental stage. | ||||||
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| DOI: | 10.21430/M3Z1K1Q8KR | ||||||
| Subjects: | 3 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1597: Immune Cell Repertoires in Breast Cancer Patients after Adjuvant Chemotherapy | |||||||
| Status: | New | ||||||
| Description: | Adjuvant chemotherapy in breast cancer patients causes immune cell depletion at an age when the regenerative capacity is compromised. Successful regeneration requires the recovery of both quantity and quality of immune cell subsets. Although immune cell numbers rebound within a year post-treatment, it is unclear whether overall compositional diversity is recovered. We investigated the regeneration of immune cell complexity by comparing peripheral blood mononuclear cells from breast cancer patients ranging from one to five years post-chemotherapy with those of age-matched healthy controls using mass cytometry and T cell receptor sequencing. These data revealed universal changes in patients' CD4 T cells that persisted for years and consisted of expansion of TH17-like CD4 memory populations with incomplete recovery of CD4 naive T cells. Conversely, CD8 T cells fully recovered within a year. Mechanisms of T cell regeneration however were unbiased as CD4 and CD8 T cell receptor diversity remained high. Likewise, TEMRAs were not expanded indicating that regeneration was not driven by recognition of latent viruses. These data suggest that while CD8 T cell immunity is successfully regenerated, the CD4 compartment may be irreversibly impacted. Moreover, the bias of CD4 memory towards inflammatory effector cells may impact responses to vaccination and infection. | ||||||
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| DOI: | 10.21430/M3FVW3Z3TN | ||||||
| Subjects: | 30 | ||||||
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| Publications: | None | ||||||
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| SDY1628: Study of Antithymocyte Globulin for Treatment of New-onset T1DM (START) | |||||||
| Status: | New | ||||||
| Description: | Clinical protocol ITN028AI is a multicenter, double-arm, blinded, placebo-controlled, 2:1 randomized, phase II clinical trial in individuals with new-onset T1DM. Participants will be blinded and randomly assigned to receive either Thymoglobulin or placebo. The Thymoglobulin group will receive one course of Thymoglobulin, the placebo group will receive one course of matching saline solution. Thymoglobulin administration can elicit adverse reactions during infusion that may potentially unblind patients and caregivers. To correct for this possibility, the study design includes two sequential patient-care teams, an unblinded study-drug administration team (for the first 8 weeks), and a blinded diabetes management team (for the remainder of the study). Both teams will meet the participants prior to random assignment. The study-drug administration team will care for participants during their hospital stay and drug infusions through week 8 of the study and will remain involved in non-diabetes-related issues thereafter. After week 8, the diabetes management team will assume care of the participants' diabetes care and the study drug administration team will no longer be involved in diabetes management. The study drug administration team will continue to receive and review all laboratory studies not directly related to the diabetes care beyond week 8, and will manage any possible issues related to drug administration. After week 8, if participants develop serious infectious complications, the study drug administration team will evaluate and manage the participant and will be free to consult with infectious disease experts as necessary. Both treatment and placebo groups will undergo identical procedures and will be followed for 24 months; if they preserve any beta-cell function, they will be followed longer for up to 60 months. The primary endpoint will be measured at 12 months. Safety, diabetes control, beta-cell function, and immune function will be assessed for 24 months. Participants will be asked to contact the study site for a period of up to 5 years after study entry in case of secondary malignancies. Both groups will receive intensive diabetes management. A major goal of clinical protocol ITN028AI is to obtain immunologic evidence that supports a state of clinical and immunologic tolerance, i.e. to determine if a short-term drug therapy results in the halting or elimination of autoimmune destruction of beta cells without ongoing therapy. During the follow-up phase, participants will undergo clinical and immunologic assessments similar to the ones they underwent during the first 12 study months. Possible mechanisms of Thymoglobulin action will also be assessed. | ||||||
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| DOI: | 10.21430/M39Q379SFJ | ||||||
| Subjects: | 58 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY702: Human T Cell Profile | |||||||
| Status: | Updated | ||||||
| Description: | We present a quantitative, system-wide analysis of T cell differentiation, homeostasis and persistence in blood, lymphoid, and mucosal tissues obtained from a highly diverse cohort of 56 organ donors aged 3?73 years. We incorporate an analysis of naive, memory, and effector T cells with functional markers of homeostasis, activation, and tissue residence along with quantification of in situ turnover and TCR clonal distribution to reveal distinct patterns of compartmentalization, maintenance and proliferation of human T cells. | ||||||
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| DOI: | 10.21430/M39EBHNRYF | ||||||
| Subjects: | 56 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1109: CD4 Nicaragua Epitope ID | |||||||
| Status: | Updated | ||||||
| Description: | We performed DENV-specific epitope screening studies in the general population of Managua. Peptides with the capacity to bind HLA DR molecules most common in the Nicaraguan population have been predicted and screened in an HLA matched fashion in blood donors from the Nicaraguan Red Cross previously exposed to dengue virus. | ||||||
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| DOI: | 10.21430/M3VF5F8ANE | ||||||
| Subjects: | 128 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1328: Transcriptional profiling of HBV-naive subjects before vaccination against Hepatitis A/B viruses, Diphtheria/Tetanus toxoids and Cholera. | |||||||
| Status: | Updated | ||||||
| Description: | Mechanisms of poor responses to vaccines remain unknown. Hepatitis B virus-naive elderly subjects received three vaccines, including a vaccine against hepatitis B virus (HBV). Pre-vaccination high dimensional analyses of blood using transcriptional profiling and flow cytometry revealed that subjects having increased memory B cell frequencies and higher expression of genes downstream of B cell receptor signaling responded more strongly to the HBV vaccine whereas subjects having higher expression of inflammatory related genes and greater numbers of activated innate immune cells showed a weaker response to this vaccine. The heme-induced response was associated with the poor response to the hepatitis B vaccine. Transcriptional profiling and flow cytometry results were validated in a distinct set of elderly subjects with accuracy greater than 60%. Our study is the first that identifies baseline predictors of responses to vaccines in a population of subjects known to be highly susceptible to infections. | ||||||
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| DOI: | 10.21430/M3ID8ZC1AT | ||||||
| Subjects: | 174 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1364: Roles for Treg Expansion and HMGB1 Signaling through the TLR1-2-6 Axis in Determining the Magnitude of the Antigen-Specific Immune Response to MVA85A | |||||||||
| Status: | Updated | ||||||||
| Description: | A better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-_ (IFN-g) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2R_ two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans. | ||||||||
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| DOI: | 10.21430/M3NJTLGRT4 | ||||||||
| Subjects: | 24 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1370: Smallpox vaccination with LC16m8 vaccinia virus provides a gene expression profile similar to DryVax vaccination | |||||||
| Status: | Updated | ||||||
| Description: | Transcriptional analysis of global gene expression changes in naive subjects in response to smallpox vaccination with either DryVax or the replication-competent, attenuated LC16m8 vaccinia virus. | ||||||
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| DOI: | 10.21430/M3QHF445NF | ||||||
| Subjects: | 10 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||