VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED

Summary

Principal Investigator: Rafi Ahmed
Abstract: DESCRIPTION (provided by applicant): The present application is a competing renewal of a U19 grant that was awarded in 2003. The stated goals of the original application were threefold: (i) To study the human immune response to a vaccine in its entirety;starting from the innate responses, to the peak effector T and B cell responses, to the development and maintenance of immunologic memory, (ii) To understand how a successful vaccine works, and to use this knowledge for designing strategies for enhancing vaccine efficacy, (iii) To understand the cellular basis of immune senescence and develop strategies for improving responses of the elderly to vaccination. A major emphasis of this proposal was to use genomics to define molecular signatures of a successful vaccine, and to use this knowledge to develop new vaccines against emerging infections. To achieve these goals, we studied one of the most effective human vaccines ever developed, the yellow fever vaccine-17D (YFV-17D) as a model. Our efforts resulted in several important advances, including the elucidation of: (i) the dynamics of antigen-specific T cell responses in humans vaccinated with YFV-17D and smallpox, (ii) innate immune mechamisms by which YFV-17D acts to launch a broad and robust T cell immunity, (iii) genomic signatures capable of predicting the T cell immunogenicity of YFV-17D in humans and (iv) identification of potential molecular defects that underlie the sub-optimal response of aged T cells to vaccination. In this renewal application, we aim to follow up on these exciting observations and to determine the extent to which such responses are unique to YFV-17D relative to other vaccines or viruses. This overall goal will be achieved in three Research Projects: 1. Immune Memory (Ahmed/Boss), 2. Innate Immunity (Pulendran/Rice), 3. Immune Senescence (Goronzy), and a Technology Development Project on Human Monoclonal Antibodies (Wilson/Lanzavecchia). This overall research effort will be supported by an Administrative Core (Ahmed/Ansari), a Clinical Research Core (Mulligan/Chokephaibulkit/Yu) and a Genomics &Computational Biology Core (Haining/Lee). In addition, there will be a program for education of scientists aspiring to do human immunology research, and a mechanism for funding pilot projects in human immunology. RELEVANCE: Vaccination is the most effective means of preventing infectious disease. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. In the present proposal, we aim to understand the immune mechamisms by which a successful vaccine induces long-term protective immunity. PROJECT 1: [IMMUNE MEMORY (Ahmed, R)] PROJECT 1 DESCRIPTION (provided by applicant): Our goal is to understand how a successful vaccine induces long-term immunological memory and protective immunity in humans. To achieve this goal we have initiated a detailed cellular and molecular characterization of human immune responses induced by the yellow fever virus (YFV-17D) vaccine. This is one of our most efficacious vaccines and induces long-term immunity that lasts for decades. Also, since YFV-17D is a live attenuated vaccine and most of the US population is not exposed to YFV-, this provides a unique opportunity to analyze antiviral responses in humans during the course of a primary infection and then to monitor the generation and maintenance of immune memory after resolution of the infection. One of the potential benefits of understanding how a successful vaccine induces long-term protective immunity is that this knowledge can be applied to improving other less effective vaccines and, more importantly, to develop new vaccines against emerging diseases. During the previous cycle of funding we have made substantial progress in characterizing human memory T and B cell responses not only to YFV but also after immunization with small pox and influenza vaccines. In this renewal application we will focus our studies on CD8 T cells and examine the mechanisms that regulate human effector and memory CD8 T cell differentiation. The following specific aims are proposed to achieve our goals: 1) To identify transcription factors that regulate naive to effector CD8 T cell differentiation. 2) To analyze the in vivo turnover of human YFV specific CD8 T cells and to examine their homing potential. 3) To define the genomic and epigenetic changes that occur during human memory CD8 T cell differentiation. These studies will provide the first view of the transcriptional changes that occur following CD8 T cell differentiation in humans and will provide unique markers that will enable identification, isolation, and characterization of the differentiated cell subsets. Examination of the epigenetic DMA methylation marks during the progression of the T cell response, as well as between CD8 T cells responding to acute versus chronic viral infections will provide a potential mechanistic view of how memory CD8 T cell differentiation is globally regulated. RELEVANCE: YFV-17D is an ideal model to study memory T cell generation in the context of an acute viral infection. The underlying importance of this study is that the longitudinal analysis of YFV specific CD8 T cells in vaccinees, offers a unique opportunity to track differentiation of highly functional and long-lived human memory CD8 T cells and generate a signature that may be a benchmark for other vaccines.
Funding Period: 2003-09-01 - 2014-04-30
more information: NIH RePORT

Top Publications

  1. pmc Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis
    Kisha Piggott
    Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA
    Circulation 123:309-18. 2011
  2. pmc Systems vaccinology: its promise and challenge for HIV vaccine development
    Helder I Nakaya
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
    Curr Opin HIV AIDS 7:24-31. 2012
  3. pmc Deconvolving heterogeneity in the CD8+ T-cell response to HIV
    W Nicholas Haining
    Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
    Curr Opin HIV AIDS 7:38-43. 2012
  4. pmc An open-ended plea for the development of a global database of HIV vaccine responses
    Peter Wilkinson
    Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, Florida, USA
    Curr Opin HIV AIDS 7:10-6. 2012
  5. pmc Infection of bone marrow cells by dengue virus in vivo
    Sansanee Noisakran
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
    Exp Hematol 40:250-259.e4. 2012
  6. ncbi Deconstructing hepatitis C virus infection in humanized mice
    Marcus Dorner
    Center for the Study of Hepatitis C, Laboratory for Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
    Ann N Y Acad Sci 1245:59-62. 2011
  7. ncbi Mechanisms of immunosenescence: lessons from models of accelerated immune aging
    Sabine Le Saux
    Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA
    Ann N Y Acad Sci 1247:69-82. 2012
  8. pmc Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates
    Marcin Kwissa
    Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA
    Blood 119:2044-55. 2012
  9. pmc Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses
    Natalie Pica
    Department of Microbiology, Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, USA
    Proc Natl Acad Sci U S A 109:2573-8. 2012
  10. pmc Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age
    Mingcan Yu
    Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 109:E879-88. 2012

Detail Information

Publications138 found, 100 shown here

  1. pmc Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis
    Kisha Piggott
    Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA
    Circulation 123:309-18. 2011
    ....
  2. pmc Systems vaccinology: its promise and challenge for HIV vaccine development
    Helder I Nakaya
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
    Curr Opin HIV AIDS 7:24-31. 2012
    ....
  3. pmc Deconvolving heterogeneity in the CD8+ T-cell response to HIV
    W Nicholas Haining
    Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
    Curr Opin HIV AIDS 7:38-43. 2012
    ..This review will discuss the use of systems biology approaches to dissect the heterogeneity of the HIV-specific CD8+ T-cell response...
  4. pmc An open-ended plea for the development of a global database of HIV vaccine responses
    Peter Wilkinson
    Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, Florida, USA
    Curr Opin HIV AIDS 7:10-6. 2012
    ..We also discuss examples of databases that complement our needs and could be integrated into our proposed database requirements...
  5. pmc Infection of bone marrow cells by dengue virus in vivo
    Sansanee Noisakran
    Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
    Exp Hematol 40:250-259.e4. 2012
    ....
  6. ncbi Deconstructing hepatitis C virus infection in humanized mice
    Marcus Dorner
    Center for the Study of Hepatitis C, Laboratory for Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
    Ann N Y Acad Sci 1245:59-62. 2011
    ..Hepatitis C virus is a major medical problem. Novel small-animal models are likely to accelerate the development of more effective therapeutics and a vaccine...
  7. ncbi Mechanisms of immunosenescence: lessons from models of accelerated immune aging
    Sabine Le Saux
    Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA
    Ann N Y Acad Sci 1247:69-82. 2012
    ..Studies of accelerated immune aging in autoimmune diseases have identified an unexpected link to chronic DNA damage responses that are known to be important in aging, but so far had not been implicated in immune aging...
  8. pmc Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates
    Marcin Kwissa
    Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA
    Blood 119:2044-55. 2012
    ..Finally, both TLR9-L and TLR7/8-L induced the expression of genes related to chemokines and type-I IFNs in LNs. Thus different TLR-Ls mediate distinct signatures of early innate responses both locally and systemically...
  9. pmc Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses
    Natalie Pica
    Department of Microbiology, Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, USA
    Proc Natl Acad Sci U S A 109:2573-8. 2012
    ..In addition, we describe assays that can be used to measure influenza virus-neutralizing antibodies that are not detected in the traditional hemagglutination inhibition assay...
  10. pmc Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age
    Mingcan Yu
    Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 109:E879-88. 2012
    ..004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses...
  11. ncbi Immune aging and autoimmunity
    Jorg J Goronzy
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive West, Stanford, CA, 94305 5166, USA
    Cell Mol Life Sci 69:1615-23. 2012
    ....
  12. pmc Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis
    Toidi Adekambi
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America
    PLoS ONE 7:e36046. 2012
    ..Our data suggest that differentiation into CD27(-)PD-1(+) subsets in LTBI is driven by Mtb antigenic stimulation in vivo and that CD27 and PD-1 have the potential to improve our ability to evaluate true LTBI status...
  13. pmc Chronic inflammation and aging: DNA damage tips the balance
    Mary M Cavanagh
    Department of Medicine, Stanford University, Stanford, CA 94305, United States
    Curr Opin Immunol 24:488-93. 2012
    ..When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity...
  14. pmc Development of humanized mouse models to study human malaria parasite infection
    Ashley M Vaughan
    Seattle Biomedical Research Institute, WA 98109, USA
    Future Microbiol 7:657-65. 2012
    ..falciparum infection that will accelerate fundamental research into human parasite biology and could accelerate drug and vaccine design in the future...
  15. pmc Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells
    Gui mei Li
    Emory Vaccine Center, Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA 30322, USA
    Proc Natl Acad Sci U S A 109:9047-52. 2012
    ..The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection...
  16. pmc Identifying gnostic predictors of the vaccine response
    W Nicholas Haining
    Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    Curr Opin Immunol 24:332-6. 2012
    ..The challenge for vaccinologists is therefore to use these tools to embed mechanistic insights into predictors of vaccine response...
  17. pmc Fitness costs limit influenza A virus hemagglutinin glycosylation as an immune evasion strategy
    Suman R Das
    Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
    Proc Natl Acad Sci U S A 108:E1417-22. 2011
    ..These findings show that, although N-linked glycosylation can broadly diminish HA antigenicity, fitness costs restrict its deployment in immune evasion...
  18. pmc Improving gene expression data interpretation by finding latent factors that co-regulate gene modules with clinical factors
    Tianwei Yu
    Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
    BMC Genomics 12:563. 2011
    ..Here we test the hypothesis that unobserved factors can be mobilized by the living system to coordinate the response to the clinical factors...
  19. pmc Spatial clustering of HIV prevalence in Atlanta, Georgia and population characteristics associated with case concentrations
    Brooke A Hixson
    The Hope Clinic of the Emory Vaccine Center, Decatur, GA, USA
    J Urban Health 88:129-41. 2011
    ..Prevention efforts targeted to the population living in this area as well as efforts to address the specific needs of these populations may be most beneficial in curtailing the epidemic within the identified cluster...
  20. pmc Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rγ(null) humanized mice
    Eva Billerbeck
    Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
    Blood 117:3076-86. 2011
    ....
  21. ncbi Insights into human CD8(+) T-cell memory using the yellow fever and smallpox vaccines
    Rafi Ahmed
    Emory Vaccine Center, Emory University, 1462 Clifton Road, Atlanta, GA, 30322, USA
    Immunol Cell Biol 89:340-5. 2011
    ..These findings provide insights into the attributes of the human immune system as well as provide a benchmark for the optimal quality of a CD8(+) T-cell response that can be used to evaluate novel candidate vaccines...
  22. ncbi Dissecting the human immunologic memory for pathogens
    Christina E Zielinski
    Institute for Research in Biomedicine, Bellinzona, Switzerland
    Immunol Rev 240:40-51. 2011
    ..We discuss how these approaches can provide new tools and information for vaccine design, in a process that we define as 'analytic vaccinology'...
  23. pmc Programming the magnitude and persistence of antibody responses with innate immunity
    Sudhir Pai Kasturi
    Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA
    Nature 470:543-7. 2011
    ..Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques...
  24. pmc Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults
    Jaikumar Duraiswamy
    Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
    J Immunol 186:4200-12. 2011
    ..In conclusion, our study shows that most PD-1(hi) CD8 T cells in healthy adult humans are effector memory cells rather than exhausted cells...
  25. pmc Regulation of T cell receptor signaling by activation-induced zinc influx
    Mingcan Yu
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    J Exp Med 208:775-85. 2011
    ..By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli...
  26. ncbi Distinctive TLR7 signaling, type I IFN production, and attenuated innate and adaptive immune responses to yellow fever virus in a primate reservoir host
    Judith N Mandl
    Emory University, Atlanta, GA 30329, USA
    J Immunol 186:6406-16. 2011
    ....
  27. pmc Socioecological influences on community involvement in HIV vaccine research
    Paula M Frew
    Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, GA, United States
    Vaccine 29:6136-43. 2011
    ..This study investigated socioecological factors influencing HIV vaccine research participation among communities living in geographic areas with high HIV prevalence and high poverty rates...
  28. pmc Systems biology of vaccination for seasonal influenza in humans
    Helder I Nakaya
    Emory Vaccine Center, Emory University, Atlanta, Georgia, USA
    Nat Immunol 12:786-95. 2011
    ..Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines...
  29. pmc Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies
    Sanae Sasaki
    Department of Immunology and Microbiology, Stanford University School of Medicine, Stanford, California, USA
    J Clin Invest 121:3109-19. 2011
    ..They also suggest that exposure history affects the cross-reactivity of vaccination-induced antibodies...
  30. pmc Targeting B cell responses in universal influenza vaccine design
    Kaval Kaur
    Committee on Immunology, The University of Chicago, Chicago, IL, USA
    Trends Immunol 32:524-31. 2011
    ..Such approaches take us away from the limited range of protection provided by current seasonal influenza vaccines and towards a future with a pan-influenza vaccine capable of providing universal strain coverage...
  31. pmc Capturing changes in gene expression dynamics by gene set differential coordination analysis
    Tianwei Yu
    Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
    Genomics 98:469-77. 2011
    ..We demonstrate that the method can identify biologically relevant gene sets, many of which do not show first-order relationship with the clinical outcome...
  32. pmc Complement-dependent lysis of influenza a virus-infected cells by broadly cross-reactive human monoclonal antibodies
    Masanori Terajima
    Center for Infectious Disease and Vaccine Research, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
    J Virol 85:13463-7. 2011
    ....
  33. pmc Use of replication restricted recombinant vesicular stomatitis virus vectors for detection of antigen-specific T cells
    Nelson B Moseley
    Emory Vaccine Center at the Yerkes National Primate Center at Emory University, United States
    J Immunol Methods 375:118-28. 2012
    ....
  34. pmc ROCS: receiver operating characteristic surface for class-skewed high-throughput data
    Tianwei Yu
    Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America
    PLoS ONE 7:e40598. 2012
    ..The implementation as an R package is available at http://userwww.service.emory.edu/~tyu8/ROCS/...
  35. pmc CD8+CD45RA+CCR7+FOXP3+ T cells with immunosuppressive properties: a novel subset of inducible human regulatory T cells
    Masakatsu Suzuki
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    J Immunol 189:2118-30. 2012
    ..Loss of CD8+CCR7+ Tregs in the elderly host may be of relevance in the aging immune system as immunosenescence is associated with a state of chronic smoldering inflammation...
  36. pmc New paradigms in type 2 immunity
    Bali Pulendran
    Department of Pathology, Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA
    Science 337:431-5. 2012
    ....
  37. pmc Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice
    Eva Billerbeck
    Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA
    J Immunol 191:1753-64. 2013
    ..The adenovirus reporter system used in our study may serve as simple in vivo method to evaluate future strategies for improving human intrahepatic immune responses in humanized mice. ..
  38. pmc Predicting network activity from high throughput metabolomics
    Shuzhao Li
    Emory Vaccine Center, Emory University, Atlanta, Georgia, USA
    PLoS Comput Biol 9:e1003123. 2013
    ..The algorithms were experimentally validated on the activation of innate immune cells. ..
  39. pmc Immunity to viruses: learning from successful human vaccines
    Bali Pulendran
    Emory Vaccine Center, Atlanta, GA 30329, USA
    Immunol Rev 255:243-55. 2013
    ..Vaccines that have been proven to be of immense benefit in saving lives offer us a new fringe benefit: lessons in viral immunology. ..
  40. pmc Global DNA methylation remodeling accompanies CD8 T cell effector function
    Christopher D Scharer
    Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA
    J Immunol 191:3419-29. 2013
    ..Therefore, these data provide the framework for an epigenetic mechanism that is required for effector CD8 T cell differentiation and adaptive immune responses. ..
  41. pmc Identification of novel markers for mouse CD4(+) T follicular helper cells
    Smita S Iyer
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA
    Eur J Immunol 43:3219-32. 2013
    ....
  42. pmc Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells
    Zhen Yang
    Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305
    J Exp Med 210:2119-34. 2013
    ....
  43. pmc The innate immune playbook for restricting West Nile virus infection
    Kendra M Quicke
    Department of Pediatrics and Children s Healthcare of Atlanta and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
    Viruses 5:2643-58. 2013
    ..In this review, we highlight the major research findings pertaining to innate immune regulation of WNV infection. ..
  44. ncbi Immune mechanisms in medium and large-vessel vasculitis
    Cornelia M Weyand
    Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, CCSR Building Room 2225, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305 5166, USA
    Nat Rev Rheumatol 9:731-40. 2013
    ..Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, might enable a more tailored therapeutic approach that avoids unwanted adverse effects of aggressive immunosuppression...
  45. pmc T-cell aging in rheumatoid arthritis
    Cornelia M Weyand
    aDivision of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California bDepartment of Medicine, Palo Alto Veteran Administration Healthcare System, Palo Alto, California, USA
    Curr Opin Rheumatol 26:93-100. 2014
    ..The process of immunosenescence is accelerated in rheumatoid arthritis (RA)...
  46. pmc Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation
    Rajesh Ravindran
    Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA
    Science 343:313-7. 2014
    ..These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response. ..
  47. pmc Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing
    Natalia Frias-Staheli
    Center for the Study of Hepatitis C, Laboratory for Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
    J Virol 88:2205-18. 2014
    ..We further show that this mouse model can be used to test preclinically the efficacy of antiviral drugs. ..
  48. pmc Molecular signatures of antibody responses derived from a systems biology study of five human vaccines
    Shuzhao Li
    1 Emory Vaccine Center, Emory University, Atlanta, Georgia, USA 2 Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA 3
    Nat Immunol 15:195-204. 2014
    ..Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling. ..
  49. pmc Mechanisms shaping the naïve T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation?
    Qian Qi
    Department of Medicine, Palo Alto Veterans Administration Health Care System, Palo Alto, CA 94304, United States Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
    Exp Gerontol 54:71-4. 2014
    ..With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality. ..
  50. pmc Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV
    Christopher Chiu
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America Centre for Respiratory Infection, National Heart and Lung Institute, Imperial College London, London, United Kingdom
    PLoS Pathog 10:e1004008. 2014
    ..We discuss the concept of a "pan-herpesvirus" vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this. ..
  51. ncbi Targets of immune regeneration in rheumatoid arthritis
    Philipp J Hohensinner
    Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA
    Mayo Clin Proc 89:563-75. 2014
    ..With increasing knowledge of the molecular pathways that cause immunosenescence, therapeutic interventions can be designed to slow or halt the seemingly inevitable deterioration of protective immunity with aging...
  52. pmc Systems biological approaches to measure and understand vaccine immunity in humans
    Shuzhao Li
    Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA
    Semin Immunol 25:209-18. 2013
    ..In this review, we present a broad review of the methodologies involved in these studies, and discuss the promise and challenges involved in this emerging field of "systems vaccinology." ..
  53. pmc Using epigenetics to define vaccine-induced memory T cells
    Ben Youngblood
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, United States
    Curr Opin Virol 3:371-6. 2013
    ..We discuss the usefulness of epigenetic profiling in characterizing T cell differentiation state and function for preclinical evaluation of vaccines and the current methodologies for single locus versus genome-wide epigenetic profiling. ..
  54. ncbi Systems biology of vaccination in the elderly
    Sai S Duraisingham
    Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA, 30329, USA
    Curr Top Microbiol Immunol 363:117-42. 2013
    ..Moreover, the identification of specific defects may be used to target novel vaccination strategies that improve efficacy in elderly populations...
  55. ncbi The immunopathology of giant cell arteritis: diagnostic and therapeutic implications
    Cornelia M Weyand
    Department of Medicine, and the Byers Eye Institute at Stanford, Stanford University, Stanford, CA, USA
    J Neuroophthalmol 32:259-65. 2012
    ..Expansion of the therapeutic armamentarium for GCA needs to focus on approaches that mitigate the impact of the aging artery and adapt to the needs of the immunosenescent host...
  56. pmc Role of CD61+ cells in thrombocytopenia of dengue patients
    Sansanee Noisakran
    Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory University School of Medicine, Dental School Building, Room 429, 1462 Clifton Road, Atlanta, GA 30322, USA
    Int J Hematol 96:600-10. 2012
    ..Our results indicate that virus containing CD61(+) cells may be directly linked to the platelet dysfunction and low platelet count characteristics of dengue patients...
  57. pmc Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity
    Guangjin Li
    Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
    Nat Med 18:1518-24. 2012
    ..DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination...
  58. pmc Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T-cell diversity with age
    Philip L F Johnson
    Department of Biology, Emory University, Atlanta, GA 30322, USA
    Proc Natl Acad Sci U S A 109:21432-7. 2012
    ..g., by an increased division rate or decreased death rate), with the person as a whole incurring the long-term cost of a decreased ability to fight infections...
  59. pmc Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity
    Sarah F Andrews
    Section of Rheumatology, Department of Medicine, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA
    J Exp Med 210:125-42. 2013
    ..Notably, we demonstrate that the LC has profound effects on tolerance and can lead to exacerbated autoantibody production...
  60. pmc Multiploid CD61+ cells are the pre-dominant cell lineage infected during acute dengue virus infection in bone marrow
    Kristina B Clark
    Department of Pathology and Laboratory Medicine and the Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America
    PLoS ONE 7:e52902. 2012
    ..These data suggest that megakaryocytes are likely the predominant cell type infected by DENV in BM, which provides one explanation for the thrombocytopenia and the dysfunctional platelets characteristic of dengue virus infection...
  61. pmc IL-7- and IL-15-mediated TCR sensitization enables T cell responses to self-antigens
    Pratima Deshpande
    Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    J Immunol 190:1416-23. 2013
    ..We propose that HCs, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA...
  62. pmc Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid
    Richard M Dunham
    Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA
    J Immunol 190:2009-16. 2013
    ..Thus, we conclude that HSCs preferentially generate Foxp3(+) Tregs and, therefore, may play a role in the tolerogenic nature of the liver...
  63. ncbi Cross-reactive humoral responses to influenza and their implications for a universal vaccine
    Christopher Chiu
    Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Ann N Y Acad Sci 1283:13-21. 2013
    ..Having shown that cross-reactive antibodies are preferentially induced by a pandemic hemagglutinin, the challenge is now to design a vaccine that applies these principles to the induction of heterosubtypic immunity...
  64. pmc Chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific T cell immunity
    Brian A Norris
    Vaccine Research Center, Emory University, Atlanta, GA 30329, USA
    Immunity 38:309-21. 2013
    ..The reduction of monocytic cells in Ccr2(-/-) mice or after Gr-1 antibody depletion enhanced antiviral T cell function. Thus, innate cells have an important immunomodulatory role throughout chronic infection...
  65. pmc Understanding immunosenescence to improve responses to vaccines
    Jorg J Goronzy
    The Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA
    Nat Immunol 14:428-36. 2013
    ....
  66. ncbi The gracefully aging immune system
    Diana Boraschi
    Institute of Biomedical Technologies, National Research Council, Pisa 56124, Italy
    Sci Transl Med 5:185ps8. 2013
    ..In addition, examples of diseases that should be targeted by vaccination in the senior population were considered...
  67. pmc Translating glycolytic metabolism to innate immunity in dendritic cells
    Mario Cortese
    Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA
    Cell Metab 19:737-9. 2014
    ..This enhances ER and Golgi membrane synthesis and innate activation of dendritic cells. ..
  68. pmc Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity
    Troy Querec
    Emory Vaccine Center, Emory University, Atlanta, GA 30329, USA
    J Exp Med 203:413-24. 2006
    ..Together, these data enhance our understanding of the molecular mechanism of action of YF-17D, and highlight the potential of vaccination strategies that use combinations of different TLR ligands to stimulate polyvalent immune responses...
  69. pmc Division of labor, plasticity, and crosstalk between dendritic cell subsets
    Bali Pulendran
    Emory Vaccine Center, 954 Gatewood Road, Atlanta, GA 30329, USA
    Curr Opin Immunol 20:61-7. 2008
    ..Here we review the recent advances in this area...
  70. pmc T cell subset-specific susceptibility to aging
    Marta Czesnikiewicz-Guzik
    Kathleen B and Mason I Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA30322, USA
    Clin Immunol 127:107-18. 2008
    ..The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules...
  71. pmc TLR-mediated induction of negative regulatory ligands on dendritic cells
    Stefan Gröschel
    Kathleen B and Mason I Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Room 1003 Woodruff Memorial Research Building, 101 Woodruff Circle, Atlanta, GA 30322, USA
    J Mol Med (Berl) 86:443-55. 2008
    ..Conversely, TLR3 ligands may have therapeutic value in silencing pathogenic immune responses...
  72. pmc Rapid cloning of high-affinity human monoclonal antibodies against influenza virus
    Jens Wrammert
    Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
    Nature 453:667-71. 2008
    ..However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination...
  73. pmc Case of yellow fever vaccine--associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes
    Bali Pulendran
    Emory Vaccine Center, 954 Gatewood Rd, Atlanta, GA 30329, USA
    J Infect Dis 198:500-7. 2008
    ..The mechanisms underlying such events remain a mystery. Here, we present an analysis of the immunologic and genetic factors driving disease in a 64-year-old male who developed viscerotropic symptoms...
  74. pmc Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway
    Weiping Cao
    Emory Vaccine Center, Atlanta, GA 30329, USA
    Nat Immunol 9:1157-64. 2008
    ..Thus, mTOR signaling is crucial in TLR-mediated IFN-alpha/beta responses by pDCs...
  75. pmc Vessel-specific Toll-like receptor profiles in human medium and large arteries
    Olga Pryshchep
    Lowance Center for Human Immunology and Rheumatology, Emory University, School of Medicine, Atlanta, GA 30322, USA
    Circulation 118:1276-84. 2008
    ....
  76. ncbi Reversal of IFN-gamma, oxLDL and prolactin serum levels correlate with clinical improvement in patients with peripartum cardiomyopathy
    Olaf Forster
    Soweto Cardiovascular Research Unit, Department of Cardiology, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa
    Eur J Heart Fail 10:861-8. 2008
    ..Peripartum cardiomyopathy (PPCM) is characterized by acute onset of heart failure of unknown aetiology. We aimed to identify mechanisms involved in initiation and progression of the disease...
  77. pmc Retinoic acid-dependent regulation of immune responses by dendritic cells and macrophages
    Santhakumar Manicassamy
    Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA
    Semin Immunol 21:22-7. 2009
    ..Here, we review these recent advances, in the context of the pleiotropic effects of RA in regulating diverse biological processes...
  78. pmc Inhibitory CD8+ T cells in autoimmune disease
    Masakatsu Suzuki
    The Kathleen B and Mason I Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA
    Hum Immunol 69:781-9. 2008
    ..In essence, disease-specific approaches may be necessary to identify CD8(+) Ts optimally suited to treat immune dysfunctions in different autoimmune syndromes...
  79. pmc T cells in arteritis and atherosclerosis
    Cornelia M Weyand
    Kathleen B and Mason Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, Georgia 30322, USA
    Curr Opin Lipidol 19:469-77. 2008
    ..Pro-inflammatory and anti-inflammatory T cells regulate master pathogenic pathways, providing a framework for novel immunotherapeutic strategies...
  80. pmc Protection against lethal challenge by Ebola virus-like particles produced in insect cells
    Yuliang Sun
    Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, 1510 Clifton Road, Room 3086 Rollins Research Center, Atlanta, GA 30322, USA
    Virology 383:12-21. 2009
    ....
  81. pmc Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans
    Troy D Querec
    Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA
    Nat Immunol 10:116-25. 2009
    ..A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy...
  82. pmc The stimulation of CD8+ T cells by dendritic cells pulsed with polyketal microparticles containing ion-paired protein antigen and poly(inosinic acid)-poly(cytidylic acid)
    Michael J Heffernan
    Wallace H Coulter Department of Biomedical Engineering and Parker H Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332, USA
    Biomaterials 30:910-8. 2009
    ..These data demonstrate the potential of polyketal microparticles in formulating effective CD8(+) T cell-inducing vaccines comprising protein antigens and dsRNA adjuvants...
  83. pmc Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling
    Won Woo Lee
    Kathleen B and Mason I Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
    Rejuvenation Res 11:1001-11. 2008
    ....
  84. ncbi The strength of T cell stimulation determines IL-7 responsiveness, secondary expansion, and lineage commitment of primed human CD4+IL-7Rhi T cells
    Laura Lozza
    Institute for Research in Biomedicine, Bellinzona, Switzerland
    Eur J Immunol 38:30-9. 2008
    ..These results show that the strength of stimulation determines properties of activated IL-7R(hi) T cells, and suggest that memory T cell subsets could be derived from CCR7(+) precursors that received different strengths of stimulation...
  85. pmc ProbCD: enrichment analysis accounting for categorization uncertainty
    Ricardo Z N Vencio
    Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103 8904, USA
    BMC Bioinformatics 8:383. 2007
    ....
  86. ncbi Characterization and role of lentivirus-associated host proteins
    Keli Kolegraff
    Department of Pathology and Laboratory Medicine, Emory University, WMB Room 2309, 101 Woodruff Circle, Atlanta, GA 30322, USA
    Exp Biol Med (Maywood) 231:252-63. 2006
    ....
  87. ncbi Toll-like receptor stimulation as a third signal required for activation of human naive B cells
    Claudia R Ruprecht
    Institute for Research in Biomedicine, Bellinzona, Switzerland
    Eur J Immunol 36:810-6. 2006
    ..The coupling of BCR stimulation to TLR expression endows the human system with a high degree of specificity since it allows focusing of innate signals only on antigen-stimulated B cells...
  88. ncbi Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8 T cells
    Ellen N Kersh
    Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
    J Immunol 176:4083-93. 2006
    ....
  89. ncbi ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis
    Anshu Agrawal
    Emory Vaccine Center and Department of Pathology, 954 Gatewood Road, Atlanta, GA 30329, USA
    J Immunol 176:5788-96. 2006
    ..Taken together, our data suggest that deficiency of ERK1 biases the immune response toward Th1 resulting in increased susceptibility to EAE...
  90. ncbi Ebola virus-like particles produced in insect cells exhibit dendritic cell stimulating activity and induce neutralizing antibodies
    Ling Ye
    Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA
    Virology 351:260-70. 2006
    ..These results show that production of Ebola VLPs in insect cells using recombinant baculoviruses represents a promising approach for vaccine development against Ebola virus infection...
  91. ncbi Understanding and making use of human memory B cells
    Antonio Lanzavecchia
    Institute for Research in Biomedicine, Bellinzona, Switzerland
    Immunol Rev 211:303-9. 2006
    ..This method can be exploited for the production of neutralizing antibodies for serotherapy and for "analytic vaccinology"...
  92. ncbi Impaired memory CD8 T cell development in the absence of methyl-CpG-binding domain protein 2
    Ellen N Kersh
    Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA
    J Immunol 177:3821-6. 2006
    ..These data demonstrate that MBD2 is a previously unrecognized intracellular factor required for the efficient generation of protective memory CD8 T cells...
  93. pmc Treatment of chronic inflammatory diseases with biologic agents: opportunities and risks for the elderly
    Alejandro Diaz-Borjon
    Kathleen B and Mason I Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA
    Exp Gerontol 41:1250-5. 2006
    ....
  94. ncbi Understanding the role of innate immunity in the mechanism of action of the live attenuated Yellow Fever Vaccine 17D
    Troy D Querec
    Department of Pathology and Emory Vaccine Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA
    Adv Exp Med Biol 590:43-53. 2007
  95. pmc Aging and T-cell diversity
    Jorg J Goronzy
    Lowance Center for Human Immunology, Emory University School of Medicine, 101 Woodruff Circle 1003, Atlanta, GA 30322, USA
    Exp Gerontol 42:400-6. 2007
    ..Research efforts need to aim at understanding T-cell homeostatic control mechanisms to ultimately expand the time period of repertoire stability...
  96. ncbi Toll-like receptors and innate immunity in B-cell activation and antibody responses
    Antonio Lanzavecchia
    Institute for Research in Biomedicine, Via Vincenzo Vela 6, Bellinzona, Switzerland
    Curr Opin Immunol 19:268-74. 2007
    ..However, the scientific fecundity in this rapidly evolving field will probably give rise to discoveries that could be translated into more effective vaccines and immunotherapies...
  97. ncbi Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells
    Eva V Acosta-Rodriguez
    Institute for Research in Biomedicine, CH 6500 Bellinzona, Switzerland
    Nat Immunol 8:639-46. 2007
    ..Our results demonstrate that human T(H)-17 cells have distinct migratory capacity and antigenic specificities and establish a link between microbial products, T helper cell differentiation and homing in response to fungal antigens...
  98. pmc Simcluster: clustering enumeration gene expression data on the simplex space
    Ricardo Z N Vencio
    Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103 8904, USA
    BMC Bioinformatics 8:246. 2007
    ..Therefore, pattern recognition methods commonly used for microarray data analysis may be non-informative for the data generated by transcript enumeration techniques since they ignore certain fundamental properties of this space...
  99. ncbi Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells
    Eva V Acosta-Rodriguez
    Institute for Research in Biomedicine, CH 6500 Bellinzona, Switzerland
    Nat Immunol 8:942-9. 2007
    ....

Research Grants30

  1. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  2. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  3. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  4. Cellular Immunity to Category A-C Viruses in Humans
    ROBERT WILLIAM FINBERG; Fiscal Year: 2013
    ....
  5. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  6. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  7. Harnessing Human DC Subsets for Improved Muscosal Vaccines
    Gerard Zurawski; Fiscal Year: 2013
    ..We propose four projects and two technical development components which will be supported by six cores. ..
  8. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..