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Baylor Institute for Immunology Research
3434 Live Oak St.
Dallas, Texas 75204
PWSBIIR@baylorhealth.edu
Tel: (214) 820-7451
Fax: (214) 820-4813
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Pilot Projects
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PI: Jacques Banchereau, Ph.D.
Our proposal for a Center for Translational Research in Human Immunology and Biodefense gathers investigators from different backgrounds, yet unified through their interest in the biology of Dendritic Cells. As we planned this Center, we identified experts that we thought would synergize to provide the best possible program on the topic of Human Dendritic Cells and in vivo Immunity to Biothreat.
This Center is expected to be an integral component of the larger Network of Centers that are expected to contribute complementary expertise. Thus, the Network Center ' expertise should broadly encompass the fields of Human Immunology and Biodefense.
Given the breadth of the topic we should expect to identify gaps on the repertoire of collective expertise. It will be the objective of these pilot projects to fill these knowledge gaps and expand the discoveries made in the center. In doing so, we are hoping to attract to the field of human immunology investigators who have proven to be outstanding contributors to Basic Immunology and possibly to other fields as it applies to the Technology Development.
The five years of the Center Cycle will permit us to support up to ten Pilot Projects. These projects will be financed for up to two years. Though the Center's Director is ultimately responsible for the proper use of the Center's resources, the Center's Steering Committee will play a critical role in the initiation and follow-up of each of these Pilot Projects. It is proposed that each Pilot Project will be overseen/chaperoned from inception to completion by two of the Center's Investigators.
Pilot Project 1: Establishment of breeding colony for in utero transplantation; transplant of human HPCs
PI: Alan Flake, MD
Children's Hospital of Philadelphia
The goal of this pilot project is to develop an intact human immune system in the mouse. This novel approach which takes advantage of normal events during fetal development to engraft components of the human immune system.
The specific aim of this application is to utilize techniques developed in the allogeneic murine mouse model of IUHSCT to establish the components of a human immune system in a mouse host.
In collaboration with Dr. Banchereau, this project will include the transplantation of human HSC, mesenchymal stem cells (thymic stromal cells), and specific subpopulations of human dendritic cells into the 15 day gestation normal of immune deficient (NOD/SCID) mouse. In these studies, we will determine the ability of each of these populations, individually or in combination, to engraft in hematopoietic, thymic and lymphopoietic tissues. If human lymphohematopoietic chimerism can be established at significant levels in this study, then it will set the stage for a series of experiments that will test for the functional capacity of this surrogate human immune system.
Pilot Project 2: Establishment of whole Humouse sectioning allowing detection of human immune cells throughout the animal body
PI: Marc Jenkins, PhD
University of Minnesota
There are two specific aims in this project. The first is to use whole mouse immunohistology to characterize the tissue distribution of human dendritic cell subsets in human HPC-reconstituted NOD/SCID mice under steady state conditions or after infection with influenza virus. Once steady state conditions are established for levels of dendritic cells in the lungs, the test will be repeated on these mice that have been infected with influenza virus. This will provide information on dendritic cell trafficking and the effects on the total dendritic cell population due to influenza infection.
The second aim is designed to assess the capacity of human HPC-reconstituted NOD/SCID mice to support human influenza virus-specific T cell activation and trafficking to the lungs following influenza virus infection. This approach will be used to determine whether these mice can support in vivo activation of human T cells.
Pilot Project 3: Role of DCs in immunoglobulin class switching toward IgA2
PI: SangKon Oh, PhD
Baylor Institute for Immunology Research
The goal of this study is to develop new vaccine strategies that induce a strong humoral immunity, the front line of host defense against microbial infections. Dendritic cells (DCs) play a pivotal role in the induction and regulation of both innate and adaptive immune responses against microbial infections. Different subsets of DCs can also induce and regulate host immune responses in different directions, suggesting that future vaccines should target appropriate DC subsets to induce optimal immune responses against infections.
Our hypothesis is that unique DC subsets will preferentially induce the production of IgA2. To address this hypothesis, we propose two aims: 1) Test the capacity of different subsets of DCs to induce IgA2 class switching. 2) We will also examine the role of new anti-CD40 in the activation of DCs that could result in the enhanced IgA2 class switching.
Pilot Project 4: Identification of memory T cell repertoires cross-reactive to H5N1 influenza virus
PI: Hideki Ueno, MD, PhD
Baylor Institute for Immunology Research
The recent spread of highly pathogenic avian influenza H5N1 viruses has resulted in lethal outbreak in humans. Fears of a new influenza pandemic are prompting development of reliable preventive vaccines. We are in process to design a new H5N1 vaccine which elicits both humoral and cellular immunity. To date, there has been no epitopes identified in avian influenza proteins, therefore limiting the study with regard to avian influenza-specific T cells.
In this pilot project, we propose to determine the T cell repertoires within memory/effector T cell populations which cross-react with H5-hemagglutinin (HA) and N1-neuraminidase (NA) in healthy volunteers. To this end, we will apply the EPIMAX (download PowerPoint presentation describing EPIMAX) approach to determine the epitope, subset, and the type of memory/effector T cells. H5 or N1-cross reactive T cell lines will be established by stimulating T cells with the identified peptides. Their biological functions, including cytokine production, phenotype, and cytotoxicity, will be assessed. We will clarify the breadth and magnitude of the memory T cell repertoires which would be activated upon H5N1 infection. Importantly, this pilot study will enable us to segregate naive and memory T cell repertoires reactive to H5N1.
Pilot Project 5: Transcriptional profiling of in vitro antigenic response to assess vaccine immunogenicity in a non-human primate model
PI: Damien Chaussabel, PhD
Baylor Institute for Immunology Research
This pilot project will leverage microarray technology to comprehensively assess the immunogenic properties of candidate DC targeting vaccines bearing the influenza virus HA1 antigen. Three recombinant vaccines produced by our center (G. Zurawski, S. Oh) targeting the molecules LOX1, DCIR and Langerin will be tested in a non human primate model (pilot project: R. Legrand).
Aim 1 will assess qualitatively and quantitatively transcriptional responses measured in blood restimulated with HA1 protein in vitro after 6 and 24 hours of culture. The data will be generated using Illumina's Sentrix Hu6 V2 BeadChips. The assay will be carried out 28, 60 and 180 days post-immunization in order to evaluate the robustness as well as the longevity of the recall response. The data will be compared to results obtained by alternate means (e.g. Elispot).
Aim 2 of this pilot project will identify based on these results a subset of ~400 transcripts with the ability to distinguish in vitro immunoreactivity quantitatively as well as qualitatively. This knowledge will be used to develop a custom focused assay for the fraction of the cost/sample of a whole genome microarray screen. Moving forward, such assay would prove a valuable tool for monitoring responses to vaccine in the context of planned follow up studies.
Pilot Project 6: Immunogenicity in non human primates of Flu HA fusion protein with antibodies targeting different dendritic cell subsets
PI: Roger Legrand, PhD
Atomic Energy Commission, France
The objective of this Pilot Project is to perform pilot studies in order to assess, in small groups of non human primates (NHP), the quality of the immune response induced with vaccines composed of a viral antigen (HA of influenza) and antibody targeting different subsets of dendritic cells (DCs) of the skin. These studies are preliminary to larger trials including larger numbers of animals per group. Vaccines selected in theses studies will be then evaluated for immunogenicity at the systemic and mucosal level and for efficacy against intranasal (IN) virulent challenge. The ultimate goal is to identify in a relevant animal model, the correlates of protection that could be used as surrogate markers of vaccine efficacy in future clinical trials in humans. We hypothesize that non human primates can be used to assess immunogenicity and efficacy of anti-human anti-DC-antigen fusion proteins.
The specific aim of this project is to assess the generation of anti-HA recall response induced by vaccination HA fusion proteins with anti-Lox-1, anti-DCIR or anti-Langerin antibodies in macaques that have been primed with PR8 flu virus strain.
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