DAIT-Funded research programs that will be submitting data into ImmPort



Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations

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Principal Investigator Title Institute Contract Number Description
Wilson, Christopher Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations: TLRs in Innate Immunity and the Induction of Adaptive Immunity in the Neonate and Infant University of Washington NO1-AI-50023* The overall goal of research proposed is to define comprehensively and in molecular and cellular detail differences in recognition and response to microbe-derived danger signals between adults, neonates and infants, and how these, in turn, contribute to differences in innate immunity and the induction of antigen-specific (adaptive) immunity. In so doing, we aim to discover candidate strategies by which immediate protection against potential bioterrorism agents might be provided to this vulnerable population, while at the same time facilitating the development of antigen-specific immunity to infection or immunization. The experience of our investigative team in host defense to infection, Toll-like receptor (TLR) biology and neonatal immunology, their history of cross-disciplinary collaborations, and their ongoing participation in the WWAMI (Washington, Wyoming, Alaska, Montana, Idaho) Regional Center for Excellence in Biodefense (RCE) provide a strong foundation for the proposed work.
Sullivan, Kathleen Kinetic analysis of immunologic repletion and influenza vaccine responsiveness Children´s Hospital of Philadelphia NO1-AI-50024 We propose a comprehensive analysis of the immunologic response to killed trivalent influenza vaccine in different immunocompromised populations in order to understand how to improve vaccine responses. This will provide insight into how to avoid vaccine failure. We hypothesize that there are specific immunologic mechanisms that are aberrant in cases of influenza vaccine failure in immunocompromised populations. By analyzing six populations with different immunologic deficits, we will identify functional predictors of vaccine failure/response. Detailed investigations of T cell precursor frequency, T cell cytokine production, T cell proliferation and B cell responses will be performed to identify the defects responsible for vaccine failure/response. The six populations are patients undergoing an autologous stem cell transplant for multiple myeloma, patients undergoing a tandem stem cell transplant for neuroblastoma, patients receiving chemotherapy, patients receiving a dendritic cell vaccine, patients receiving rituximab, and patients with chromosome 22q11.2 deletion syndrome.
Larsen, Christian Protective Immunity in Transplant Recipients Emory University NO1-AI-50025* Our projects seek to improve our understanding of the biological mechanisms that underlie the distinct immunosuppressive regimens in practice today (calcineurin-inhibitor, or CNI, and sirolimus based regimens) and in emerging regimens that employ agents with novel mechanisms of action, such as the CD28 costimulation blockers, and/or JAK3 kinase inhibitors. Such knowledge will be critical to strategies for enhancing desirable immune responses while not precipitating rejection. We are undertaking three complementary studies:
Study 1: Characterization of the impact of CNI-based, sirolimus-based, and novel immunosuppressive regimens on protective immunity over time in renal transplant recipients,
Study 2: A prospective comparison the magnitude and character of the immune response to influenza vaccine in defined transplant populations and healthy aged-matched volunteers, and
Study 3: Responses to and control of vaccinia in immunosuppressed Rhesus Macaques.
Thompson, Linda Responses to Influenza Vaccination in Systemic Lupus Oklahoma Medical Research Foundation (OMRF) NO1-AI-50026* The goal of the proposed work is to understand why many patients with systemic lupus erythematosus (SLE) fail to make adequate responses to immunization with the influenza vaccine. Our approach is to compare the major components of the normal immune response to vaccination in SLE patients and control subjects in order to identify abnormalities in this group of immunocompromised individuals. These are the first steps in devising a strategy to modify the current vaccine protocol to improve the immune response of SLE patients and other individuals undergoing immunosuppressive therapy.
Objective I. To establish and serially follow a collection of SLE patients and matched controls before and after influenza vaccination (or documented influenza infection).
Objective II. To evaluate the antibody responses of SLE patients and controls to influenza vaccination to determine the relative titers and specificities of protective vs. non-protective antibodies.
Objective III. To analyze the differentiation of influenza-specific B cells in SLE patients and controls following immunization and to generate and characterize anti-influenza monoclonal antibodies.
Objective IV. To evaluate the expression levels of regulatory molecules of B cell signaling by flow cytometry and to determine whether signaling thresholds are altered in SLE patients compared to controls.
Objective V. To evaluate T cell responses to influenza vaccination by measuring IFN production and CD4 T cell activation.
Objective VI. To evaluate changes in autoantibody titers, specificities and epitopes in SLE patients who are high and low responders to immunization with the influenza vaccine.
The results of the above studies will reveal which step(s) in the normal response to influenza immunization are defective in SLE patients. Characteristics of SLE patients who will not make an adequate response to immunization will also be identified. These are the first steps in devising a strategy to modify the current vaccine protocol in order to improve the immune response of SLE patients and other individuals undergoing immunosuppressive therapy.
Nikolich-Zugich, Janko Immune function and Biodefense in Children, Elderly and Immunocompromised Populations Oregon Health and Science University NO1-AI-50027* The overarching long-term goal is to characterize immune markers and mechanisms in the elderly that determine their vulnerability to infectious and bioterrorism agents in categories A-C. The contractor has developed both rodent and primate models to examine potential immune defects associated with aging. Since one cannot examine all potential biodefense organisms, we have chosen the category B pathogen WNV as a model system. This emerging virus provides a unique opportunity to understand general features of immune vulnerability in the elderly since:
(i) Elderly humans are highly susceptible to WNV compared to immunocompetent adults;
(ii) WNV infects both mice and rhesus macaques and the contractor has developed well defined models in both animals to examine age-related defects in immunity, as well as the mouse model of age-related vulnerability to WNV; and
(iii) the WNV epidemics in the US provides an opportunity to assess immunity in both the adult and elderly populations and to verify mechanisms of immune vulnerability to WNV;
(iv) there is currently no approved WNV vaccine, increasing the urgency of this research. The goal of this contract is to establish and/or exploit well-defined aged mouse and Rhesus macaque (RM) models to elucidate mechanisms of vulnerability to WNV, to validate these mechanisms in elderly humans and to select the best defined ones for manipulation and correction.
Moran, Thomas Immune Response to Virus Infection During Pregnancy Mt. Sinai School of Medicine NO1-AI-50028* Pregnancy is a uniquely advantageous system to evaluate the consequences of immunosuppression in that a woman returns to normal immune function following its resolution. Therefore, individual level correlates of immune function, such as vaccination status, allergies, medical history, and background genetic characteristics, become irrelevant when she acts as her own control. Moreover, altered immunity during pregnancy may have consequences on the efficacy of vaccines or immunotherapeutic treatments. Susceptibility to infection may also be affected at specific times during pregnancy. Levels of circulating estrogen, progesterone, and other placental hormones/peptides are suspected to be critical factors that modulate the adaptive changes observed in maternal systemic immunity. Thus, individuals in high-risk periods may need to be treated differently. We propose to enroll 50-75 women in a prospective cohort study to examine the longitudinal changes in immunity over the course of pregnancy, the post-partum lactation period, and post-lactation normal period. As such, each woman will act as her own control, allowing us to characterize the nature, extent and correlates of immune competence during the pregnancy and neonatal period. The study will determine whether the different trimesters of pregnancy, characterized by unique hormonal environments, are associated with (a) identifiable, discrete changes in maternal systemic immunity and/or (b) recognizable alterations in susceptibility to select bio-defense pathogens and/or (c) differential responses to influenza vaccination
Sanz, Ignacio   University of Rochester NO1-AI-50029* One of the major threats to our society in the foreseeable future is the possibility of a terrorist attack with lethal biological agents. In the event of such an attack, immuno-compromised patients which prominently include autoimmune patients subject to therapeutic immunosuppression will be at a very high risk. Therefore, there is a clear need to identify the specific immune defects that make these populations specially susceptible. One of the more prevalent forms of immunosuppresion used for a growing number of autoimmune conditions is chronic blockade of Tumor Necrosis Factor (TNF). It is expected that in the near future candidates for this type of therapy will include several million American citizens. In this application, we propose to develop and apply the University of Rochester Program for Biodefense of Immunocompromised Populations (URPBIP) to the systematic study of human immune function with the goal of identifying defective mechanisms of immune response in patients treated with TNF blockade (anti-TNF). Although our study will not be specifically designed to understand immune function in the elderly, the inclusion of a subset of patients and controls over and under 50 may result in the discovery of age-specific defects.
Ertl, Hildegund An Improved Influenza A Vaccine for Rapid Protection of the Elderly The Wistar Institute NO1-AI-50030* The goal of this application is to conduct pre-clinical studies for a vaccine designed to provide protection to the elderly in the event of a bioterror attack with influenza A virus. Protection against most viral infections, including those with influenza A virus can most readily be achieved by vaccines that elicit serotype-specific neutralizing antibodies. This may not be attainable in the event of a bioterror attack, as generation of such a vaccine could not be achieved in a timely fashion. CD8+ T cells directed against more conserved viral sequences can lower the impact of viral infections and it is the goal of this application to develop a CD8+ T cell-inducing vaccine suitable for use in the elderly that provides broad protection against different types of Influenza A virus. Adaptive immune responses of the elderly are commonly impaired in part due to physiological cell senescence and in part due to a loss of equilibrium between activating and inhibitory pathways following chronic antigenic stress. The latter are expected to be amenable to pharmacological adjustment as will be addressed by this application. Suitable cohorts of human subjects will be identified and blood samples collected for analyses. In addition, potential targets or regulatory circuits will be identified in mice and human samples that may be exploited in increase the efficacy of the influenza vaccine vector in the elderly. The vaccine generated will be based on an E1-deleted adenoviral vector of the simian serotype 68 (AdC68) expressing internal proteins of Influenza A virus and shall be supplemented with suitable monoclonal antibody preparations to improve its performance in the elderly by circumventing negative co-stimulation and/or increasing positive co-stimulation.
Fikrig, Erol Innate Immune Responsiveness in the Elderly and the Immunosuppressed Yale School of Medicine-Howard Hughes Medical Institute NO1-AI-50031* The growing threats of bioterrorism and emerging infectious diseases such as West Nile (WN) virus infection, SARS, and avian influenza represent a crucial challenge to health care providers, to the public health infrastructure, and to the biomedical research community. Our understanding of the immune responses to potential agents of bioterrorism remains incomplete in particularly vulnerable populations with impaired immunity, such as immunosuppressed and elderly individuals. Elucidation of the consequences of aging and immunosuppression on infection with, or vaccination against such agents is therefore essential to the development of clinical tests and interventions aimed at identifying individuals likely to be at particular risk for adverse outcomes following an attack of bioterrorism or outbreak of an emerging infectious agent. In addition, by identifying potential mechanisms for augmentation of immune responses, these new clinical approaches will also be of general benefit to global health, particularly given the potential for the use of more virulent or drug-resistant bioterror agents. This proposal will explore the hypothesis that altered innate immune responsiveness in the elderly and the immunosuppressed contributes to vaccine unresponsiveness or disease susceptibility. This premise is based upon our preliminary data, first, that individuals that respond poorly to a lipoprotein-based vaccine have defects in TLR1/2 signaling, and second, that TLR3-responsiveness contributes to susceptibility to West Nile virus infection. Here we will initially delineate innate immune responses in the elderly and immunosuppressed focusing on TLRs and a prototype TLR-dependent cytokine, macrophage migration inhibitory factor (MIF), that differ from the general population. We will then determine whether these differences alter immune responses to selected NIAID Biodefense priority pathogens, using West Nile virus infection and influenza vaccination as paradigms. These mechanistic studies will lead to new approaches for vaccine development and for the treatment of infectious diseases.
Gorski, Jack Generation and Decay of Memory T cells in Young, Old and Immunocompromised Populations Blood Center of Wisconsin NO1-AI-50032* The generation of T cell memory is the basis of immunity to repeat pathogen exposure and is the goal of vaccination. How this memory is generated in man is still poorly understood. We have observed that robust T cell memory to influenza in man involves the generation of complex memory repertoires for both class I and class II restricted responses. A detailed longitudinal analysis of T cell memory in healthy adults is being currently conducted. Our objectives in this contract are to expand our study of T cell memory repertoires to include an aging population in which the repertoires may be decaying as well as to children who should still be in the process of generating memory repertoires. These studies will provide data about the age dynamics of memory repertoires. In addition to healthy children, we will examine flu-specific memory repertoires in children with autoimmune diseases who are undergoing mild immunosuppression. This should describe the effects of immunosuppressive therapy on memory formation and function. We will also investigate the extent to which the memory repertoires in these sample populations contain regulatory T cells and T cells with natural killer-like phenotypes. The role of these subsets in immune memory is still poorly understood yet is very likely to be important. The data obtained from these studies, which all include an longitudinal sampling component, should provide important insights into what constitutes a robust memory repertoire that protects an individual from influenza, and how aspects of such memory differ in the young, old and the immunocompromised.
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Population Genetics Analysis Program: Immunity to Vaccines/Infections

Principal Investigator Title Institute Contract Number Description
Gulcher, Jeffrey Population Genetics Analysis Program: Immunity to Vaccines/Infections Immune Response Polymorphisms: Smallpox, tuberculosis, influenza deCODE genetics HHSN266200400064C* Microbiological infections and their complications occur at the interface of host genes, microbial genes, and the environment. While exposure to a microbial agent is necessary, it is not sufficient to cause infection in the host. The final outcome depends on the relative weight of host defense versus microbe virulence. Differences among individuals in host defense factors are now thought to be related to genetic variants. Notwithstanding the potential roles of other cells, it is widely accepted that the T lymphocyte plays a critical role with respect to both organizing, facilitating and co-ordinating immune responses against both bacterial and viral infections (1). In this regard, numerous signal transduction pathways have been well characterized in both CD4+ and CD8+ T cells, including but not limited to the T cell receptor itself and other accessory molecules at the immunological synapse (CTLA-4, ICAM-1, LFA-1, CD40-L, CD28, and CD80) that have distinct signaling systems (LCK, Zap-70, PLCg1, various Smad molecules and transcription factors such as NFAT, AP-1 and NFkB) (2) and TH1 (IL2, IL12, IFNg) and TH2 (IL4, IL5, IL9, IL13)-type cytokines and their receptors. The innate immune system including the various Toll receptors or CD14 that deal with endotoxin and other responses is also critically important and identification of polymorphisms in these genes is therefore of particular interest (3). Whether any of these host genes have variants that may be of clinical relevance with respect to modulation of immune function remains unknown. However, there are several dramatic examples of lack of host defense factors resulting from a mutated gene such as the example of autosomal dominant inheritance in meningococcal meningitis susceptibility in a few large families due to a defective properdin gene in the alternative complement pathway (4). There are other examples where variants in immune response genes affect suseptibility including the MHC for numerous infections, CCR5 in HIV infection, and Toll receptor 2 in Mycobacerium and non-immune response genes such as Nramp in Mycobacterium (5-8). However, for most common infections and their corresponding clinical syndomes, the genetic effects are likely to be more subtle than for a Mendelian disorder. We propose here to combine the human population genetics infrastructure of deCODE Genetics with the University of New Mexico (UNM) system to validate candidate genes from population genetics approaches in animal models of infectious disease and human cell in vitro assays to discover and validate human genes that determine host defenses and susceptibility to important high-priority pathogens. Another subcontractor, National Center for Genomic Research, led by Susan Baxter, will use their expertise and past track record in creating informatics systems for analysis of large expression datasets and to create and update of databases of linkage and expression results and the corresponding candidate genes.
Poland, Gregory Population Genetics Analysis Program: Immunity to Vaccines/Infections Immune Response Polymorphisms: Typhoid/Choler Vaccines Mayo Clinic Rochester HHSN266200400065C* Our broad objective is to examine the role of candidate human immune response gene polymorphisms (and their receptors, expression and function) in inter-individual variability in vaccinia vaccine-induced humoral and cell-mediated immune responses among a cohort of 1,000 recently vaccinated subjects. In Research Area 1, we propose to study associations between specific class I and II HLA alleles (HLA-A, -B, -C, DRB, -DQA, -DQB, -DPA, DPB), specific cytokine genes, polymorphisms of the above cytokine receptors, a genome-wide SNP analysis; and variations in immune response to smallpox vaccine. In Research Area 2, we focus on identifying associations between expression and function of these same candidate genes likely to regulate immune response variations and humoral and cell-mediated immune responses following smallpox vaccination in selected human subjects. Both gene products (i.e., secreted proteins), cell surface expression, and measures of gene regulation/activation will be pursued. We focus on gene families involved in initiating, sustaining and regulating innate and adaptive immune responses, as well as those directly involved in directing specific antibody and cytotoxic T cell responses. We have significant experience with these genes as determinants of immune response to other viral and bacterial vaccines experience that will serve us well in efficiently completing the proposed aims of this study.
Loeb, Mark NIAID Population Genetics Program on West Nile Virus Project McMaster University HHSN266200400066C* Since the first US outbreak in 1999 in New York City1, WNv has emerged as an important human pathogen in North America. There has been a steady increase in the annual incidence of human cases of WNv infection in the United States and Canada. This reached epidemic proportions in the summer of 2003. As of January 7, 2003, 8,977 human cases of WNv infection (2,667 cases of meningoencephalitis and 218 deaths) have been reported to CDC 2. In Canada, 1,317 human cases were reported in 20033. Given the low background of immunity in the population, the spread of West Nile virus through migrating birds will likely result in continued future human epidemics. We hypothesize that severity of West Nile virus (WNv) infection is a consequence of genetic factors that result in increased WNv replication and subsequent immune pathology in individuals with severe (encephalitis or meningitis) disease. We will address our hypothesis through the following objectives:
1. To assess the association between known and discovered candidate immune response genotype sets and susceptibility to meningoencephalitis in patients infected with WNv.
2. To characterize the relationship between candidate immune response gene polymorphisms, protein function, and WNv infection using in vitro and in vivo models, including natural infection in humans.
We acknowledge that there is a paucity of classical epidemiological data in families, communities and twins to evaluate the genetic risk for susceptibility to WNV. However, there is a strong parallel between what is known about West Nile virus and other infections where a genetic basis has been described. For example, in tuberculosis less than 10 percent of infected persons ever have clinical disease, and only a minority of such persons have an identifiable risk factor. The natural resistance associated macrophage protein 1 gene (Nramp1 ) has an important role in determining resistance to mycobacteria in mice. Investigators tested the hypothesis that NRAMP1 polymorphisms were significantly associated with tuberculosis, and proved that this in fact the case by doing a case-control study (N Engl J Med 1998 338:640-4). The work of Schurr, Abel and Hudson (Mira et al, Nature 2004) associating genetic variation in the Parkin genes and susceptibility to leprosy is another example. We anticipate an important role for human immune response gene polymorphisms on the basis of the known gene polymorphisms linked to susceptibility in animal models, the fact that only a minority of WNv infected individuals develop neurological complications, and the limited variability in the viral genome.
Wagener, Diane Immune Response Polymorphisms: Typhoid/Cholera Vaccines Research Triangle Institute HHSN266200400067C* The objective is to understand role of polymorphisms in genes of innate and adaptive immunity in modulating the response to vaccines for two gastrointestinal tract infections: typhoid and cholera.
Kaslow, Richard Population Genetics Analysis Program: Immunity to Vaccines/Infections University of Alabama at Birmingham HHSN266200400068C Our central purpose is to investigate variability in host genes predicting variation in antibody reponses and adverse reactions to Anthrax Caccine Adsorbed (AVA). The results should more generally enhance our understanding of the immune response in the context of vaccines, pathogenic agents and autoimmunity.
Wilson, Christopher Genetic Risk for Smallpox Vaccine Related to Myocarditis University of Washington HHSN266200400069C The overall goal of this proposal is to identify genetic differences that increase the risk for a major adverse event associated with smallpox vaccination - myocarditis - and to determine the mechanism by which these genetic differences confer risk.
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HLA Region Genetics in Immune-Mediated Diseases

Principal Investigator Title Institute Contract Number Description
Rosenberg, Lynn HLA Region Genetics and SLE in U.S. Black Women Boston U-Slone Epidemiology 1 UO1 AI067146-01 Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects African-American women. Numerous studies have shown that HLA-region genes play a key role in genetic susceptibility to SLE, but studies so far have not established which factors in the HLA region are important and how much of overall risk is explained by HLA. We propose to address these questions with a large and uniformly collected group of samples from the Black Women's Health Study (BWHS), the largest follow-up study of African American women yet conducted. We will use cheek cell samples collected from 400 BWHS participants with SLE and 800 matched controls. Since the collection of cheek cell samples is already funded, the present grant will focus on (a) DMA extraction from the samples, (b) DMA amplification, (c) SNP haplotyping of the HLA region, (d) PCR-based genotyping for the C4A deletion allele for which there is particular evidence of association to SLE in order to control for its effect, and (e) genotyping a panel of SNPs to control for European admixture in African Americans. We will exhaustively survey the HLA region for genetic associations with SLE; this will involve typing a high-density panel of SNPs over the region, which will provide excellent power to detect variants that confer 2-fold or greater increased risk for SLE. Among the specific genes that we will assess are TNF, IKBL, MICA, and HLA-DRB1, with adjustment for C4A gene deletion status. In addition, we will genotype a panel of SNPs across the genome to ensure that any associations with HLA alleles that we detect are real rather than due to population stratification (systematic differences in allele frequency between cases and controls due to differences in their population ancestry). This will also allow us to assess whether specific regions of the genome show unusually high or low levels of European ancestry in African-American SLE patients, thus allowing us to use an 'admixture mapping' approach to find sections of the genome containing genes that modify HLA-induced risk for SLE. The proposed study is population-based and not only uses an innovative and statistically high-powered design which will exhaustively survey the HLA region for SLE risk, as well as search the rest of the genome for modifiers of that risk but also focuses on African-American women, a population that is high-risk for SLE but medically and scientifically underserved.
Glass, David HLA Region Genetics in Immune Mediated Disease: HLA/KIR Region Genetics in Pediatric Arthritis Cincinnati Children´s Hospital 1 UO1 AI067150-01 JRA (also known as JIA) includes the commonest chronic autoimmune arthropathies of childhood. The MHC is involved with respect to risk, either susceptibility or protection in a subtype specific manner with strong gender bias and differences between ethnicities. Multiple MHC effects have been shown, especially in the commonest subtype, so called early onset pauciarticular JRA (Persistent Oligo in the JIA terminology) with three or more MHC regions believed to interact in generating susceptibility. An additional feature of the disease, unlike some other forms of autoimmunity, is the relative absence of common extended or ancestral haplotypes, especially those carrying HLA-DR4 and HLA-DR7 both of which are protective. The three regions include a class I region, or an area telomeric to it, and two class II regions those around HLA DR/DQ and HLA-DP. None of the regions involved are well defined nor were the specific genes involved identified. The alleles marking these regions (HLA-DR8, 11 and HLA-DPB1*0201) are atypical for autoimmunity. This is therefore an unusual MHC contribution to autoimmunity, the elucidation of which lends itself to high throughput technologies. The genetic features, although involving arthritis, are quite distinct from adult rheumatoid arthritis except for about 5% of older children. It is proposed to construct high throughput SNP maps in a family based study. Subtypes have different MHC profiles and in the rarest and most severe form of disease, systemic onset JRA, the MHC effect is rather minimal. In this form, preliminary data involving KIR gene haplotypes is available. Pursuing these KIR gene observations is proposed. The ability to leverage ongoing phenotyping and family based sample collection ensures a large and continuously growing pool of available DNAs for this project. Some of the patients will also have extensive gene expression studies allowing a comprehensive approach to the MHC and KIR genes in JRA and its subtypes.
Petersdorf, Effie Epigenomics of Hematopoietic Cell Transplantation Fred Hutchinson Cancer Research Center 1 UO1 AI069197-01* The overall goal of Project 1 is to define the genetic barriers to successful allogeneic hematopoietic cell transplantation (HCT). HCT from unrelated donors can cure blood disorders. Complete and precise donor HLA matching is associated with superior transplant outcome. However, risks of graft-versus-host disease and mortality are still increased compared to sibling donor transplantation. Furthermore, 20 - 40% of patients who start a search fail to identify suitably matched donors. Criteria for selecting optimal mismatched donors are ill-defined. Recently, new information on KIR receptors demonstrates the importance of HLA-KIR interactions in alloresponses after HCT. The long-term objectives of Project 1 are to improve the availability, safety and efficacy of HCT by optimizing donor genetic selection. The specific aims are to: 1) define the extent to which availability of unrelated HCT can be increased through the use of HLA mismatched donors by identifying permissible mismatches; 2) identify new MHC-resident genes associated with transplant outcome, and 3) determine if HLA-KIR interactions modify risk of post-transplant complications. Success in achieving these goals will broaden the applicability of unrelated HCT to the treatment of blood disorders.
Erlich, Henry The Role of HLA and KIR in Rheumatoid Arthritis and Crohns Disease Children´s Hospital Oakland Research Institute (CHORI) 1 UO1 AI067068-01* The association of specific alleles and haplotypes at the HLA class I and class II loci with a variety of autoimmune diseases is well established. Recently, polymorphisms in the Killer Immunoglobulin-like Receptors (KIR) genes that encode the stimulatory and inhibitory receptors on NK cells have been reported to be associated with a few of the same HLA-associated diseases, (e.g. psoriatic arthritis, scleroderma, and T1D). The ligands recognized by many of these receptors are epitopes on HLA class I molecules. Our goal is to carry out case/control association analyses for Crohn's Disease and Rheumatoid Arthritis using our high resolution HLA and KIR genotyping methods. We have developed high throughput, robust, and high resolution immobilized probe methods for genotyping the HLA class I and class II loci and a high throughput MALDI-TOF method for genotyping the KIR loci. Specific DRB1 alleles have already been associated with each of these diseases (DRB1*0103 for CD and DRB1*0401 and *0404for RA) but we will evaluate the role of other HLA loci in these diseases. HLA class I typing is also critical in evaluating the role of the KIR genes since the association data must be stratified on the presence or absence of the HLA epitope ligand to examine the effects of KIR-HLA combinations. In addition, we will genotype another well established disease gene polymorphism, the PTNP22 locus, allowing stratification of the HLA and KIR association data. The analyses of HLA-KIR in population-based studies will add significantly to our understanding of the role of the innate immune system in these complex autoimmune disorders.
Hauser, Steve Molecular Genetics of HLA and Disease University of California, San Francisco 1 U19 AI067152-01* The goal of this application is to identify and characterize the complete repertoire of genes encoded in the MHC region that predispose and/or modulate the expression of autoimmune disease. Following the recent NINDS-sponsored workshop on MHC Genetics in Autoimmune Diseases and the subsequent announcement of an RFA to extend interdisciplinary science in this area, we created a Consortium, named The International MHC and Autoimmunity Genetics Network (IMAGEN) to tackle this problem in a meaningful and decisive manner. The IMAGEN investigators represent a large, diverse, and broad-based collaborative team of scientists at eight academic centers with synergistic skills; demonstrated expertise in MHC genetics and biology; clinical expertise in identifying endophenotypes; history of mutual productive collaborations; and experience in large scale genotyping and state-of-the-art analytical approaches. The basic structure of this collaborative project proposes a common base screen with a panel of -1500 highly informative SNPs and replication for all diseases. Biologically relevant clinical endpoints will be incorporated into the analysis to assess the role of HLA variants in progression. Specific aim 3 for each project will address disease-specific questions. The primary screen will allow us to: 1) map the association signal(s) across the entire MHC to identify regions of the maximal signal; 2) identify extended MHC haplotypes carrying the strongest association signals; 3) identify recombinant chromosomes that maximally delimit the association; 4) make testable hypotheses as to whether different autoimmune diseases are influenced by a single association with a particular locus, or a single association with an extended haplotype or multiple, independent associations across the MHC. The focus is on Multiple Sclerosis in project 1; Rheumatoid Arthritis project 2; IgA Deficiency, Common Variable Immunodeficiency, and Myasthenia Gravis in project 3; and Systemic Lupus Erythematosus and Ulcerative Colitis in project 4. We believe that the clinical dataset assembled for this project is unmatched anywhere in the world. An administrative Core at UCSF will coordinate activities and interactions for the overall project. A second Core at the Broad Institute will be responsible for generation of genotypes, data QC, storage, and interaction with BISC.


(MS project): Multiple sclerosis (MS) is a common autoimmune demyelinating disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. The most compelling and consistently replicated evidence for an MS susceptibility gene has been found at the major histocompatibility complex (MHC) superlocus on chromosome 6p21.3. However, the exact gene or genes and mechanisms by which the MHC affects MS are still undefined. Our overall objective is to characterize the complete repertoire of MHC genes that predispose to MS and modulate its presentation. Their identification is now possible as a result of the rapid progress in delineating the landscape of genetic organization and variation across the human genome. In specific aim 1 we describe a high density association analysis of the causal variation(s) within the 4 MB MHC locus. Over 1500 validated SNPs will be genotyped in 1,000 MS trios. Family-based association testing for alleles, haplotypes and genotypes in each block will be performed using transmission disequilibrium testing methods. In specific aim 2, discrete segments of interest identified in specific aim 1 will be followed-up with additional association mapping using additional SNP markers in the original and confirmatory datasets. MS susceptibility genes located within blocks of interest will then be identified by direct sequencing. In the third aim, we will address the issue of genetic modifiers in the MHC region focusing first on the underlying causes of primary progressive MS. Clinical and laboratory data such as age and site of disease onset, disability at entry of study (EDSS), lesion distribution, and progression will be also incorporated into the analysis of genomic data to directly address the question of heterogeneity in MS by analysis of the correlation between different phenotypes and genotypes.

(RA project): The overall goal of this project is to identify all of the genetic elements within the MHC that predispose to rheumatoid arthritis (RA). Preliminary data from the PI and others indicates that at least two regions outside of the DRB1 locus contain risk genes for RA. One of these regions lies in the central MHC and is likely to reflect the presence of polymorphisms that are present on a common extended haplotype found in white populations, the A1-B8-DR3 ("8.1") haplotype. A second risk region appears to be located in the MHC class I region, and may contribute to the very high relative risk (RR) associated with certain compound heterozygote genotypes such as DRB1*0401/0404. In specific aim 1 we will confirm and extend these observations by carrying out a dense SNP scan of the MHC on an initial set of 1,500 RA cases and 1,500 matched controls from the Swedish population. In specific aim 2, we will replicate the findings in specific aim 1, and narrow the risk regions further using dense association mapping. These studies will draw on a set of -6,000 RA patients and controls from the U.S. populations, as well as an additional 1500 RA cases and matched controls from Sweden. Finally, in specific aim 3, we will search for genetic interactions between the genes identified within the MHC, including the DRB1 locus, and risk genes found outside the MHC. These studies will initially focus on the C2ta/MHC2TA gene on chromosome 16. This gene is a transcriptional regulator of HLA gene expression, and polymorphisms of this gene have recently been shown to influence MHC class II expression in the rat in response to injury and inflammation. Furthermore, preliminary data indicate an association of a C2ta regulatory SNP with rheumatoid arthritis and other inflammatory disorders. Thus, in specific aim 3 we will specifically investigate whether interactive genetic effects can be observed between C2ta and any of the risk regions within the MHC that are identified in specific aims 1 and 2. Since multiple non-MHC genes, as well as environmental factors, are likely to contribute to RA susceptibility, the precise delineation of the genetic risk factors within the MHC will facilitate investigation of additional interactive effects in the future.

((IgAD, CVID, MG projects): IgA deficiency (IGAD) is the most common primary immunodeficiency in man, and likely shares genetic susceptibility alleles with the more severe disease common variable immune deficiency (CVID). Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. Each of these disorders has a major MHC genetic component, with recent evidence suggesting important effects in the MHC Class III region in IGAD and MG. In the proposed studies of Project 3, association signals will be mapped across the MHC region in 500 Swedish MG and 500 Swedish IGAD cases using a dense panel of SNPs. In parallel, these SNPs will be typed in a large set of 1500 Swedish controls. Association signals will be identified and compared to those obtained in other diseases studied as part of the IMAGEN consortium. A number of Swedish multiplex families for IGAD and CVID are- available, and these will be used to assess haplotype structure, and to examine segregation of haplotypes and SNP alleles with disease. Additional IGAD and CVID samples from Sweden and the U.S. are also available for typing. Based on the initial association data, we will seek to narrow the associated segments by typing additional SNPs and re-sequencing candidate genes, with a goal of identifying the causal allele(s) for IGAD, CVID and MG. Later in the project, we will study families from the Multiple Autoimmune Disease Genetics Consortium (MADGC) to determine the prevalence and segregation of associated MHC alleles and haplotypes identified in the various consortium projects. Currently, there are 343 MADGC families available, each containing 2 or more individuals with 2 or more major autoimmune diseases (average of -3.2 affecteds per pedigree). RA, SLE, MS, and autoimmune thyroid disease are well represented in these families, and together there are more than 25 autoimmune disorders represented in these families. The studies proposed will be integrated with the other projects of the consortium at many levels, and should advance significantly our understanding of the MHC contribution to IGAD, CVID and MG.

(SLE and UC projects): The long term objectives of this application are to obtain a precise understanding of how genetic variants located in the major histocompatibility complex (MHC) can influence an individual's risk to developing ulcerative colitis (UC) or systemic lupus erythematosus (SLE); two chronic inflammatory diseases. The MHC region is a large region on chromosome 6p that contains -150 genes; many of which have important roles in the human immune system, including the human leukocyte antigen (HLA) genes. Such an understanding will improve our knowledge of the mechanisms that lead to these and other inflammatory diseases and may provide important molecular markers of disease. Previous studies have been limited by the number of samples examined and by the availability of appropriate genetics tools. The current proposal takes advantage of recent advances in our understanding of the patterns of genetic variation in the human genome. Furthermore, this proposal will take advantage of a very high density map of the genetic variation in the MHC region (approximately 1 SNP per 500-1000 bp). This map will enable the selection of an informative screening set of SNPs to perform a powerful association mapping study. This screening set of SNPs will be applied to large well-characterized UC and SLE patient cohorts. The identical screening set of SNPs will also be applied to multiple other autoimmune diseases, as described in Projects 1-3. Comprehensive association mapping of the regions identified in this screen will be pursued. In addition, recent work has demonstrated the importance of functionally relevant combinations of alleles of the killer immunoglobulin-like receptor (KIR) and HLA genes in influencing the human immune response. It is believed that this influence of allelic combinations acts in part at the level of the NK cell. Given the emerging importance of NK cells in SLE, we will specifically test for association between KIR/HLA combinations and susceptibility to SLE. This work promises to have an impact on public health by identifying the genetic factors that influence an individual's susceptibility to ulcerative colitis or systemic lupus erythematosus, two chronic inflammatory diseases. This work will also provide important molecular markers of diseases that may be useful in clinical management of these debilitating diseases.
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Atopic Dermatitus and Vaccinia Network (ADVN)

Principal Investigator Title Institute Contract Number Description
Leung, Donald Atopic Dermatitis and Vaccinia Network (ADVN ) many 1-U19-AI070448 Atopic dermatitis (AD) is a common allergic disease seen in 10-20% of infants. While severity often diminishes with age, AD can persist throughout life. Moreover, AD severity can be a predictor of subsequent allergic disease as 60% of children who have AD will develop other atopic diseases, including asthma. Thus, it is often thought that AD is the first step on the "Allergic March" towards more severe atopic disease. While both defects in skin and a predisposition towards a hyper-Th2 response contribute towards AD, it is not clear which is the primary defect in the pathogenesis of AD. Chronic lesions convert to inflammation more characteristic of Th1-mediated immunity though what triggers this switch is unclear. In this AADCRC application, we will define several of the factors that contribute to disease initiation and exacerbation. In Project 1, patient samples and a mouse model of AD resulting from hyper-Th2 responses will be used to determine which cytokine and signaling pathways correlate with, or are required for, AD development. The mouse model of AD will also be used to define the effects of AD concurrent with the development of other atopic diseases. Project 2 will examine the contribution of dendritic cells as mediators of innate immunity in the development of AD by examining the function of DC populations in patient samples and mice that have AD and their ability to direct either Th2 or Th1 dependent immunity. Project 3 will qualitatively and quantitatively define bacteria and bacterial products from infected AD lesions. The role of the lipid mediator platelet-activating factor (PAF) and toll-like receptors in bacterial product-mediated inflammation and immunomodulation will be assessed both in vitro as well as in vivo using cellular and murine models.
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