Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.
|William Andrews, MD, Dept of OB & GYN-Maternal & Fetal Medicine
|T. Prescott Atkinson, MD, PhD, Department of Pediatrics
|Khurram Bashir, MD, Department of Neurology
|Suresh Boppana, MD, Department of Pediatrics
|Louis Bridges, MD,, PhD, Dept of Medicine/Clin Immunol & Rheumatology
|Donald Buchsbaum, PhD, Department of Radiation Oncology
|R. Pat Bucy, MD, PhD, Department of Pathology
|Noel K. Childers, DDS, PhD, Department of Pediatric Dentistry
|Randy Q. Cron, MD, PhD, Department of Pediatrics
|Randall S. Davis, MD, Department of Medicine
|Jessy Deshane, PhD, Department of Medicine
|Jeffrey Edberg, MD, Dept of Medicine/Clin Immunol & Rheumatology
|Craig Elmets, MD, Department of Dermatology
|Charles O. Elson III, MD, Department of Medicine
|Maaike Everts, PhD, Pediatrics/Infectious Diseases
|David O. Freedman, MD, Department of Medicine
|James F. George, PhD, Department of Surgery
|Robert Kimberly, Dept of Medicine/Clin Immunol & Rheumatology
|Roslyn Mannon, MD, Dept of Medicine and Surgery
|Jiri Mestecky, MD, PhD, Department of Medicine
|John Mountz, MD, PhD, Dept of Medicine/Clin Immunol & Rheumatology
|Joseph Murphy, PhD, Southern Research Institute
|Moon Nahm, MD, Department of Pathology
|Harry Schroeder, MD, PhD Dept of Medicine/Clin Immun & Rheumatology
|Lisa M. Schwiebert, PhD Department of Cell, Developmental, & Integrative Biology
|Tong Zhou, MD, Department of Medicine
William W. Andrews, MDDr. Andrews is a Professor in the UAB Maternal-Fetal Medicine Division, and has been the Director of the Obstetrics and Gynecology Infectious Disease Research Laboratory since its creation in 1990. Dr. Andrews' research interests relate to obstetrical infections and infection-related preterm birth. He is the PI for an investigation of Interconceptional Antibiotics to Prevent Recurrent Preterm Birth that was recently completed and is the protocol chairman of a prospective randomized trial within the NICHD MFM Units Network of antibiotics to prevent preterm birth in women with elevated mid-trimester cervical fibronectin that is in the analysis phase. He is also the PI of Project IV within the UAB Rural Perinatal Emphasis Research Center which is an evaluation of a neonatal sepsis-like syndrome related to in utero maternal cytokine exposure. Most recently he was awarded a contract to perform "A Longitudinal Study of Bacterial Vaginosis". Dr. Andrews is a consultant and co-investigator on numerous other interdisciplinary projects related to genital tract infections, sexually transmitted diseases, and preterm birth, and he is a co-investigator within the International Clinical Epidemiology Network (INCLEN).
T. Prescott Atkinson, MD, PhD Research in my laboratory is focused on the role of infection in chronic diseases, especially arthritis and asthma. Ongoing projects in coordination with the UAB Diagnostic Mycoplasma Laboratory are designed to identify mycoplasmas and ureaplasmas in human samples with particular emphasis on the role of those organisms in chronic asthma and extreme prematurity respectively. Previous studies in my laboratory established that Mycoplasma pneumoniae is able to activate mast cells to produce IL-4 through sialic acid-dependent binding to the high affinity receptor for IgE, a finding with potential implications in the pathogenesis of asthma and potentially a general mechanism in the activation of cells of the immune system by that organism. Work is currently proceeding to determine the current prevalence of macrolide resistance strains of M. pneumoniae in the Birmingham area. I am also actively engaged in the development of rational strategies to determine the molecular basis for unidentified immunodeficiencies in patients in my weekly clinical immunology clinics at Children’s of Alabama. Such patients may represent natural “knockouts” or dominant negative mutations in signaling molecules and provide valuable insights into critical steps in receptor signaling in the human immune system.
Khurram Bashir, MD Clinical, epidemiological and outcomes research in immunologic disorders of the central nervous system, specifically multiple sclerosis
Suresh Boppana, MD Dr. Boppana’s laboratory is studying the pathogenesis of congenital cytomegalovirus (CMV) infections. Congenital CMV infection is the most frequent congenital infection and a leading cause of brain damage and sensorineural hearing loss in children. The focus of the work in our laboratory include: 1. Understanding the intrauterine transmission of CMV in women who were CMV seropositive before pregnancy. We recently showed that acquisition of a new CMV strain is associated with intrauterine transmission and damaging congenital infection in immune mothers. Our ongoing studies will attempt to define the role of maternal reinfection, maternal strain-specific immune responses and other factors in transplacental transmission and damaging congenital infections in infants born to immune mothers; 2. Definition of the mechanisms of hearing loss, in particular, the development of late onset and/or progressive hearing loss in children with congenital CMV infection. We are investigating the role of virus burden and characterizing the virus specific cellular immune responses in congenitally infected children to better delineate the pathogenesis of hearing loss in children with congenital CMV infection; 3. Understanding the virologic and immunologic characteristics of primary CMV infection.
S. Louis Bridges, Jr MD, PhD Genetic and racial/ethnic influences on susceptibility, severity, and treatment response in rheumatoid arthritis. We are currently examining the role of single nucleotide polymorphisms (SNPs) in genes encoding TNF-α, LT, TNF receptors, and other related proteins, as well as HLA DRB1 alleles, in clinical response of rheumatoid arthritis (RA) to the inhibitor etanercept. In addition, we are using the same strategy to identify genetic markers of treatment response or toxicity to the antifolate drug methotrexate. We are uniquely positioned in that we have access to several well-characterized cohort of patients with RA who have completed clinical trials or are part of registries. In addition, we are interested in racial/ethnic differences in disease severity of RA, defined by radiographic evidence of bony erosions and joint space narrowing. I am the co-Director of the NIH-funded Consortium for the Longitudinal Evaluation of African-Americans (A-A) with Early Rheumatoid Arthritis (CLEAR). This consortium is identifying and collecting 450 A-A with RA of less than 2 years disease duration and establishing a centralized clinical database, DNA, serum, and cell bank. The primary outcome will be the presence or absence of radiographic erosions of hands or feet at 3 years disease duration. The effect of polymorphisms in candidate genes will be analyzed in future studies. B Lymphocytes in Rheumatoid Arthritis and Chronic Hepatitis C Virus (HCV) Infection. Dr. Bridges has an active interest in the role of B lymphocytes in RA and HCV. In normal lymphoid organs, recombination activating genes (RAG)-1 and RAG-2 are expressed in a subset of germinal center B cells to allow replacement of autoreactive V gene sequences with non autoreactive V gene sequences, so-called receptor editing. Dr. Bridges and colleagues have demonstrated that this important mechanism of peripheral B-cell tolerance occurs in RA synovial B lymphocytes. This finding has important implications regarding the role of synovium as a lymphoid organ in RA and other chronic autoimmune diseases. Structures resembling germinal centers also occur in periportal tracts of liver in patients with chronic HCV. The role of these B cells in generating cryoglobulins, antibodies associated with vasculitis, are also being examined.
Donald J. Buchsbaum, PhD. Dr. Buchsbaum’s research is focused on the use of agonistic monoclonal antibodies that bind to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors for cancer therapy in combination with chemotherapy agents or radiation. The research involves investigation of the mechanisms of enhanced cytotoxicity produced by combination treatment with TRAIL death receptor antibodies and chemotherapy or radiation therapy. Orthotopic and metastatic breast, ovarian, and pancreatic cancer xenograft models are being used to optimize therapeutic regimens. In collaboration with investigators from the Divisions of Gynecologic Oncology and Clinical Immunology, surgical specimens from patients with ovarian cancer are being utilized to develop a tumor slice assay to attempt to correlate in vitro cytotoxicity sensitivity to treatment with death receptor antibody and chemotherapy to patient survival following treatment with humanized antibody and taxol/carboplatin. If successful, this could be used as a predictive assay to select patients for treatment. We are also investigating the use of small molecule modulators of apoptosis to increase the level of tumor cell killing. Other research involves investigating the mechanism by which basal-like triple negative breast cancers are sensitive to death receptor antibody treatment, and the response of basal-type breast cancer stem cells to treatment with TRAIL receptor antibodies, gamma secretase inhibitors, and chemotherapy.
R. Pat Bucy, MD, PhD Dr. Bucy is interested in the regulation of immune responses by T cells, particularly the forms of regulation that develop in vivo in situations with chronic antigen presence. Conventional experimental systems have used model antigens given in discreet inoculations so that the clearance of antigen is the dominant overall control mechanism. In physiological situations such as solid organ transplantation, chronic viral diseases, and organ specific autoimmune diseases, antigen is usually not cleared, but the immune system develops various control mechanisms that limit immune damage. In addition to his role as the Director of the UAB Medical Scientist Training Program (joint MD/PhD training), Dr. Bucy's lab is engaged in a wide range of projects with a translational focus, that span the gamut of basic mechanistic studies in mice to active design of human clinical trials. Active current projects include use of TCR transgenic mice to study murine heart transplant tolerance, analysis of T cell population dynamics in response to various forms of immunization, studies of viral and cellular dynamics in SHIV infected Rhesus Macaques, and a substantial series of studies focused on therapeutic immunization of HIV infected people and assessment of changes in immune function in these people. In all of these systems, multiple techniques are used including flow cytometry, immunohistochemistry, cell culture techniques, production of novel transgenic mice, real-time RT-PCR,. and in situ hybridization analysis of viral and cellular RNA species.
Noel K. Childers, DDS, PhD Dr. Childer's current studies involve investigations aimed at identifying safe and effective mucosal immunization delivery systems. Specifically, studies examine the characteristics of liposomes that are important in potentiating immune responses to orally or nasally administered S. mutans antigens. This involves in vitro studies of the physical characteristics of liposomal antigen preparations as well as in vivo studies into the uptake and processing of liposome preparations in rats. Following animals studies of the efficacy of liposomal S. mutans antigen vaccines, studies have been initiated for human FDA Phase I clinical trials studying the safety and immunogenicity of liposomal oral and nasal immunization. The overall goal of these studies are to identify a safe and effective oral immunization strategy which is protective against dental caries.
Clinical research interests also include studies to determine risk factors for oral complications in children with cancer and HIV infection. These studies have assessed various clinical and immunological factors involved in the development of oral lesions in medically compromised children. The goal of this research is to develop and test protocols that will prevent the occurrence or severity of oral complications in children identified to be at risk. Additionally, research efforts have involved assessment of the prevalence of dental disease in children as related to access to care. Related studies have assessed the effectiveness of dental sealants in prevention of dental caries using Medicaid claims as well as Jefferson County Department of Public Health records.
Randy Q. Cron, MD, PhD CD154 (CD40 ligand) dysregulation in lupus. Systemic lupus erythematosus, the prototypic autoimmune disorder, affects 1 in 2,000 women in the United States. Although the etiology and pathogenesis are unclear, the over-expression of the TNF family member, CD154, on CD4 T lymphocytes clearly contributes to disease pathology, both in mouse models and in humans with disease. Ourultimate goal is to identify cis- and trans-acting elements that contribute to the dysregulated expression of CD154 in SLE and other autoimmune disorders. We initially characterized the human CD154 transcriptional promoter and demonstrated its cyclosporin A (CsA) sensitivity. We are currently probing the hCD154 gene locus by DNase I hypersensitive site mapping to identify novel regulatory elements. We have identified and partially characterized a 5’ transcriptional enhancer, a 3’ transcriptional enhancer, and a 3’ untranslated mRNA stability element. In addition, we have identified an uncharacterized 5’ hypersensitive site farther upstream of the transcription start site. We are currently exploring the activities of these various CD154 regulatory elements as transgenes in a mouse model of SLE. In conjunction, we have identified various transcription factors and RNA binding proteins, which had not been previously described to regulate CD154 expression. We are currently exploring these factors for their contributions to CD154 dysregulation in SLE.
Host transcription factors exploited by HIV-1. HIV-1, the cause of AIDS, has infected over 40 million individuals world-wide. Although vast improvements in therapy have been developed over the last decade, HIV-1 cannot be totally eliminated from the host due to its ability to enter a resting or latent state in CD4 T cells. Because HIV-1 relies on host transcription factors to replicate, we are exploring the role of the calcium activated nuclear factor of activated T cells (NFAT) transcription factors in regulating HIV-1 transcription. We and others have shown that the CsA-sensitive NFAT proteins bind to the proximal HIV-1 promoter/long terminal repeat (LTR) in vitro and up-regulate HIV-1 transcription. We have further demonstrated that NFAT proteins bind to the integrated HIV-1 LTR in primary human CD4 T cells in vivo by chromatin immunoprecipitation, and this binding is disrupted by the regulatory T cell transcription factor, FOXP3. In addition, we are attempting to exploit NFAT activation as a means of activating HIV-1 LTR activity in latently infected cells. Recently, we identified a novel binding site for the c-maf transcription factor located adjacent to the proximal NFAT sites in the HIV-1 LTR. Our studies reveal synergistic transcriptional activation and increased infection of HIV-1 by c-maf, NFAT2, and NFB p65 in primary human IL-4-producing CD4 T cells. Thus, c-maf will likely be a novel therapeutic target in the treatment of HIV-1.
Randall S. Davis, MD Dr. Davis’ laboratory investigates pathways of normal lymphocyte differentiation to determine the mechanisms that contribute to lymphomagenesis, autoimmunity and immunodeficiency. This work largely focuses on an ancient family of Ig-like receptors with tyrosine-based activating or inhibitory signaling potential. A search for possible Fc receptor relatives identified several novel Ig superfamily genes in humans and mice termed Fc receptor-like molecules (FcRL). FcRL family members are preferentially expressed in B lymphocytes and differentially identified in B lineage malignancies. Follow-up studies have identified eight human and seven mouse relatives in total. The recognition of this family has significant implications for understanding connections between innate and adaptive humoral immunity, the regulation and terminal differentiation of B cells into memory and plasma cells, and possibly, the pathogenesis of B cell malignancies and autoimmunity. Their expression patterns, signaling potential, ligands, and translational potential are areas of active investigation.
Jessy Deshane, PhD Dr. Deshane is committed to an academic career combining basic and translational research with an emphasis on inflammatory diseases of the airway. The focus of Dr. Deshane's research program is to enhance our understanding of the role of myeloid-derived regulatory cells in chronic airway inflammatory diseases. Asthma is a chronic inflammatory disease of the airways in which innate and adaptive immune cells participate as drivers of the inflammatory response. Free radical species have long been implicated as critical mediators of the asthmatic inflammatory process. Dr. Deshane's studies in a mouse model of allergic airway inflammation have established that subsets of free radical-producing myeloid-derived regulatory cells (MDRC) are master regulators of airway inflammation. They are potent modulators of both T cell responses and airway hyper-responsiveness. Dr. Deshane has identified human MDRC with similar function in bronchoalveolar lavage of asthmatics. Her current research interests are (1) to explore the free radical and cytokine/chemokine mediated mechanisms underlying the differentiation and function of myeloid derived regulatory cells in the establishment of airway inflammation and resolution of inflammation (2) to investigate MDRC- mediated regulation of the balance of Tregulatory cells and Th17 cells which control the tolerance vs inflammation (3) to understand how environmental pollutants such as tobacco smoke would impact MDRC function and contribute to exacerbation of inflammation in asthmatic smokers. These studies will provide insight into the role of MDRC in tobacco related pathology of the lung.
Jeffrey C Edberg, MD Wegener’s granulomatosis, an anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic small vessel vasculitide, is characterized by inflammatory lesions with granuloma formation in the upper and lower airways, pauci-immune glomerulonephritis, and anti-proteinase 3 autoantibodies. Although Wegener’s granulomatosis is considered idiopathic, there has been substantial interest in environmental factors as either etiologic or accelerating risk factors, with Staphylococcus aureus having attracted substantial attention as one such environmental factor. Although consensus about etiology remains elusive, the nature of the host response has emerged as an important determinant for disease phenotype and severity. Although Wegener’s granulomatosis occurs sporadically, and does not show classical familial clustering and transmission characteristic of some autoimmune diseases, the identification of important genetic factors in Wegener’s granulomatosis is not only feasible but also potentially very fruitful in providing insights into pathogenesis and potential therapeutic targets. Building on the clinical trial of etanercept in Wegener’s granulomatosis, Dr. Edberg, in collaboration with Drs. Kimberly and Kaslow, is developing a renewable genetic repository to explore the relationship between the Wegener’s granulomatosis diathesis and genetic polymorphisms in candidate molecules, selected for their role in pathophysiology. These studies also will involve identification of new polymorphisms in such molecules and application of these to this cohort.
Craig A. Elmets, MD Dr. Elmets’ research focuses on the interaction of environmental agents with the skin. His research has particular relevance to skin cancer and cutaneous allergic reactions. In the area of skin cancer, his interests are on skin cancer chemoprevention and therapy. He has played a key role in defining the mechanisms by which the immune system controls the development of skin cancers. More recent studies have centered on the identification of new agents that can protect against skin cancer and on the non-surgical treatment of these malignancies. These include the arthritis drug celecoxib and extracts of green tea. He has also played a major role in the development of photodynamic therapy as a treatment for cancer. Photodynamic therapy utilizes light activated drugs to eradicate cancer. Dr. Elmets’ other area of research is on allergic contact dermatitis, of which poison ivy is the best-known example. He is evaluating better and more accurate diagnostic techniques for contact allergies. His studies have shown that certain proteins called cytokines are synthesized in skin cells from allergic individuals exposed to contact allergens but not in those obtained from people who are the not allergic. These findings provide the conceptual framework for the development of a diagnostic test for skin allergy testing, which can used by physicians and by industry as an alternative to animal testing prior to the introduction of new products into the marketplace.
Charles O. Elson III, MD The central focus of the laboratory is on the regulation of mucosal immune responses, particularly the mucosal immune response to the microbiota, which represent the largest mass of antigen encountered by the immune system. The cellular and molecular mechanisms that maintain mucosal immune homeostasis are being defined. When these mechanisms fail, pathogenic effector T cells are generated that result in colitis. We have cloned a set of immunodominant antigens of the microbiota that stimulate such pathogenic T cells and result in inflammatory bowel disease. Among these cloned antigens, previously unknown bacterial flagellins have emerged as a major cluster. Seroreactivity to these flagellins is found in multiple experimental models of colitis in mice and in half of patients with Crohn's disease. These antigens drive a newly described CD4 T cell effector subset making IL-17 (Th17) which appears to be responsible for disease progression. A T cell receptor transgenic mouse reactive to CBir1 flagellin has been generated and is being used to study the innate and adaptive immune response to these microbiota antigens. A second major effort is in the identification of T reg cells in the intestine that recognize microbial antigens and maintain homeostasis. The mechanisms whereby such cells are induced are being defined and the application of these cells to prevent or treat intestinal inflammation is being tested. Lastly, a microbiota antigen microarray has been constructed which can be used to analyze serologic reactivity to the microbiota in both mouse and human. Sera from various human populations are presently being analyzed.
Maaike Everts, PhD Dr. Everts is Research Project Director with the Alabama Drug Discovery Alliance; in that capacity she interfaces with a wide range of scientists involved in the drug discovery and development process, with a focus on projects in oncology, infectious diseases and neurodegenerative disorders. She is trained in the pharmaceutical sciences and has a broad range of publications in drug delivery, adenovirus-based gene therapy as well as nanotechnology, highlighting her experience in interdisciplinary research teams.
David O. Freedman, MD Dr. Freedman's research program encompasses four areas of investigation: 1) Development of global provider-based surveillance networks for characterization of infectious disease morbidity in travelers and migrants using innovative electronic communications modalities. Director of GeoSentinel, a CDC-funded global surveillance network of 33 travel/tropical medicine units on 6 continents; 2) Development of novel techniques for the clinical teaching of tropical medicine to graduate physicians from industrialized countries, on-site in the tropics while maintaining all traditional accreditation standards. Director of the Gorgas Courses in Clinical Tropical in Lima, Peru with 50 participants/years from 12-20 countries; 3) Development of novel strategies to track global trends in disease and occupational health risk among employees of multinational corporations; and 4) Development of a simple, low-cost diagnostic platform that performs multiple parallel bioassays (nucleic acid-based assays and immunoassays) at the point of care in the developing world using nanotechnnology.
James F. George, PhD Dr. George’s research focuses on the mechanisms of transplantation tolerance induction and immunologic mechanisms of vascular disease in solid organ transplant patients. He and his colleagues perform clinical studies using patient data as well as basic molecular studies using a mouse heart and kidney transplantation models. They study the role of T cell mediated innate immune responses in the development of intimal proliferative lesions of the type that are typically found in over 30% of heart transplantation patients after the first three years post-transplantation. They use induced mutant mice to study the role of Interferon-g and other cytokines in the initiation and progression of vascular lesions. Other interests include the mechanisms by which extracorporeal photopheresis results in downregulation of anti-donor responses in vivo, both in animal models and clinical heart transplant patients.
Other Immungenetic Investigations. My colleagues and I have also studied host genetic factors involved in various other conditions. These include non-Hodgkin lymphoma, Kaposi sarcoma, varicella-zoster virus infection, Kawasaki syndrome, and response to other vaccines (e.g., HBV).
Robert P. Kimberly, MD Our laboratory is interested in the role of genetic factors in the normal function of the immune system and in development of autoimmune and immune-mediated inflammatory diseases such as systemic lupus erythematosus and systemic vasculitis. Our approach has focused on receptors for immunoglobulin (Fc receptors) as a model system and has explored molecular mechanisms of receptor signaling and the molecular basis for receptor polymorphisms in humans. Studies in cell lines and in normal donors have demonstrated that despite the common theme of receptor-induced tyrosine phosphorylation, the various human Fc receptors engage different signaling elements which are reflected in important distinctions in function. Similarly, allelic variations in receptor structure profoundly affect receptor function, and certain low-binding alleles are enriched in SLE patients. More active alleles are over-represented in patients with vasculitis and severe renal disease. Other genes and gene families are being pursued as they are identified as candidate genes through genome wide association studies. These genes include complement receptors, cytokine genes and their promoters, signal transduction molecules, and members of the TNF superfamily.
Roslyn Mannon, MD Long term kidney graft failure continues to be a difficult problem in spite of potent immunosuppressive strategies with improved acute rejection rates and short term graft survivals. This is due both to death with a functioning allograft and the associated co-morbidities of kidney failure, as well as primary graft failure. The leading cause of late graft dysfunction and failure is due to a pathological entity characterized by allograft fibrosis and tubular atrophy (IF/TA), a disease with both immunological and non-immunological etiologies, and no specific therapies. To this end, we have developed an active research program in kidney and kidney/pancreas transplantation that spans the spectrum of basic science, translational studies, and clinical research.
Our Transplant Clinical Research Center provides the personnel and infrastructure to engage not only in pharmaceutical-based studies, but supports clinical studies in transplantation that are investigator initiated and sponsored by the National Institutes of Health. Our current studies include investigating the clinical etiologies of kidney allograft failure (NIAID), the genomics of early and late allograft injury (NIAID), immune monitoring after depletional induction therapies (Immune Tolerance Network) and major clinical interventional immunosuppression trials (Clinical Trials in Organ Transplantation—CTOT) sponsored by NIAID.
The long term goal of our laboratory is to identify new mechanisms and associated biomarkers in the detection and treatment of IF/TA. Utilizing rodent models of kidney and heart transplantation and models of calcineurin inhibitor toxicity, we study the cellular, molecular, and physiologic events following transplantation. We have used these models as platforms for translation into our human patients following kidney transplantation through a broad series of analytical techniques including genomics and proteomics.
Jiri Mestecky, MD, PhD Molecular-cellular interactions involved in the differentiation of B lymphocytes and epithelial cells of the mucosal immune system and the novel approaches for the induction of the humoral immune response in external secretions represent the primary area of interest in our laboratory. Regulation of the expression of immunoglobulin isotypes, with emphasis on IgA and J chain synthesis, are studied in human systems under normal as well as pathologic conditions. The interactions of IgA molecules of various properties (including those found in IgA-containing immune complexes) with lymphoid cells, macrophages, hepatocytes, eosinophils, and epithelial cells are investigated in a variety of human diseases afflicting the gastrointestinal and genitourinary tracts. Development of vaccines against AIDS and sexually transmitted diseases is pursued using novel antigen delivery systems and combination of immunization routes to stimulate mucosal immunity in the genital tract.
John D. Mountz, MD, PhD A hallmark of autoimmune disease is the development of autoantibodies that can cause disease. My laboratory has identified that the second recombinant inbred strain of B6 x DBA/2 (BXD2) spontaneously produces very high levels of pathogenic autoantibodies. Single antibodies produced by hybridomas from spleens of these mice transfer arthritis or glomerulonephritis in normal mice. By 3 months of age, the spleens of BXD2 mice are greatly enlarged and are packed with numerous large, spontaneous germinal centers (GCs). This GC development is promoted by high levels of Th17 and IL-17 in these mice. IL-17 signals through the IL-17a receptor in B cells resulting in increased classical NF-κB pathway activation. This activates several genes, including regulators of G-protein signaling (RGS) 13 and 16. Upregulation of RGS genes impairs signaling through CXCR4/CXCL12 and CXCR5/CXCL13 to arrest migration and movement of T cells and B cells. This enables prolonged and stable interaction of B cells and CD4 T cells. Key ongoing questions in my laboratory include what is the mechanism for increased Th17 development. IL-6 is highly produced by B cells, macrophages and plasmacytoid dendritic cells (PDCs). TGF-β, however, is not greatly increased. What are the factors, in combination with IL-6, that promote high Th17 development in BXD2 mice? How does Th17 signal through B cells? Our recent evidence indicates that IL-17 signaling requires both TRAF6 and ACT1, which has been identified in IL-17 signaling pathways. Current ongoing work is to determine the mechanism of increased NF-κB signaling in response to IL-17 in B cells. Also using RGS13 KO and RGS16 KO mice, we wish to determine which of these RGS proteins is highly essential for development of spontaneous autoreactive GCs. We also wish to identify the most promising points for interruption of IL-17 signaling that upregulates RGS expression in B cells. Other studies include detailed analysis of the effect of IL-17 on B cell chemotaxis in response to CXCL12 and CXCL13. These include in vitro chemotactic chamber analysis, and live imaging analysis using confocal microscopy.
A second area of interest is the role of DR5 apoptosis in arthritis and autoimmune Disease. TRAIL-DR5 apoptosis signaling is very similar to FAS apoptosis signaling involving mitochondrial amplification loop and Bcl-2 family members, as well as direct induction of apoptosis through caspase activation resulting in terminal caspases 3, 5, and 7 activation. The TRAIL-DR5 apoptosis signaling pathway, like Fas, is inhibited by FLIP-L and XIAP (inhibitors of apoptosis proteins). DR5 is upregulated on synovial fibroblasts of patients with rheumatoid arthritis and in Collagen-II mouse model of arthritis. To determine mechanisms of DR5 apoptosis in vivo, we have produced a human-mouse (hu/mo) chimeric DR5 transgenic mouse. This mouse transgene is driven by the 3 kB mouse DR5 promoter and is regulated by a Floxed-STOP between the promoter and the hu/mo chimeric DR5 transgene. Thus, expression of hu/mo DR5 chimeric transgene can be targeted to synovial fibroblasts, B cells, T cells, or macrophages. In collaboration with Dr. Tong Zhou, we are analyzing the ability of a novel anti-human DR5 antibody (TRA8) to regulate arthritis and immune responses in these chimeric DR5 transgenic mice.
My laboratory has longstanding interest in age-related immune senescence. We were one of the first investigators to propose that T cell senescence is due to decreased, rather than increased, apoptosis. This was directly demonstrated using a CD2-Fas Tg mouse that resulted in increased expression of Fas throughout the lifespan of the mouse. This resulted in decreased T cell senescence. Our recent interest in T cell senescence is being carried out in a study of nonagenarians in collaboration with Dr. Michal Jazwinski (Tulane University) and Dr. Donald Scott (University of Pittsburgh). Nonagenarians are protected from immune senescence by several factors including increased levels of certain hormones, such as leptin and Insulin like growth factor binding protein 3(IGFBP3). Our ongoing studies are further characterizing methods to prevent immunosenescence with aging. This is relevant to preservation of immune responses tat may help prevent development of cancer, and provide adequate protection against viruses.
Joseph Murphy, PhD Dr. Murphy's specific interests are in: (a) Symbiotic relationship between cancer and angiogenesis; (b) Immune modulation as a means of anti-cancer and anti-angiogenic therapy; (c) Microarray analysis and target validation; (d) Cyclooxygenase mediation of angiogenesis and cancer; (e) Integrin modulation of angiogenesis; (f) Endothelial cell adhesion molecules involved in leukocyte adhesion and angiogenesis; (g) Enzyme-linked immunosorbent assay development for early detection of cancer
Moon Nahm, MD Dr. Nahm's laboratory is interested in vaccines against Streptococcus pneumoniae, an important human pathogen. Currently available pneumococcal vaccines use capsular polysaccharides themselves or the polysaccharides conjugated to carrier proteins. To evaluate these currently available vaccines, it is critical to be able to reliably measure the amount and protective capacities of the antibodies to capsular polysaccharides, which provide vaccine-induced protection. We have investigated the molecular structure and the protective capacity of the antibodies to pneumococcal capsular polysaccharides. His group has also improved and standardized the assays used to measure the protective capacity of these antibodies. To facilitate the adoption of these standardized assays worldwide, we are currently serving as the pneumococcal vaccine reference laboratory for the National Institute of Health and the World Health Organization.
Since the currently available pneumococcal vaccines have limitations, Dr. Nahm's laboratory is investigating pneumococcal lipoteichoic acid (LTA) as a new vaccine candidate. LTA is found on Gram-positive bacteria and is analogous to LPS from Gram-negative bacteria. LTA is an amphipathic molecule with a polysaccharide chain and two acyl chains. Because its purification has been difficult, its pathogenic role and its ability to stimulate the innate and adaptive immune systems are unknown. In view of this, they have developed a novel method of purifying LTA and are currently investigating its ability to stimulate innate immune responses as well as its role in pneumococcal adhesion to host cells. The group has shown that pneumococcal LTA stimulates cells via TLR2 and perhaps via the platelet-activating factor receptor as well. They are currently evaluating the role of LTA-induced lipid rafts in pneumococcal adhesion to host cells and its stimulation of these receptors.
Harry W. Schroeder, MD, PhD Ultimately, it is the identity and specificity of the lymphocyte antigen receptor that determines the nature of the immune response to antigen. The mechanisms that underlie the diversification of the B- and T-cell antigen receptor repertoires appear to generate receptor diversity at random. However, repeated examples of near to absolute identity of receptor sequences between individuals suggest the existence of genetically programmed constraints that may be designed to bias the immune system to produce preferred, and perhaps optimal, repertoires. The implication is that violation of these programs could lead to immune dysfunction, and thus to disease. To test this hypothesis, we are developing mouse models wherein we force expression of altered, polyclonal repertoires that violate normal constraints on antigen receptor sequence or structure. In the first of these mice, where we have forced expression of arginine, histidine and asparagine in the HCDR3 interval of immunoglobulin H chains, we observed somatic selection against antigen binding sites that contained an excess number of these charged amino acids, yet the system ultimately failed to recapture the tyrosine and glycine residues normally encoded by wild-type germline sequence. B-cell development was impeded, immunity to influenza virus was impaired, and expression of IgG anti-DNA antibodies was enhanced. These results support the view that optimal distinction between self and non-self is a product of evolutionary selection.
Lisa M Schwiebert, PhD The major research interests of the laboratory include studying the physiology and pathophysiology of immune responses within the lung. These interests encompass the study of respiratory disorders in order to understand the cellular and molecular mechanisms that underlie airway inflammation. On-going projects examine how surface molecules, such as CFTR and CD40, regulate the airway epithelial expression of pro-inflammatory mediators, including chemokines and adhesion molecules, that initiate and exacerbate leukocyte migration. In addition, we are examining the anti-inflammatory effects of aerobic exercise on asthma-related immune responses. Through increased understanding of the mechanisms that trigger airway inflammation, we hope to develop novel therapeutic agents that combat airway inflammatory diseases such as cystic fibrosis and asthma.
Tong Zhou, MD Dr. Zhou’s research is centered on the characterization of apoptotic pathways with a view to therapeutic manipulation in autoimmune and inflammatory disease. In the first approach, Dr. Zhou has collaborated closely with Dr. Mountz, to demonstrate that strategies centered on Fas ligand might prove useful in the therapeutic regulation of autoimmune disease. To by-pass the toxic effect of soluble Fas ligand, Dr. Zhou, in close collaboration with Dr. Mountz, has used cell-gene therapy consisting of an antigen presenting cell transfected with AdFas ligand to eliminate chronic inflammation and autoimmune disease in a number of murine models of these disease. The utility of this approach is being improved by the incorporation of elements that permit timed induction of discrete levels of Fas ligand to eliminate activated T cells in an antigen-specific manner. This APC-Fas L cell-gene therapy approach has proven useful in the experimental analysis of Fas-mediated apoptosis and antigen-induced cell death in autoimmune disease and may prove useful as a therapeutic strategy in the prevention of post-infectious chronic inflammation or organ-specific disease. In the second approach, Dr. Zhou has developed agonistic and antagonistic monoclonal antibodies that discriminate the DR5 TRAIL receptor and is using these to characterize the distribution of this receptor among T cell populations during activation responses as well as the associated signal transduction events. The ability of these monoclonal antibodies to specifically inhibit autoimmune reactions is being analyzed in various murine models, including models of SLE, collagen II-induced arthritis, and experimental allergic encephalitis. Similar approaches are now being used to characterize the role of B lymphocyte stimulator (BLyS) in SLE in a coordinated effort involving collaboration with Drs. Alarcon, Fessler, and Kimberly.