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.
|Daniel C. Bullard , PhD, Department of Genetics
|David Chaplin, MD, PhD, Department of Microbiology
|Irshad H. Chaudry, PhD, Department of Surgery
|Jessy Deshane, PhD, Department of Medicine
|Craig A. Elmets, MD, Department of Dermatology
|Kent T. Keyser, PhD, Department of Vision Sciences
|Robert Kimberly, MD, Dept of Medicine/Clin Immunol & Rheumatology
|John Mountz, MD, PhD, Dept of Medicine/Clin Immunol & Rheumatology
|Laura Timares, PhD, Department of Dermatology
|Casey Weaver, MD, Department of Pathology
|Nabiha Yusuf, PhD, Department of Dermatology
Daniel C. Bullard, PhD My research interests are centered on defining the mechanisms that regulate inflammation. For these investigations, we have focused our studies on defining the roles of leukocyte/endothelial cell adhesion molecules in mediating inflammatory responses. These proteins, along with chemoattractant/activating molecules, mediate the process by which leukocytes exit the vasculature into tissue in response to an inflammatory stimulus. Many different adhesion molecules have been described, including the selectins, integrins, and members of the immunoglobulin superfamily of adhesion receptors. Recent evidence from our lab and others suggest that these molecules play both pro- and anti-inflammatory roles, and we are using a genetic approach in mice to further define these functions. For our studies, we have developed many different lines of adhesion molecule mutant mice using gene-targeting methodologies. Mice with single or multiple mutations are currently being analyzed in models of rheumatoid arthritis, lupus erythematosus, vasculitis, and inflammatory bowel disease to determine their specific roles in the pathogenesis of these diseases. Our lab has also characterized a novel model of psoriasis that develops in Beta-2 integrin mutant mice backcrossed onto the PL/J strain background. We are now trying to map and clone the loci that control the initiation and progression of skin disease in PL/J mice. Other studies include analyzing the roles of T cells in the development of skin inflammation in this model.
David D. Chaplin, MD, PhD Cytokines of the TNF/lymphotoxin (LT) family signal the development of organized lymphoid tissues. Mice deficient in LT-alpha fail to form lymph nodes and Peyer's patches. They also show disturbed spleen white pulp structure, with failure to segregate B cell and T cell zones, and to form primary B cell follicles with clusters of follicular dendritic cells (FDC). TNF also is required for the formation of primary B cell follicles. Infusion of purified LT-expressing B cells restores development of FDC and primary follicle structure. This demonstrates an unexpected role of B cells as organizers of the lymphoid tissue microenvironment in which the B cells themselves ultimately mature. Normal lymphoid architecture is particularly important for the development of mature antibody responses. This manifests itself in failure of antibody affinity maturation in LT-deficient mice, including failure both to form and to express B cell memory responses. Future studies will define additional signals that establish the normal structure of lymphoid tissues and will define the ways this structure supports a properly regulated immune responses, particularly memory B cell responses. Other studies investigate cytokines as regulators of tissue inflammatory responses, particularly allergic inflammation. These studies have shown that in the skin, IL-1 beta is required for recognition that new antigens have penetrated the epidermis. Without IL-1 beta, there is no activation of Langerhans cells (LC), and these LC fail to deliver antigens from the epidermis to draining lymph nodes. These studies have also shown that in the lungs Th2 cell-dependent allergic inflammation is characterized by an influx of both Th1 and Th2 cells. In fact, Th1 and Th2 cells cooperate to elicit the eosinophil-predominant infiltrates that are characteristic of this response. The long-term aim of these studies is to define the signals that initiate recruitment of helper T cells to peripheral tissues and that modulate the character of the inflammatory response. A major signal for this recruitment is locally produced TNF, acting largely through activation of expression of endothelial adhesion proteins that then support Th cell recruitment.
Irshad H. Chaudry, PhDCurrent research interests include determining the mechanisms responsible for cellular and subcellular alterations following soft tissue trauma, bone fracture, hemorrhage and sepsis. Additionally, the use of novel, readily available, FDA approved inexpensive therapeutic agents to attenuate such alterations in patients following trauma is planned. Other areas include evaluation of: (1) gender dimorphism and the mechanisms responsible for producing cardiovascular and hepatocellular dysfunction and immunological alterations following trauma-hemorrhage; (2) trauma-induced changes in the hypothalamus-pituitary-adrenal axis; (3) apoptosis of immune cells; and (4) wound healing. Specific research interests include determining the mechanism of regulation of estradiol levels by hypothalamic/pituitary factors, adrenals and steroidogenic enzyme activity and how differences in estradiol levels or the estradiol: androgen ratio due to the estrus cycle, ovariectomy, and age affect immune responses after trauma. Studies of T lymphocytes, macrophages and Kupffer cell functions using molecular biological techniques are being conducted to determine why low estradiol fails to maintain immune functions in aged females after trauma. The use of estradiol, Raloxifene, prolactin, metoclopramide, or flutamide to restore immune/cardiovascular functions following trauma should yield novel information and provide an innovative approach for improving the host responses and reducing mortality from sepsis following trauma in postmenopausal and in surgically ovariectomized patients with low estrogen activity. Additional interests encompass the mechanisms by which androgen depletion/androgen antagonists improve cardiac performance and other organ functions after trauma. These studies also examine whether androgen depletion/androgen antagonists affect the adrenals and modify the response of the heart, liver and vascular smooth muscle to catecholamines. The hemodynamic parameters and organ functions being measured include blood flow, circulating blood volume, cardiac output, left ventricular performance, vascular reactivity, liver, gut, adrenal and pulmonary functions. The integration of cardiac function with other organ functions and detailed mechanistic studies at the cellular and subcellular levels using physiological, pharmacological and molecular biology techniques to identify targets for novel treatment modalities using sex steroid antagonists/agonists or hormones should provide new information for the improved treatment of trauma victims with major blood loss and for decreasing the susceptibility to sepsis following trauma.
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.
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.
Kent T. Keyser, PhD Dr. Keyser's research interests center on acetylcholine (Ach) and Ach receptors. Acetylcholine is used as a transmitter in many portions of the vertebrate nervous system and much information is available concerning the cells that contain it and its synthesis and release mechanisms. However, until recently little was known about Ach receptors and the neurons that express them, During the past several years various groups have 1) purified the ligand-binding (a) and structural (b) subunits of neuronal nicotinic acetylcholine receptors (nAChRs), 2) cloned their cDNAs, and 3) raised antibodies against them. These studies have revealed that there are at least 11 different subunits which, in various combinations, can theoretically yield a vast number of nAChR subtypes, each characterized by a unique subunit composition. Many of the subtypes that have been described to date differ from one another in their pharmacological characteristics. Therefore, the effects of Ach or its agonists depends upon which receptor subtype is present at a given synapse. Acetylcholine is known to act as a transmitter in the retina and affects the response properties of many ganglion cells, including those that display directional selectivity. My research program involves the investigation of the normal pattern of expression of nAChRs in the retina and central visual structures during embryogenesis and in the adult animal. Another aspect of the research involves the detection of additional receptor subunits/subtypes and the determination of what receptor subunits are found together within individual receptor complexes. Among his long term goals are studies of the factors that regulate expression of different Ach receptor subtypes in various areas of the nervous system.
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.
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.
Laura Timares, PhD My lab is interested in understanding aspects of cutaneous immunology and carcinogenesis. Most of my research has focused on understanding the biology of skin-resident antigen presenting dendritic cells (DCs), termed Langerhans cells (LCs), with the aim of targeting them for the development of “next generation” topical vaccines. Depending on the environmental cues they receive at the affected skin site, LCs can initiate either tolerogenic or immunogenic adaptive immune responses.
Recently, we discovered that murine LCs specifically undergo cell death following successful activation of antigen-specific naïve CD4+ T cells, which limits their immunogenic potential. We have shown that LC apoptosis depends on the pro-apoptotic Bcl-2 family molecule BID; BID-deficient LCs are resistant to CD4+ T cell-induced death as well as mechanisms of UV radiation-induced tolerance and are highly immunogenic. How such apoptosis-resistant DCs induce enhanced T cell responses, evade induction of regulatory T cell (Treg) development, and how T cells trigger DC death are under investigation. Using engineered LC-deficient mouse strains, we are investigating LCs role in mediating tolerance and in promoting or protecting against skin carcinogenesis.
We have genetically engineered DCs and DNA-based “epitope-focused” vaccines to test whether we can bolster immune surveillance effectors that can block carcinogen-induced tumors at early stages. These engineered vaccines can induce antigen-specific immunity to a single point mutation, which boosts immune-surveillance and partially prevents the formation of carcinogen-induced skin tumors. These results have encouraged us to develop humanized vaccines to test in translational studies in a select group of high-risk patient populations (in collaboration with Dr. C.A. Elmets).
A relatively new area of research is in defining molecular mechanisms that drive cell transformation. We are developing new murine models of spontaneous melanoma with the aim of elucidating the role of immune-modulatory factors in regulating melanoma initiation and progression, and to identify oncogene mutations that may model human melanoma and test their potential as protective epitope-focused vaccines. In other studies, we have found that a novel pro-survival isoform of the pro-apoptotic molecule BID is associated with repair functions in cycling keratinocytes damaged by UV radiation. The opposing functions, defined by differential post-translational modifications of BID, are reminiscent of modifications that regulate p53, the “master regulator” of cell fate. We are working with Dr. M. Athar to explore potential cooperative mechanisms that may exist between BID and p53, with the hope of defining interdependencies that might be exploited for treating or inhibiting cancer initiation, growth and/or progression.
Casey Weaver, MD The research in my laboratory concerns the mechanisms by which CD4 T cells control adaptive immunity. Major current projects are: the generation and characterization of transgenic and knock-in mouse models for tracking T cell fate during CD4 effector and memory T cell development (Saparov et al., Immunity 11:271, 1999; Hurez et al., J. Exp. Med., 198:123, 2003); studies defining mechanisms that induce development of the Th17 effector lineage (Harrington et al., Nature Immunology 6:1123, 2005); characterization of mechanisms by which dysregulation of CD4 T cells leads to inflammatory bowel disease (Iqbal et al., J. Exp. Med., 195:71, 2002; Elson et al., Curr. Opinion in Gastroenterology 20:360, 2004); delineation of the adhesion pathways that control effector T cell trafficking (Mangan et al., Amer. J. Pathology, in press); and, characterization of the genetic elements that regulate cytokine gene expression in Th1 and Th17 cells (Dzialo-Hatton et al., J. Immunol. 166:4534, 2001).
Nabiha Yusuf, PhD Our laboratory is involved in evaluating the effect of environmental influences such as chemical carcinogens and ultraviolet radiation on the skin immune system. The focus of our research is on the role of innate immunity in the development of skin carcinogenesis. Toll-like receptors (TLRs), one component of innate immunity, are intricately associated with a number of dermatologic conditions. We have found that the innate immune system mediates through Toll like receptor-4 (TLR4) signaling to activate the cell mediated adaptive immune response against chemically induced tumors. TLR4 signaling had a protective effect against 7,12-dimethylbenz(a)anthracene (DMBA) induced skin cancer in certain strains of mice which develop cell mediated immune response to this chemical carcinogen. We are currently in the process of evaluating the role of innate immune system in ultraviolet B (UVB) radiation induced skin cancer. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, there is little information on the role of innate immunity in this process. Our recent experiments suggest that certain components of innate immunity, especially TLR4, may play an important role in photoimmunosuppression. Currently, we are investigating whether the resistance of TLR4 gene knockout mice to UVB-induced immunosuppression has implications for photocarcinogenesis. The ultimate goal of these studies will be to define the role of TLR4 in the development of immune suppression and tumor development that occurs following UV radiation. This may allow us to identify genetic loci that are involved in these processes and to develop immunopreventive and immunotherapeutic approaches towards them.