Inflammation

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.


Scott Barnum, PhD, Department of Microbiology
Daniel C. Bullard, PhD, Department of Genetics
David D. Chaplin, MD, PhD, Department of Microbiology
Jessy Deshane, PhD, Department of Medicine
Steven R. Duncan, Department of Medicine/ Division of Pulmonary, Allergy and Critical Care Medicine
Jeffrey Edberg, MD, Dept of Medicine/Clin Immunology & Rheumatology
Charles O. Elson, III, MD, Department of Medicine
F. Shawn Galin, PhD, Department of Medicine
James, F. George, PhD, Division of Cardiothoracic Surgery
Hui Hu, PhD, Department of Microbiology
Janusz H. Kabarowski, Ph.D, Department of Microbiology
Jannet Katz, PhD, Department of Pediatric Dentistry
Robert Kimberly, MD, Dept of Medicine/Clin Immunol & Rheumatology
Robin G. Lorenz, MD PhD, Department of Pathology
Frances E. Lund, Department of Microbiology
Suzanne M. Michalek, PhD, Department of Microbiology
Joseph Murphy, PhD, Southern Research Institute
Chander Raman, PhD, Department of Medicine
Trenton R. Schoeb, DVM, PhD, Department of Genetics
Lisa Schwiebert, PhD, Department of Cell, Developmental, & Integrative Biology
Chad Steele, PhD, Dept of Medicine/Pulmonary, Allergy & Critical Care
Alexander Szalai, PhD, Dept of Medicine/Clin Immunol & Rheumatology
Hubert Tse, PhD, Department of Microbiology
Tong Zhou, MD, Department of Medicine



Scott R. Barnum, PhD My research interests have been on the production and regulation of several components in the complement system. These interests focused on the central nervous system (CNS) based on growing evidence for a role for complement in CNS diseases. This led us to examine for the production and cytokine-mediated regulation of additional activation components, as well as, complement regulatory proteins. It is now clear that, at least in vitro, most if not all complement proteins can be synthesized by astrocytes, microglia, and to our surprise, neurons. Since these initial observations, we have moved into in vivo models systems. Using a variety of disease models, including bacterial meningitis, brain trauma, experimental allergic encephalomyelitis (EAE) and a murine stroke model, we have demonstrated that a number of complement proteins and receptors are widely produced in the intact CNS under pathological conditions. We have recently expanded our interest in complement in the CNS to include C-reactive protein (CRP) and beta2-integrins and several of their ligands. We are examining the role of these molecules in EAE using several complement and adhesion molecule knock-out mice. In addition, we are using mice transgenic for CRP and several transgenic mouse lines that express either the complement regulatory protein (sCrry) or the complement anaphylatoxins, C3a or C5a, only in the CNS under the control of an astrocyte-specific promoter. Our data suggest that targeting these molecules has therapeutic value.

In other studies, we are examining the role of gamma/delta T cells in autoimmune disease in the CNS with a particular interest in trafficking and activation mechanisms. We have recently shown that these cells are critical to the development of EAE, but surprisingly little is known about the function of these cells in the pathogenesis of demyelinating disease.


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.


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.


Steven R. Duncan, MD Research interests of Dr. Duncan center on parsing out the immunological mechanisms involved in the pathogenesis of some morbid and mostly refractory chronic lung diseases, particularly idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease. Ongoing studies include those to better understand the processes by which human T-cells undergo genomic, phenotypic, and functional changes after repeated antigen encounters, and explorations of ways to specifically target these cells or interfere with their functions. A recently developed human-chimeric mouse model, in which these animals are reconstituted with a human adaptive immune system will be helpful. Other investigations in progress include more detailed characterization of the autoantibody repertoires in these disease populations, with the aim of identifying autoantibody (and T-cell) specificities with greatest utility in diagnostic or prognostic assays. Additional, interrelated projects include further explorations of recently discovered mechanisms by which T-cells regulate fibroblast production of extracellular matrix, and high resolution sequencing (and functional studies) of novel immunogenetic regulatory polymorphisms that confer high risks of developing these chronic lung diseases. In addition to these bench studies, we plan to continue and extend early phase trials of novel immunological response modifiers in these patients.


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.


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.

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F. Shawn Galin, PhD   Dr. Galin's current research objectives are focused around studying the effectiveness of a particular monoclonal antibody, F28C4, raised against an encephalitogenic peptide of myelin basic protein, as an idiotypic vaccine in the animal model of Multiple Sclerosis, experimental allergic encephalomyelitis (EAE). The rationale for using F28C4 as a vaccine results from the finding that an anti-idiotypic antibody to F28C4 cross-reacts with both F28C4 and encephalitogenic T-cell receptors and can suppress EAE. In addition to determining the efficacy of the vaccine in various animal models of EAE, his group is also involved in defining the mechanisms (i.e. humoral or T-cell mediated) involved in such protection. Lastly, they are attempting to resolve the X-ray crystallographic structure of the binding site of F28C4 to see how it relates to the binding sites of encephalitogenic T-cell receptors involved in the pathogenesis of EAE.


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.


Hui Hu, PhD  Utilizing a broad variety of techniques including cellular immunology, molecular biology, biochemistry, gene-targeting (knockout and knockin), functional genomics and in vivo animal models, the Hu laboratory is interested in identifying novel regulatory genes and transcriptional networks that play critical roles in regulating the adaptive immunity. One of the research projects in the Hu laboratory is to study T follicular helper (Tfh) cells and germinal center (GC) responses (Nat. Immunol. 2014). The complex regulation that determines the initial development of Tfh cells, their developmental progression in germinal centers, and their fates after an immune response dissolves, is still not fully understood. The Hu laboratory is interested in identifying novel pathways underlying the differentiation of Tfh cells in humoral responses and designing new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders. The Hu laboratory is also working to find ways to activate T cells under immunosuppressive circumstances. The Hu laboratory has demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state. If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge (Nat. Immunol. 2011). The Hu laboratory is interested in identifying regulatory genes and pathways that actively restrain T cell activation, and defining the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.


Janusz Kabarowski, PhD Dr. Kabarowski’s research program is focused on the study of lipids and lipoprotein metabolism in chronic inflammatory disease (notably atherosclerosis and autoimmune disease). Early work characterized the role of the G2A lipid receptor in atherosclerosis and lipoprotein metabolism, showing that pro-atherogenic effects of this receptor may be mediated through its modulatory influence on hepatic High-Density Lipoprotein (HDL) biogenesis. More recently, Dr. Kabarowski’s group described autoimmune-mediated effects on HDL metabolism in normolipidemic mouse models of Systemic Lupus Erythematosus (SLE) and currently a major effort of his laboratory is directed toward developing therapeutic approaches by which anti-inflammatory and immunosuppressive properties of HDL may be harnessed to improve major Lupus phenotypes and combat premature atherosclerosis, a major cause of morbidity and mortality in this and other rheumatic autoimmune diseases. Emphasis is placed on determining the mechanisms by which protective anti-inflammatory properties of HDL are subverted by chronic inflammation, understanding how this influences immunoregulatory processes involved in SLE and atherosclerosis, and establishing the therapeutic efficacy of HDL-targeted approaches such as HDL mimetic peptides in SLE and other autoimmune diseases.


Jannet Katz, DDS, PhD My research program is primarily directed to understand host/microbial interactions with emphasis on the pathogens Porphyromonas gingivalis and Francisella tularensis. P. gingivalis is involved in the development of periodontal disease, a disease that has been linked to cardiovascular disorders, diabetes, rheumatoid arthritis, low weight babies and complications of patients on hemodyalisis. My studies with P. gingivalis or its purified virulence antigens are centered around the innate and T cell host responses, as well as the signaling molecules and transcription factors involved in order to develop therapies or vaccines against infection. In addition, I recently began studies on the effect of P. gingivalis infection on DNA methylation patterns in general and specifically in the obese population. The second pathogen I work with is F. tularensis, the cause of tularemia. Due to the rapid dissemination of F. tularensis by various routes, it’s ability to infect the host through various mucosal surfaces and the high virulence of some of the strains, F. tularensis is considered a bioterrorism agent. My studies with F. tularensis are geared to understand the potential of this bacterium to infect various organs/tissues, the innate and adaptive immune responses induced upon infection in the context of signaling molecules and pathways, and the potential use of rapamycin as an innovative therapy to ameliorate the infectious process by dampening an exacerbated host response.


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.


Robin G. Lorenz, MD, PhD The focus of research in our laboratory is the study of the cellular components of the mucosal immune system and their interactions with the gastrointestinal epithelium, the GI microbiome, and the systemic immune response. Our first area of interest is the cellular immune response to Helicobacter in a mouse model of gastric infection and inflammation. The bacteria Helicobacter pylori is a major pathogen which is linked to acute and chronic gastritis and adenocarcinoma. It is also linked to protection from esophageal cancers and allergic asthma. We are currently investigating the interactions between gastric Helicobacter infection and asthma susceptibility in a mouse model of lung inflammation.

The second area of focus in our laboratory is the role of the intestinal epithelium and innate immune responses in the development of inflammatory bowel disease (IBD). The chronic intestinal inflammation that characterizes IBD is the result of a poorly controlled mucosal immune response to normal intestinal microbiota. The mechanisms that initiate this aberrant response are not well elucidated; however, one possibility is that a change in the intestinal epithelial barrier results in increased systemic exposure to microbial products. The P-glycoprotein (mdr1a-/-) deficient mouse is a unique model of spontaneous colitis that demonstrates an increase in colonic epithelial permeability, as well as a change in the sensitivity of toll-like receptors (TLRs) to bacterial products. Our laboratory focuses on investigating the relationships between the membrane pump- P-glycoprotein, microbial sensors-such as TLRs, and IBD. These studies utilize both in vivo models of IBD, as well as in vitro primary and continuous epithelial cell culture systems. The understanding of the basic mechanisms by which the host maintains intestinal homeostasis and barrier integrity will lay the foundation for future studies on the regulation of the inflammatory response and the design of therapies for human IBD.

The third focus of our laboratory is the influence of mucosal immune factors on the risk of type 1 diabetes development. The incidence of autoimmune Type I Diabetes (T1D) in both human patients and animal models is altered by genetic and environmental factors. These factors include an increased incidence after exposure to high fat diets and hygienic environments. These environmental effects are reproduced in the NOD mouse model of disease, where animals raised in a sterile environment have an increased incidence of disease. In addition to diabetic effects, these environmental exposures have in common the fact that they alter two components of the gastrointestinal (GI) ecosystem, the resident microbiota and the intestinal immune response. Our research focuses on the interrelationship between the GI microbiota, the intestinal immune response, and the risk of T1D development in the NOD mouse model.


Frances E. Lund, PhD The overarching research objective of the Lund laboratory is to identify the key players that suppress or exacerbate mucosal inflammatory responses with the long-term goal of developing therapeutics to treat immunopathology associated with chronic infectious, allergic and autoimmune disease. One of the lab’s major projects is to characterize the roles that cytokine-producing “effector” B cells play in modulating inflammation and T cell-mediated immune responses to pathogens, autoantigens and allergens. In a second project, the lab evaluates how inflammatory signals regulate the balance between the development of the antibody-producing long-lived plasma cells and the memory B cell compartment within lymphoid tissues. The lab also studies how these cells are maintained long-term at inflammatory sites. Finally, the lab examines how oxidative stress induced by reactive oxygen species impacts inflammation, immune responses and cellular metabolism. In particular, the lab is experimentally modulating the NAD metabolome of immune cell in order to alter the responsiveness of these cells to oxidative stress.


Suzanne M. Michalek, PhD Dr. Michalek’s research program centers around two major themes; the mucosal immune system and the development of mucosal vaccines for the induction of protective immunity, and host mechanisms involved in inflammation, with emphasis on those associated with periodontal disease. Studies related to the former theme are investigating the vectors and adjuvants for the development of mucosal vaccines effective in inducing immune responses. These studies are being done in humans and experimental animal models. Current in vivo studies in humans are testing the effectiveness of mucosal vaccines consisting of a recombinant microbial polypeptide from Streptococcus mutans and adjuvants in inducing mucosal and systemic immune responses. Concurrent studies in vitro are investigating the cell surface receptor (including the co-stimulatory molecules and the Toll-like receptors) and signaling pathways involved in adjuvant activity and in the host’s recognition of the microbial virulence factor. These studies should define improved safe ways to elicit protective responses by mucosal-based vaccines. We are also using these approaches for the development of mucosal vaccines against biological threat agents. Other studies in collaboration with Dr. Noel Childers are designed to develop a childhood vaccine against dental caries. Studies are in collaboration with Drs. Jannet Katz and Ping Zhang involve immunologic, molecular biology and cell biology approaches to define microbial components and host factors involved in periodontal disease. In vivo and in vitro models are being used to define virulence factors of the periodontal pathogens, Porphrymonas gingivalis, which are likely involved in microbial adherence and invasion of the epithelial barrier. Other studies are investigating the cellular mechanisms involve in the ability of this gram-negative bacteria or its components such as lipopolysaccharide to mediate inflammatory responses. These studies also are assessing the role of the Toll-like receptors and the co-stimulatory molecules in responses. The cell types and signaling pathways involved in mediating an inflammatory response, as well as bone loss are also being investigated. Finally, studies are being performed in experimental rodent models to define the role of T cells and their cytokines in periodontitis and to develop vaccines effective in protecting against this inflammatory disease. The results of these studies should help in the development of means to treat/prevent inflammatory diseases.


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.


Chander Raman, PhD The overall research focus of the laboratory is the elucidation of mechanisms that regulate generation and maintenance of immune tolerance in T and B lymphocytes. Autoimmunity and predisposition to development of leukemias are the often of the outcomes of alterations in generation and/or maintenance of tolerance. The development of inability of T and B lymphocytes to respond to self antigens while maintaining the ability to respond to self antigens is an active process in which the signals initiated by the engagement of the T cell antigen receptor (TCR) or B cell antigen receptor (BCR) are regulated by a complex of other lymphocyte surface molecules. Signaling cascades initiated by these lymphocyte surface molecules range form those that directly alter the quality and quantity of antigen receptor signals to those that promote cell survival or initiate programmed cell death or apoptosis. Our experimental approaches include in vitro structure function studies to define protein-protein interactions to the use of animal models of disease that naturally occur or are genetically created. Currently our focus is on the cell surface receptors CD5, DR6 and the family of receptors that bind to lignads Blys and April. Each of these receptors play a key role in regulating lymphocyte function and homeostasis and alterations in their signaling activities leads to diverse pathologies. The ultimate goal of our studies is to identify key targets for the development of therapeutic strategies for the treatment of leukemias and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. 


Trenton R. Schoeb, DVM, PhDPathology and phenotyping of mutant mice; gnotobiotic mouse models of chronic inflammatory diseases


Lisa M. Schwiebert, PhDThe 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.


Chad Steele, PhD Research in the Steele Laboratory investigates the innate immune response to pathogens of the lung, specifically the fungal organisms Pneumocystis carinii and Aspergillus fumigatus and the bacterium Pseudomonas aeruginosa. In our fungal work, we have published original articles identifying the beta-glucan receptor Dectin-1 as the predominant pattern recognition receptor for alveolar macrophage-mediated recognition and responsiveness to P. carinii (J Exp Med 198:1677-1688; 2003) and A. fumigatus (PLoS Pathogens 1:e42; 2005) and recently published the phenotype of mice deficient in Dectin-1 in response to A. fumigatus (J Immunol 182: 4938-4946; 2009). Current studies are underway to further define the involvement of Dectin-1 in myeloid cell responses to both organisms using Dectin-1 deficient mice. Moreover, the involvement of Dectin-1 in shaping an “innate IL-17” response to A. fumigatus is also a major focus. With respect to P. carinii, we have recently published that deficiency in the myeloid Src-family tyrosine kinases (SFKs) Hck, Fgr and Lyn paradoxically results in better clearance of P. carinii from the lungs as a result of enhanced alveolar macrophage effector function and heightened lung inflammatory responses (Infect Immun 77:1790-1797; 2009). Current studies are focusing on the SFK-mediated mechanism(s) behind the hyper-inflammatory phenotype and whether it extends to augmented adaptive immune responses as well as parameters of alveolar macrophage activation during SFK deficiency. Finally, we have had a long-standing interest in gamma delta T cells and their role in the immune response to lung pathogens (Infect Immun 70:5208-5215; 2002). Currently, we are investigating the mechanism(s) of gamma delta T cell mediated regulation of lung inflammation and injury driven by the Gram-negative bacterium Pseudomonas aeruginosa.


Alexander J. Szalai, PhD Dr. Szalai is collaborating extensively with several members of the faculty in a series of integrated studies of C-reactive protein (CRP), complement, and Fc receptors; different components of the innate immune system. These studies currently include analysis of the mechanisms that operate to affect the host defense function of CRP and complement against pathogens (Streptococcus pneumoniae), the role of CRP and complement in autoimmune diseases (SLE, MS), and the role of CRP in cardiovascular diseases (atherosclerosis, restenosis, heart transplant rejection). CRP is a 110-kDa protein made up of five identical subunits. It binds phosphocholine, activates the classical pathway of complement, and is recognized by FcgRI and FcgRII. CRP specifically recognizes pathogenic microorganisms and damaged cells of the host and initiates their elimination. Dr. Szalai has used CRP-transgenic mice (CRPtg) to dissect the mechanisms operating to affect the innate host defense function of CRP. His investigations established that CRP-dependent protection against pathogens, such as Streptococcus pneumoniae and Salmonella typhimurium, is effected mainly by clearance of pathogens during the early post-infection period. Complement is not required for this function. In parallel studies of the mode of induction of the CRP gene in vivo, testosterone was found to control basal expression; whereas complement protein 5a, acting together with pro-inflammatory cytokines, is critical for acute-phase induction of CRP. Current studies include determination of the contribution of Fc receptors to CRP-mediated protection using CRPtg/FcgR-deficient mice, and analysis of the effects of CRP expression on serum antibody responses. In addition, Dr. Szalai actively participates in several clinical studies, and is now investigating allelic differences in the expression of CRP in healthy versus diseased individuals. CRP is routinely used as a plasma marker of inflammation in inflammatory diseases. As family studies have demonstrated genetic influences in SLE, with linkage to several regions on human chromosome 1 and the CRP gene is located within one candidate linkage region, genetic differences in this gene could be related to the lupus diathesis. Dr. Szalai has evaluatied the association of a (GT) repeat polymorphism in the intron of the CRP gene with plasma levels of CRP and the clinical phenotype of SLE in collaboration with Dr. Robert P. Kimberly. Finally, Dr. Szalai is using two different mouse models to determine the role of CRP in the development of autoimmune disease. CRP-transgenic (NZB X NZW)F1 mice (BW) exhibited delayed onset of SLE and their lifespan was extended significantly compared to that of non-transgenic BW mice. However, the anti-double stranded DNA autoimmune response occurred earlier and was enhanced in the CRP-transgenic mice, and there was deposition of CRP in nephritic kidneys. Current studies seek to determine the mechanism for the CRP-protective effect. The onset of experimental allergic encephalomyelitis (EAE, a model for MS) is delayed in female CRP-transgenic mice compared to wild-type mice. This protective effect is causally related to the transient upregulation of the CRP transgene observed during the early stages of disease development. In collaboration with Dr. Scott Barnum, Dr. Szalai is now testing the hypothesis that the duration of CRP-mediated protection against EAE will be extended in CRP-transgenic mice by prolonging and/or increasing expression of CRP, which may be achieved through the influence of sex hormones that regulate CRP expression. Mutant mice that are not able to fully activate the complement system due to engineered deficiency in C3 or factor B, exhibit reduced clinical symptoms of EAE, cellular infiltration, and demyelination. When complement-deficient mice hybridized with CRP-transgenic mice were tested, a delay in both the CRP-mediated delay in onset of EAE and the complement deficiency-mediated reduction of disease were observed. These data show that the CRP-protective effect in EAE is realized whether or not a fully functional complement system is present, suggesting that CRP is mediating its protection through other mechanisms. Dr. Szalai's most recent work, performed in collaboration with groups at Harvard, UCSD, Baylor, and UAB, showed that CRPtg mice exhibit ia pro-thrombotic/pro-atherosclerotic phenotype, but experience reduced neointimal growth following vascular injury.


Hubert Tse, PhD The overall research objective in the Tse laboratory is to define and prevent immune-mediated effector mechanisms involved in the destruction of insulin-producing pancreatic beta-cells in autoimmune Type 1 diabetes (T1D). An overarching theme in our research is to determine the involvement of oxidative stress and the generation of reactive oxygen species (ROS) as effector and signaling molecules in autoimmune and pro-inflammatory-mediated diseases (Collagen-Induced Arthritis (CIA), Experimental Autoimmune Encephalomyelitis (EAE), Spinal Cord Injury, Traumatic Brain Injury). Research from our lab and others has shown that efficient T cell activation requires three signals mediated by antigen-presenting cell and naïve T cell interactions: signal 1 (T cell receptor – MHC), signal 2 (co-stimulatory molecules), and signal 3 (ROS and pro-inflammatory cytokines). To corroborate the importance of ROS-dependent signaling (signal 3) in T1D, a dominant negative p47phox (Ncf1m1J) mutation of the NADPH oxidase complex was introgressed into the non-obese diabetic (NOD) mouse, a murine model for studying Type 1 diabetes. NOD.Ncf1m1J mice are impaired in ROS synthesis and highly resistant to spontaneous diabetes and adoptive transfer of diabetes with diabetogenic T cells. CD4+ and CD8+ T cells are the final effector cells involved in pancreatic beta-cell destruction. Pro-inflammatory macrophages are equally important, as they constitute the first immune cells recruited into pancreatic islets to initiate beta-cell destruction and to activate naïve diabetogenic T cells. Currently, we seek to understand the synergy of oxidative stress and ROS synthesis on the activation of innate immune cells to diabetogenic viral triggers (Coxsackie B4, Encephalomyocarditis virus) and autoreactive T cells in murine models and human translational studies of Type 1 diabetes


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, Drs. 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.