Immunology

Thomas Jerrells, Ph.D.
My research interests have been the cell-mediated immune responses to infectious microorganisms. At this time, my interests and funding are involved with the effects of ethanol consumption on the immune responses to bacteria and viruses. It has been shown by me, and others, that ethanol consumption in excess by experimental animals and human beings results in a susceptibility to infections. We are studying the effects of ethanol consumption on immunity to model pathogens such as Listeria monocytogenes, Salmonella typhimurium, which are bacteria that infect the liver and gastrointestinal tract respectively. We are also studying the pathogenic effects of the immune response, both the innate and acquired immune response, to murine cytomegalovirus in the liver. The murine cytomegalovirus model seems a good model for hepatitis C virus infection of human beings, which has been shown to be much more severe in people who abuse alcohol. A major interest in my laboratory is the role of the immune response in the liver changes associated with alcoholic liver disease. All aspects of hepatocyte damage by lymphocytes including direct cytotoxicity mediated by cytotoxic T cells, FAS and FAS ligand interactions, and cytokines such as tumor necrosis factor and interferon gamma are being studied in my laboratory. We believe that much of the liver damage associated with alcoholic liver disease is mediated by both systemic and hepatitic immune responses to infectious organisms, especially viruses.

Donald Johnson, Ph.D.
My research deals with the interaction between the immune system and the central nervous system with special focus on the effect of psychological depression on natural killer (NK) cells. NK cells are a component of the immune response that recognizes and destroys virus infected cells, and are important in immunosurveillance to cancer. My main efforts are devoted to the study of biomolecular mechanisms of immune regulation by serotonin and serotonin reuptake inhibitors in vitro and in vivo and the role of exposure to oxidative stress. The ultimate aim of these studies is to understand the complex regulation of the immune system in order to prevent disease and stimulate the immune system to control malignant cell growth. I am also focusing on biocomplexity/bioinformatics of the immune system. The goal of this research is to develop bioinformatics tools for analysis of the complex biological interactions in regulation of the immune system. An additional purpose of this research is to be able to use these for computer simulation experiments of biological interactions.

Tammy Kielian, Ph.D.
My research interests involve understanding the pathogenesis of bacterial infection in the central nervous system (CNS) from both the host and bacterial perspectives. To study these interactions, we utilize a mouse experimental brain abscess model developed in our laboratory. A longstanding interest in the laboratory has been examining the role of toll-like receptors (TLRs) in facilitating S. aureus recognition in the brain and the importance of these molecules in resident glia (i.e. microglia and astrocytes) as well as peripheral immune cell infiltrates. Another area of interest is identifying signals that regulate fibrotic encapsulation of brain abscesses and examining the effects of pro-inflammatory cytokines on gap junction communication (GJC) and electrophysiological properties of glia. A new area of research in the laboratory is focused towards defining the host innate immune response to S. aureus during biofilm growth. S. aureus biofilms are associated with many biological and artificial surfaces (i.e. heart valves and indwelling catheters, respectively) and currently, little information is available to explain why these infections are capable of evading classical anti-bacterial effector mechanisms. Our research projects utilize state-of-the-art techniques including quantitative magnetic resonance imaging (MRI), and other in vivo imaging techniques, two-photon microscopy, and confocal microscopy.

Thomas McDonald, Ph.D.
Our laboratory conducts research related to acute phase proteins and their role in the inflammatory process. Acute phase proteins are produced by the liver in response to proinflammatory cytokine stimulation, primarily IL-1, IL-6, and TNFą. Our laboratory has focused on the acute phase protein serum amyloid A (SAA). Within 18 hours following stimulation, SAA is produced by the liver and blood levels reach 1000 fold higher concentrations than levels prior to stimulation. The function of SAA is unknown, although it plays a role in lipoprotein metabolism. Our laboratory has discovered a novel isoform of SAA that is produced extrahepatic and does not occur in the circulation. It was discovered in bovine colostrum and was unique to that fluid in that it was not present in milk five days following parturition. Moreover, a unique N-terminal amino acid sequence found in this bovine SAA isoform was identical for SAA isolated from the colostrum of five different animal species. As with bovine, the new SAA isoform only associated with colostrum and not milk or serum. We have prepared a variety of recombinant proteins and peptides that reflect the novel colostrum-associated amino acid sequence, and have determined that one functional role of this unique isoform of SAA causes increased mucin-3 production by intestined cells. Mucin-3 is essential for protecting the gut from bucteral adherence, colonization and infection. Based on either diagnostic assays of secreted biological fluids for detection of infection and inflammatory condition or of serum amyloid a isoform from colostrum, we have had twelve issued patents and four pending. These and other findings from our laboratory imply that this heavily conserved amino acid region of the colostrum-associated SAA molecule has an important beneficial function in the health and well being of the neonate, in particular with respect to the protection of the GI tract from pathogens encountered early in life. I have invented, developed and manufactured prototype diagnostic tests for human and veterinary applications as well as established start-up companies to manufacture and market these technologies in collaboration with companies worldwide.

Kaihong Su, Ph.D.
The long term research interest in my laboratory is to understand the molecular mechanisms for different autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and to develop potential novel diagnostic and therapeutic strategies for these diseases. We use a state-of-the-art single cell PCR approach to clone recombinant antibodies from patients with SLE or RA and identify their cognate antigens and reactivites with specific tissues such as neutrophils, kidneys, heart, and the brain. We use mouse models and patient association studies to further define the role of those tissue-specific antoantibodies in disease progression and organ destruction in SLE and RA. Our studies will shed new light on the mechanism of disease pathogenesis and help us to find specific treatments to prevent the devastation organ destruction in autoimmune diseases.

James Talmadge, Ph.D.
The Laboratory of Transplantation Immunology is focused on the role of the microenvironment and host immunity during the tumor progression and metastasis, as well as, interventional strategies to augment the host response against tumors and overcome immune suppression associated with tumor growth and myelosuppressive therapy. Our research emphasizes molecular and cellular immunology, DC vaccines, stem cell transplantation, gene therapy, T-cell responses to cytokine and molecular therapeutic intervention and the role of the host response and the tumor microenvironment to tumor progression. Our clinical and translational research is focused on the tumor microenvironment including MDSCs, DCs and T-cells; and DC vaccines primarily against breast cancer and melanoma.  Clinical studies have included breast cancer vaccines in collaboration with Dr. Ken Cowan and Dr. Beth Reed at UNMC, and Dr. Dmitry Gabrilovich at Moffitt Cancer Center. A current collaboration is with Intrexon Inc. with a focus on melanoma. Early-stage studies have also focused on immune recovery following stem cell transplantation, at present, primarily in collaboration with Dr. Greg Bociek, Internal Medicine, UNMC, as regards non-myeloablative, allogeneic, stem cell transplantation. 

Basic/translational research studies are focused on host-tumor interactions during tumor progression, metastasis and cytoreductive therapy. We have focused on the effect of mammary tumor growth on the expansion and trafficking of MDSCs and strategies to control proliferation and function including molecular therapeutics, such as COX-2 inhibitors, tyrosine kinase inhibitors, all-trans-retinoic acid (ATRA) and VEGF inhibitors. Our current focus is on sites of proliferation using BrdU labeling in vivo, trafficking using carboxyfluorescein succinimidyl ester (CFSE)-labeled cells, immunohistochemistry (IHC) targeting Gr1, CD11b and Ki-67 with exciting observations into extramedullary hematopoiesis. Studies into the mechanism of immunosuppression have revealed critical roles for granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF) and VEGF in the expansion of the MDSCs and have suggested a critical role for inducible nitric oxide synthase and arginase as regional mediators of T-cell suppression. Studies in collaboration with Dr. Shi-Jian Ding, UNMC, have identified a working hypothesis that post translational modification by S-nitrosylation may have a critical role in regulating the tumor-induced inflammation observed as part of tumor progression. These rodent studies have been in collaboration with Drs. Rakish Singh and Joyce Solheim at UNMC for many productive years.

The Laboratory of Transplantation Immunology is also very active (along with many others) in the development of the Biological Production Facility, which utilizes good manufacturing practices (GMPs) for the vaccines we deliver in support of our INDs to treat neoplasia. This includes the development of new vaccine manufacturing strategies and the development and validation of release assays, and protocols including flow cytometry and ELISA assays.

Zhixin (Jason) Zhang, Ph.D.
The research work in Dr. Zhang's laboratory focuses on understanding the molecular regulation of B lineage cell development. B lineage cells are the major players in our immune system to make antibodies against infection agents. Using the new knowledge obtained from basic research works to investigate the pathogenesis of different immunological diseases is Dr. Zhang's long term research goal and daily practice.