Leah Cook, Ph.D.
Dr. Cook's research is focused on investigation of cellular interactions within the tumor bone microenvironment that contribute to tumor progression, with a specific focus on immune cell-tumor interactions. Within bone, metastatic cancer cells highjack the normal couple process of bone remodeling, resulting in excess bone degradation and subsequent release of growth factors that promote tumor growth. Additionally, cancer cells progress and mediate bone turnover through molecular and cellular interactions with the surrounding bone stroma. My lab is currently focusing on identifying the importance of neutrophils and/or granulocytic MDSCs in prostate cancer progression and cancer-induced bone disease using a combination of transcriptome and proteomic profiling of patient samples and mouse in vivo models of bone metastasis. My goal is to identify novel immunotherapeutic targets for treating and curing bone metastatic cancers.
Tammy Kielian, Ph.D.
Dr. Kielian’s research interests span the fields of immunology, infectious diseases, and neuroscience with a unifying theme of innate immunity. Her laboratory has a long-standing interest in studying the pathogenesis and immune responses elicited by Staphylococcus aureus (S. aureus) both in the periphery and the central nervous system (CNS), with a particular emphasis on microglial and astrocyte activation. Dr. Kielian’s earlier work was focused on understanding neuroinflammatory pathways elicited during S. aureus brain abscess formation, which has transitioned to investigate immune mechanisms pertinent to S. aureus biofilm infections. To this end, her laboratory has developed mouse models of biofilm infection associated with orthopedic implants and cranial bone flaps that accurately mimic the attributes of biofilm infections in humans. Her laboratory was the first to propose that S. aureus biofilms actively elicit an anti-inflammatory immune signature to explain, in part, why these infections persist in an immune competent host. This is achieved by the preferential recruitment of myeloid-derived suppressor cells (MDSCs) in addition to polarizing macrophage infiltrates towards an anti-inflammatory, pro-fibrotic phenotype. Ongoing studies are to identify the mechanisms responsible for skewing the host innate immune response to an anti-inflammatory state following S. aureus biofilm infection and how this may be targeted to facilitate bacterial clearance. Her laboratory is utilizing high-throughput next-generation sequencing approaches (RNA-Seq and Tn-Seq) to elucidate critical molecules that promote biofilm development from both the host and bacterial perspectives. Other projects include 3D bioprinting approaches for the prevention/treatment of biofilm infections and active collaborations with orthopaedic surgeons at UNMC to investigate immune pathways in patients with prosthetic joint infections.
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 interleukin (IL-) 1, IL-6, and tumor necrosis factor alpha (TNFα). 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 intestinal 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.
My laboratory conducts translational research related to autoimmune diseases and infectious diseases. Specifically, we are interested in elucidating autoreactive immune responses in patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). We integrate the high-throughput immune repertoire analysis with single cell-based antibody cloning technique to identify novel autoantibodies. The ultimate goal is to understand the disease etiology and establish novel biomarkers and pathways that can be developed into new diagnostic and/or therapeutic tools. We also study the role of neutrophils in the pathogenesis of autoimmune diseases using animal models.
A new area of research in my laboratory focuses on elucidating the humoral immunity to Ebola virus. We use high-density peptide-based microarrays to map the antigenic epitopes in patients who survived the 2014 Ebola outbreak. The goal is to identify the viral epitopes that mediate protective host immune responses and those that may induce destructive self-reactive responses. The information will be used for rational design of vaccines with improved efficacy and safety.
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, 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.