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. Our laboratory has employed a multi-disciplinary approach to investigate immune responses to the gram-positive pathogen Staphylococcus aureus (S. aureus) during abscess formation in the central nervous system and biofilm formation in the periphery. Recently, our research has extended to examine mechanisms whereby S. aureus biofilms thwart immune-mediated clearance utilizing mouse models of catheter-associated and orthopedic-device infection, as well as a novel model of cranial bone flap infection developed in the Kielian laboratory. In addition, our group is actively pursuing methods for the prevention and treatment of biofilm infections by targeting innate immune mechanisms.
A new area of research in Dr. Kielian’s laboratory is focused on identifying whether aberrant glial activation contributes to neuron loss during the childhood neurodegenerative disease, Juvenile neuronal ceroid lipofuscinosis (JNCL or Juvenile Batten Disease). Juvenile Batten Disease is a fatal lysosomal storage disease caused by an autosomal recessive mutation in the CLN3 gene. The disease typically presents in children between the ages of 5-10 years, initiating as blindness and progressing to seizures, motor loss, and cognitive decline, with a decreased life expectancy into the late teens or early twenties. Activated microglia and astrocytes are observed in the brains of Juvenile Batten Disease mouse models, and predict regions that will undergo neurodegeneration. Based on these observations, our laboratory is utilizing a CLN3Δex7/8 mouse model to investigate the possibility that aberrant glial activation during early Juvenile Batten Disease contributes to neuronal loss during later stages of disease.
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.
Our laboratory focuses on basic and translational research on autoimmune diseases. The ultimate goal is to understand the disease pathogenesis and identify novel biomarkers and pathways that can be developed into diagnostic/therapeutic tools for these diseases. We combine the state-of-art single cell PCR-based antibody cloning and proteomic techniques to identify novel autoantibodies from patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). We then use clinical samples and animal models to determine the pathogenic role of these autoantibodies. We also study the role of innate immunity such as neutrophils in the etiology of SLE and RA.
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.