Doctor of Philosophy, The Ohio State University, 2016, Comparative and Veterinary Medicine

Around 12% of human cancers are caused by viral infections. Cancer-inducing viruses, called “oncoviruses”, hijack cellular machinery to avoid normal cell growth controls and detection of the infected cell by the immune system. Epstein-Barr virus (EBV), which infects over 90% of the world's population, is the most potent of these oncoviruses and is responsible for a diverse spectrum of malignant diseases. If the immune system becomes compromised, as in patients with AIDS or undergoing organ transplant treatment, the virus can initiate its growth program and transform host B cells into malignant lymphoma. These lymphomas are typically aggressive and exhibit poor clinical outcomes in an already-vulnerable patient population. Currently there is no standard treatment for EBV-associated lymphomas, demonstrating a significant unmet need for novel preventative and therapeutic approaches. Since nearly all individuals have been infected with EBV early in life, the immune system is already able to detect these EBV-infected cells. If properly activated and released from the suppressive effects of cancer, the immune system can use this previous detection, “immune memory”, to recognize and eliminate EBV-infected tumor cells in the setting of lymphoma. When EBV infects a cell, it uses the normal cell machinery to produce viral proteins that drive cell growth and survival signals. Dysregulation of these signals contributes to the emergence of lymphoma. In individuals with a normal immune system, these viral proteins are recognized by a type of white blood cell called cytotoxic T lymphocytes (CTLs) that kill infected cells to prevent viral spread. Here we show that a compound called silvestrol selectively targets B cell cancers while sparing normal immune cells by blocking the production of viral cancer-promoting proteins, mainly latent membrane protein 1 (LMP1), increasing immune cell-mediated death of cancer cells. Animal models of EBV-driven lymphoma treated with silvestrol s (open full item for complete abstract)

Committee: Robert Baiocchi MD, PhD (Advisor); David Lucas PhD (Committee Member); Aharon Freud MD, PhD (Committee Member); Michael Caligiuri MD (Committee Member) Subjects: Cellular Biology; Immunology; Virology

Doctor of Philosophy, Case Western Reserve University, 2015, Neurosciences

Following spinal cord injury (SCI), immune-mediated secondary processes exacerbate the extent of permanent neurological deficits. We develop here a contusion model of SCI to investigate the capacity of adult bone marrow-derived stem cells, termed multipotent adult progenitor cells (MAPCs), to alter inflammation and promote recovery following SCI. MAPCs were derived from human or rat donors and delivered either locally to the lesion or systemically via intravenous injection immediately following injury. Rats receiving intravenous human MAPCs displayed greater recovery in locomotion than animals treated with rat MAPCs or MAPCs of either origin delivered to the lesion. Delaying intravenous administration of human MAPCs by one day further improved locomotor recovery and significantly enhanced lower urinary tract recovery, re-establishing coordination between the detrusor and external urethral sphincter muscles. Intravenous MAPCs altered the immune response in the spinal cord and periphery, however biodistribution studies revealed that no MAPCs were found in the cord and instead preferentially homed to the spleen. Nonetheless, in the injured cord of treated animals we observed a decrease in macrophage number and activation, which was associated with significant sparing of neural tissue. In vitro, we show that human MAPCs have the ability to modulate macrophage activation, and prior exposure of macrophages to MAPC secreted factors can reduce macrophage-mediated axonal dieback of dystrophic axons. Our results demonstrate that a single intravenous dose of human MAPCs one day following severe contusive SCI attenuates immune mediated secondary spinal cord injury, resulting in significant neural tissue sparing and substantial improvements in locomotor and lower urinary tract function. This preclinical study provides strong support for the use of MAPC therapy in acute human contusive SCI.

Committee: Jerry Silver (Advisor); Richard Zigmond (Committee Chair); Robert Miller (Committee Member); Thomas Dick (Committee Member); Yu-Shang Lee (Committee Member) Subjects: Biology; Biomedical Engineering; Biomedical Research; Immunology; Neurobiology; Neurosciences

Master of Science, University of Akron, 2009, Biology

The immune system is responsible for protecting the body from disease by identifying by destroying pathogenic microorganisms, materials and even dangerous self-cells. This protection is carried out by specialized cells which are found in the bone marrow, circulating blood, thymus, lymph nodes, spleen, as well as other lymphatic tissues. These cells each carry out specific functions and convey different types of protection. Modulation of the balance of either the number or functionality of these immune cells can lead to immune deficiency, susceptibility to disease, or autoimmune disorders such as chronic inflammation. A number of studies have shown that the immune system can be affected by both physical and psychological stresses, such as depression and post-traumatic stress disorder (PTSD). In the present study we examined immune status in women victims of intimate partner violence (IPV). Immune system parameters measured included both immune cell counts as well as functionality of the cells. The results indicated that victims of IPV who suffered from depression and PTSD showed significantly higher baseline activity of natural killer (NK) cells and decreased change in NK cell activity when stimulated with heat shock protein 60 (HSP60). This drop in reactivity to a typical cellular stress signal could put PTSD positive IPV victims at risk for a number of diseases, including cancer development and viral infection. Also, an increased basal activity of NK cells could indicate an autoimmune pathology. These results may lead to a better understanding of the health issues associated with IPV, PTSD, and depression, and will hopefully assist in the development of better and more complete therapies.

Committee: James Holda PhD (Advisor) Subjects: Biology; Health; Immunology; Psychobiology; Womens Studies