Dr. Othman’s research explores dissecting mechanisms of lymphocyte recruitment at the blood-brain barrier. Pediatric brain tumors continue to be the Achilles’ heel for researchers and clinicians engaged in discovering novel therapeutic strategies and improving the lives of pediatric oncology patients. In particular, medulloblastoma (MB) is the most common malignant brain tumor of childhood. Originating from embryonal neuroepithelial cells, MB often exhibits an aggressive growth pattern. It frequently invades surrounding CNS structures such as the regional subarachnoid and ventricular spaces, and can cause widespread seeding of the subarachnoid space. MB is one of only a few brain tumor types with a systemic metastatic potential including extraneural spread, principally to the bone marrow. To-date, available treatment options for MB remains highly problematic. Conventional multi-modality therapies such as surgery, radiotherapy and chemotherapy can all cause significant brain injury manifesting as long-term neurocognitive defects in many patients of all ages. New directions in the development of anti-tumor therapy are therefore needed. One such new direction is cell-mediated immunotherapy, in which tumor-specific lymphocytes are targeted to destroy tumor cells while preserving normal tissues.

In recent years, the application of immunotherapy for cancer has generated intense interests. The job of our immune system is to recognize foreign invaders and eliminate the threat while ignoring tissues within our own body. However, control of immune balance between tolerance to self-tissues and activation against foreign pathogens is not always perfect. In that regard, cancer and autoimmunity are on the opposite end of the same spectrum as immune-mediated diseases. Therefore, understanding how immune system operates in one condition (e.g. autoimmunity) will further our understanding of the processes in the other condition (e.g. cancer). When cells of the immune system aberrantly attack tissues of the central nervous system (CNS), multiple sclerosis (MS) ensues leading to autoimmune destruction of the CNS and resulting in devastating clinical signs and symptoms associated with MS. In designing immunotherapy approaches against MB, however, the same immune cell recruitment process to the CNS which causes the pathology in MS will be a critical step to ensuring success of using the same immune system to fight against childhood brain tumors, particularly MB.

Valuable lessons about MS have been learned by studying MS patients and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. However, precise mechanisms by which EAE is initiated in the CNS on a single-cell level are not well understood. Specifically, the mechanisms by which EAE-causing immune cells are recruited to the CNS during early induction of EAE are largely unknown. Under the tutorage of Dr. Alex Y. Huang, MD, PhD (a 2008 Hyundai Scholar) in the Department of Pediatrics, Dr. Othman aims to uncover important biological principles which govern these processes in vivo. Dr. Huang’s laboratory has recently developed a method of applying 2-photon laser scanning microscopy (2P-LSM) to directly visualize dynamic immune cell migration and interaction within various tissues in live, anesthetized animals. Using this powerful imaging tool, Dr. Huang’s laboratory has uncovered the important role of tissue microenvironment in regulating proper immune cell function during primary immune responses. Through the generous support of the Hyundai’s “Hope-on-Wheels” Scholar’s grogram Dr. Othman is now poised to bring this exciting research tool into the pre-clinical in vivo animal model to test how immune cells manage to cross the blood-brain-barrier during the induction of EAE, thereby developing therapeutic anti-tumor immune approaches in MB tumor-bearing hosts. Specific to this award, Dr. Othman proposes to take advantage of the 2P-LSM imaging tool to directly observe for the first time how immune cells traffic dynamically to the brain and its associated vasculatures in EAE-susceptible hosts in real time. Furthermore, Dr. Othman aims to understand how MS-causing immune cells are selectively retained and recruited by professional antigen-presenting cells lining the CNS vasculatures and the blood-brain barrier junction to propagate tissue destruction associated with this devastating autoimmune disorder. Investigations into the area of live high-resolution dynamic immune cell imaging within brain tissues hold promise for a unique understanding of how various immune cell components and CNS tissues communicate with one another in situ. Success in this research effort will also provide an in vivo imaging platform to uncover novel immune-modulating and pharmacologic therapies for MS, brain tumors and infections in the CNS. The Hyundai Scholars grant is vital in allowing Dr. Othman to support her work in this very important and novel research area by providing the precious resources necessary to ensure future success.