New Positron Emission Tomography Approaches to Visualize T-Cell Mediated Autoimmune Demeyelination

Caius G. Radu, M.D.

University of California, Los Angeles

Funded in December, 2007: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Understanding Commonalities in Immune Activation in Melanoma and Autoimmunity

This research will adapt techniques used to study how immune cells are activated against melanoma, a deadly cancer that quickly metastasizes to the brain, to the study of autoimmune brain disease, in which immune cells mistakenly target the brain. 

These researchers have been studying how immune T cells, in an animal model of melanoma, can be activated by administering immunotherapies to reject melanoma tumors. A PET imaging technique used in the animal model allows them to follow the actions of the immune T cells throughout the body, including the brain, in pursuit of melanoma cells that have metastasized to the brain. The imaging technique has great sensitivity, enabling them to detect small numbers of immune T cells at any specific location in the body.

Now they will adapt this technique to explore how immune T cells become activated to attack the body’s own tissues in an animal model of the autoimmune disease multiple sclerosis (MS).  In MS, immune T cells that are “autoreactive” somehow become activated in lymph tissues. They then mature and travel to the brain, mysteriously eluding the blood-brain-barrier, and attack the myelin sheath that insulates nerve fibers. This demeyelination process effectively disrupts cellular communication. By using this PET technique in the MS animal model, called EAE (experimental autoimmune encephalitis), and in the animal melanoma model, the research may identify common mechanisms of immune T cell activation and provide means for assessing the effects of immunotherapies on increasing T cell activation in melanoma and decreasing T cell activation in autoimmunity.

Significance: This research may enable the researchers to identify immune activation patterns that can serve as surrogate biomarkers for diagnosing autoimmune diseases and certain cancers affecting the brain,and for assessing the effects of immunotherapies used to treat them.

ABSTRACT

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New Positron Emission Tomography Approaches to Visualize T-Cell Mediated Autoimmune Demeyelination

Monitoring activation and trafficking of immune cells throughout the body using molecular imaging will significantly impact the diagnosis and treatment evaluation of immune disorders. In contrast to numerous applications of positron emission tomography (PET) in cancer and other diseases, relatively few studies have used this molecular imaging modality to visualize immune responses. Our group aims to develop new PET imaging approaches to visualize T cell trafficking and function in vivo in animal models of autoimmunity and cancer immunotherapy.

The objectives of the current proposal are twofold. First, we will investigate whether PET reporter gene imaging could enable visualization of T cell trafficking to the central nervous system in Experimental Autoimmune Encephalomyelitis (EAE). These studies will use the human thymidine kinase 2 (ΔhTK2), a novel PET reporter gene. Second, we propose to develop PET approaches to enable direct measurements of immune function in vivo, without the addition of a reporter gene.

We have recently demonstrated that 18fluorodeoxyglucose ([18F]FDG) can be used to monitor the onset of EAE and responses to immunosuppressive therapy (Radu et al. PNAS, 2007). To identify new probes specific for biochemical pathways upregulated in activated T cells, we have directed our attention to the nucleoside metabolism. We hypothesize that changes in the deoxyribonucleoside salvage pathway during T cell activation could be detected by microPET using 18F-labeled nucleoside analogs. Recent preliminary data support this hypothesis. Using a differential screening approach, we identified a novel 18F-labeled 2’-deoxycytidine analog that enables visualization of lymphoid organs and localized immune activation in animal models.

Successful completion of proposed studies should widen the utility of PET imaging of immune status in the preclinical and clinical settings and could shed new light on the complex spatiotemporal programming of adaptive immune responses against self antigens.

INVESTIGATOR BIOGRAPHIES

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Caius G. Radu, M.D.

Dr. Radu is an Assistant Professor in the Crump Institute for Molecular Imaging and the Department of Medical & Molecular Pharmacology at UCLA. He received his M.D. from the University of Medicine, Craiova, Romania. He completed his postdoctoral research at the UT Southwestern Medical Center in Dallas, where he trained with Dr. Sally Ward, and at UCLA in the laboratory of Dr. Owen Witte.

Dr. Radu’s laboratory is concerned with the development of novel technologies to study fundamental mechanisms involved in immune regulation and malignant transformation. The ultimate goal is to advance the understanding of molecular events at the interface between the immune system and cancer by combining in vivo noninvasive molecular imaging approaches with in vitro high-throughput data acquisition techniques. In particular, Dr. Radu and his colleagues are focusing on three main objectives: 1. To develop positron emission tomography (PET) biomarkers for diagnosis and treatment evaluation of immune disorders and cancer; 2. To investigate signaling and biochemical events involved in the regulation of key metabolic pathways in T lymphocytes and cancer cells; 3. To train the next generation of scientists by encouraging the creation of an interactive, inter-disciplinary scientific culture in which biologists join experts in engineering, physics, chemistry, mathematics, and computer science to ensure the efficient integration of new technologies.