Lymphocytes are the predominant leukocyte found in central nervous system (CNS) inflammatory lesions in multiple sclerosis (MS) and other CNS inflammatory diseases. Lymphocytes may contribute both to the initiation and maintenance of CNS inflammation via antigen-specific interactions that occur during their baseline trafficking into normal CNS for the purpose of immune surveillance. Chemoattractant cytokines, or chemokines, are small secreted proteins that recruit lymphocytes into parenchymal tissues during both homeostatic and inflammatory states. Although the mechanisms that recruit lymphocytes specifically into the CNS during this baseline trafficking are unknown, our preliminary data that chemokines are constitutively expressed by the CNS and that activated lymphocytes traffic into normal CNS tissues suggests that chemokines may play an important role in this process. With the Independent Scientist Award (K02), the applicant will place an intensive research focus toward determining the chemokines and chemokine receptors that direct the trafficking of T lymphocytes into normal CNS tissues in vivo. Using an in vivo trafficking model, we will examine the role of chemokine receptors in the movement of T cells into normal CNS and assess the loss of chemokine receptor activity in this process using mice with targeted deletions of appropriate chemokine receptors. We will then go on to determine whether inhibition of the baseline trafficking of lymphocytes into the CNS affects the development of the murine CNS inflammatory disease, experimental autoimmune encephalomyelitis (EAE), which is a model for MS. The applicant is a principal investigator at the MGH Center for Immunology and Inflammatory Diseases, which provides a rich intellectual and experimental environment to establish the groundwork for these investigations. As evidenced by almost nine years of research in the neurosciences, the applicant remains firmly committed to a long-term career in basic science investigation.
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