Research Abstract:
How do inflammatory cells enter the central nervous system (CNS) during normal and diseases states and how does their presence affect neuronal function? My laboratory focuses on the molecular mechanisms responsible for inflammation-associated dysfunction and damage in CNS with the goal of identifying potential therapeutic targets for the treatment of neuroinflammatory diseases. We have focused on two components of CNS inflammatory states: the mechanism of leukocyte recruitment into the CNS and the direct effects of inflammatory mediators on neurons. Common to both of these is the action of chemokines, which both recruit leukocytes into the CNS and signal through chemokine receptors present on neural cells, affecting their function and survival. Our experimental approach involves the development of in vitro and in vivo models of CNS mononuclear cell recruitment and neural cell chemokine receptor signaling responses. Studies using in vitro models of neural cell types focus on the role of chemokines and their receptors in neuronal and glial cell activation and survival. Using mice with targeted deletions of chemokine receptors we are evaluating how inflammation triggers both neuroprotective and neuroinjurious mechanisms. Studies using in vivo models for both autoimmune and viral encephalitides focus on identifying the chemokines and chemokine receptors responsible for the recruitment of mononuclear cells into the CNS during normal and inflammatory states and the mechanisms of chemokine up-regulation. Using mice with transgenic T cell receptors directed at CNS and non-CNS antigens, mice with targeted deletion for various chemokines and their receptors, as well as small molecule inhibitors of chemokine receptors we are mapping the chemokine expression patterns responsible for the initial migration of activated T cells into the CNS, determining the fate of T cells that do or do not encounter their antigens and examining the inflammatory responses that occur upon antigen recognition. Our viral models utilize mice infected with cytopathic (West Nile virus) and noncytopathic (lymphocytic choriomeningitis virus) RNA viruses that target neurons within the CNS.
Selected Publications:
McCandless, E.E., Zhang, B., Diamond, M.S., Klein, R.S. CXCR4 antagonism enhances survival and decreases immunopathology within the CNS during West Nile virus encephalitis. (2008) PNAS, in press.
Zhang, B., Chan, Y.K., McCandless, E.E., Lu, B., Diamond, M.S.,Klein, R.S.(2008) CXCR3 mediates region-specific antiviral T cell trafficking within the central nervous system during West Nile virus encephalitis. J. Immunol. 180(4): 2641-9.
McCandless, E.E., Piccio, L., Woerner, B.M., Schmidt, R.E., Rubin, J.B., Cross, A.H., Klein, R.S. (2008) Pathologic expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am. J. Pathol.172(3): 799-808.
McCandless, E.E., Klein, R.S. (2007) Molecular targets for disrupting leukocyte trafficking during multiple sclerosis. Exp. Rev. Mol. Med. July: 9 (20): 1-19.
McCandless, E.E., Wang, Q., Woerner, B.M., Harper, J.M., Klein, R.S. (2006) CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space During Experimental Autoimmune Encephalomyelitis. J. Immunol. 177(11): 8053-64.
Last Updated: 06/26/2008 |