This is a renewal application by Dr. William F. Hickey to study factors influencing the development of inflammation in the central nervous system (CNS) in the Lewis rat. The long-term goal is to identify the regulatory elements and cell surface molecules required for CNS inflammation to occur. The investigator has identified cell surface molecules defined by a panel of monoclonal antibodies (mAb), that appear to play a role in cell entry into the CNS and the ability of the CNS to support the development of inflammation. He proposes to utilize these reagents to delineate the specific changes that occur in the CNS which are associated with the development of inflammatory diseases.
Three specific aims are proposed. In the first aim, the investigator will define the changes which occur in a specific CNS site, the superior colliculus, which is usually resistant to EAE. He will target EAE inflammation to one superior colliculus following optic nerve transection, and compare the deafferented colliculus with the contralateral colliculus by immunohistochemistry, using the panel of mAbs which he has developed. He will also use RT-PCR to define relative changes in gene products, and will employ Differential Display PCR (DD-PCR) to further define genes that are differentially expressed in the deafferented vs. control colliculi. In the second aim, the investigator will define the early changes which occur in the CNS after encephalitogenic T cells arrive, but before onset of clinical disease, and distinguish the cascade of CNS changes following entry of encephalitogenic vs. nonencephalitogenic TH1 cells into the CNS. He will employ immunohistochemistry and RT-PCR to define these changes. As part of this aim, Dr. Hickey will also determine whether the passage of non-CNS-specific T cells into the CNS lowers the threshold of susceptibility to EAE. In the third aim, the investigator proposes to characterize the MAb-defined genes encoding membrane molecules that appear before or during the onset of EAE. Dr. Hickey postulates that some of the mAbs that he has produced define important cell surface molecules which play critical roles in the interactions of T cells with APCs and/or CNS endothelium. Ultimately, he hopes to obtain partial DNA sequences or clone the genes for these molecules.
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