GENETIC VARIANTS AS TRACERS OF T CELL FUNCTIONS IN EAE

这一建议的目的是制定一个更明确的

The objective of this proposal is to develop a clearer understanding of the roles of T lymphocytes in the induction of the autoimmune disease, experimental allergic encephalomyelitis (EAE). EAE is a paralytic and inflammatory disease of the central nervous system (CNS) and in many respects resembles the pathology of the most common human demyelinating disease, multiple sclerosis (MS). Recent development of an adoptive transfer system makes it possible now to induce chronic relapsing phases of the disease in mice. This study will use genetic, immunochemical and T lymphocyte cloning techniques to establish identity or lineage relationship between the transferred cells and the T lymphocytes localized at the CNS lesion sites. This is significant because while T lymphocytes have been implied in the induction of EAE, the mechanisms of EAE induction remain unclear. The design of the experiments takes advantage of the fact that murine T lymphocytes characteristically express a cell surface antigen, Thy-l. Although this antigen is also expressed on some neural cells, the existence of allelic forms of this antigen still makes it a useful marker for cell trafficking studies. By adoptively transferring Thy-1.2+ MBP- specific T lymphocyte clones into naive Thy-1.1+ congenic recipients, the migratory pattern of the transferred cells in the recipients can be followed. Frozen CNS sections of recipients before, during, and after the paralytic attack will be examined for the presence of the transferred cell by immunoperoxidase staining techniques. Factors such as irradiation and anti-la treatment will be examine, to determine their effects on the migratory pattern of donor cells. Recent studies show that lymphocytes localized at CNS lesion sites can be cultured and cloned in vitro. Characterization of these clones in terms of the Thy-l marker, antigen specificity, lymphokine production and encephalitogenicity will reveal whether these cells are related to the donor cells and the extent of the host's T lymphocyte participation in the manifestation of the disease. These experiments are even more important when applied to the chronic relapsing phase of the disease. The migratory pattern and functions of both the donor and host cells during the remission-relapse cycles will be studied. Experiments are designed to determine whether donor T lymphocytes migrate in and out of the CNS during the cycles and the possibility of a host-derived suppressor T lymphocyte dampening the inflammatory response during temporary remission. Taken together, these studies will provide a better appreciation of the underlying mechanisms of MS.