Experimental autoimmune encephalomyelitis (EAE) is an animal model for human multiple sclerosis. Using myelin basic protein-specific T cell receptor (TCR) transgenic mice and RAG-1 deficient TCR transgenic mice, the principal investigator has recently shown that Fas/FasL deficiency dramatically diminished EAE. The principal investigator's long-term goal of research is to elucidate the mechanisms of FasL-induced cell death in EAE. He hypothesizes that FasL expressed by encephalitogenic T cells and neural cells are actively involved in the death of both resident neuroglial cells and infiltrating leukocytes in EAE. To test this hypothesis, he has developed a TCR transgenic model in which Fas/FasL expression on different cell types can be selectively manipulated.
Two specific aims will be addressed. I. The roles of FasL expressed by encephalitogenic T cells in EAE. Activated encephalitogenic T cells express both Fas and FasL. In this aim, the principal investigator will determine whether FasL expressed by encephalitogenic T cells regulates their own fates in EAE. This will be determined by studying TCR transgenic encephalitogenic T cells that do or do not carry Fas/FasL gene mutations. The fates of encephalitogenic T cells and of neurological cells will be determined by immunohistochemistry, flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). II. The roles of FasL expressed by neural cells in EAE. FasL is constitutively expressed by neurons and microglial cells. In this aim, the principal investigator will examine whether FasL expressed by neural cells can directly kill resident neural cells, especially oligodendrocytes; he will also examine whether FasL expressed by neural cells confers immune privilege by inducing apoptosis of infiltrating leukocytes, including encephalitogenic T cells. This will be addressed by investigating the effects of FasL deficiency in neural compartment using our adoptive transfer model. Both normal and RAG-1 deficient recipient mice will be used.
| Chen, Yiguang; Chen, Youhai (2003) Cytokines, lymphocyte homeostasis and self tolerance. Adv Exp Med Biol 520:66-72 |
| Hilliard, B; Wilmen, A; Seidel, C et al. (2001) Roles of TNF-related apoptosis-inducing ligand in experimental autoimmune encephalomyelitis. J Immunol 166:1314-9 |
