Experimental autoimmune encephalomyelitis (EAE) is a T cell- mediated inflammatory demyelinating disease of the CNS that serves as a model for human multiple sclerosis. In the SJL/J mice, a relapsing-remitting form of EAE (R-EAE) is induced following active immunization with proteolipid protein (PLP), myelin basic protein (MBP), or the immunodominant epitopes on these molecules (PLP139-151 or MBP84-104) or following adoptive transfer of peptide- specific Th1 cells. Based on the relapsing-remitting course of the disease, along with the finding that Date Released: 05/15/1997 disease progression (relapses) in these peptide induced R-EAE models are due primarily to the recruitment of T cell responses against non- crossreactive endogenous myelin epitopes on the same or different myelin proteins (intermolecular or intramolecular epitope spreading), it is hypothesized that disease remission results from specific form(s) of immunoregulation.
Specific Aim 1 will continue studies from the previous funding period to test several non-mutually exculsive hypotheses by which responses to disease initiating epitopes may be down-regulated leading to disease remission: 1) potential switching of CNS cytokines from pro-inflammatory to anti-inflammatory; 2)CTLA- 4-mediated anergy and/or Fas/FasL-mediated apoptosis of disease initiating Th1 cells; 3) activation of antigen- or TCR-specific regulatory T cell populations in response to disease-initiating T cells.
Specific Aim 2 will elucidate the mechanisms responsible for downregulation of disease following extrinsic induction of antigen-specific peripheral tolerance induced by the i.v. injection of protein/peptide-pulsed, ethylene carbodiimide (ECDI)-fixed antigen presenting cells (Ag-SP).
Specific Aim 2 will further test the hypothesis that unresponsiveness induced by the i.v. injection of Ag-SP is primarily mediated by clonal anergy or encephalitogenic Th1 cells. The effects of tolerance at varying times during the disease process on the activation state, CNS homing properties, and cytokine expression patterns of effector Th1 cells will be determined. In addition, in vitro experiments utilizing encephalitogenic Th1 clones and in vivo experiments using TCR transgenic mouse systems will be employed to directly assess the relative contributions of clonal anergy vs. deletion to the unresponsive state. These studies would enhance our understanding of both intrinsic mechanisms of spontaneous disease remission, an delineate the molecular mechanisms of a highly efficient extrinsic method of inducing peripheral immune tolerance proven effective for the treatment of pre-existing autoimmune disorders.
Showing the most recent 10 out of 150 publications
