Immunoregulation and Pathology of Chronic-Relapsing EAE

Project: Research project

Project Details

Description

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory demyelinating disease of the CNS that serves as a model for human multiple sclerosis (MS). 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 the adoptive transfer of peptide-specific Th1 cells. Based on the relapsing-remitting course of the disease, along with our finding that 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 (intramolecular or intermolecular epitope spreading), we hypothesize that disease remission results from specific form(s) of immunoregulation. Specific Aim 1 of current proposal will build on our productive studies from the previous funding period to further delineate the role of several overlapping immunoregulatory mechanisms which appear to function in ameliorating CNS responses to the disease initiating epitopes leading to initiation of disease remission. These include: a switch of CNS cytokines from pro-inflammatory to anti-inflammatory (i.e., a Th1/Th2 switch) and/or the possible activation of antigen- or TcR-specific regulatory T cell populations in response to the disease-initiating T cells. Secondly, we will continue to elucidate the mechanisms responsible for downregulation of disease induction and progression 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). In comparison to tolerance induced by the i.v. or oral administration of soluble peptide, tolerance induced by Ag-SP was shown to be highly effective for prevention and treatment of R-EAE, and a powerful tool for identification of the specificity of pathologic epitopes at various stages of the relapsing-remitting disease process. 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/deletion of encephalitogenic Th1 cells. The effects of tolerance at varying times during the disease process on the T cell repertoire (using both immunoscope analysis and in vivo tracking of SJL Thy 1.1 congenic and SJL PLP139-151-specific TcR transgenic T cell populations), 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 should enhance our understanding of both intrinsic mechanisms of spontaneous disease remission, and continue to delineate the cellular and molecular mechanisms of a highly efficient extrinsic method of inducing peripheral immune tolerance proven effective for the treatment of pre-existing autoimmune disorders.
StatusFinished
Effective start/end date8/15/017/31/06

Funding

  • National Institute of Neurological Disorders and Stroke (5 R01 NS026543-17)

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