Our overall research program is directed to understanding the role of proteolipid protein (PLP) in the development, maintenance and function of CNS myelin. The goal of the present project is to elucidate the role of PLP in autoimmune responses of the nervous system. PLP is the most abundant protein of CNS myelin and is now accepted as a major encephalitogen. The experimental allergic encephalomyelitis (EAE) resulting from sensitization with PLP is frequently severe, with considerable demyelination, and there is reason to believe that the mechanism of the encephalitogenic response to PLP differs from that of the more widely studied encephalitogen, myelin basic protein. To understand the mechanism of the encephalitogenics responses in EAE and ultimately in multiple sclerosis, the characteristics of the immune response to PLP must be elucidated and eventually related to the biochemical properties of PLP as it exists in the membrane.
Our specific aims are: 1. To study the biology of PLP-specific T cell clones obtained from SJL mice. A) Clones will be characterized for cell surface markers, antigen specificity, MHC restriction and disease induction pattern. B) The functional properties of the characterized clones will be assessed by evaluating T cell receptor VBeta gene usage and the types of lymphokines secreted. Encephalitogenic and nonencephalitogenic clones will be compared to assess the phenotypic and functional characteristics which contribute to the encephalitogenic activity. II. To analyze the encephalitogenic PLP peptide (139-151) for SJL mice by identifying the determinants for interaction with a) the class II MHC molecule (agretope) and b) the T-cell receptor (epitope). The responses of T cell clones and hybridomas will be analyzed systematically using truncated and substituted peptides. III. To characterize a PLP peptide-induced relapsing EAE model which we have developed in SJL mice. A) Proliferative responses of T-cells will be studied during relapses and remissions, to determine if responses to new PLP epitopes and/or to other myelin antigens appear. B) The role of regulatory cells will be studied to attempt to modulate the disease course. These experiments are designed to provide a broad basic foundation for understandin 9 autoimmune responses to PLP and will permit development of a more complete picture of the immunologic events occurring in EAE and in human demyelinating disorders of the CNS such as multiple sclerosis.
Showing the most recent 10 out of 39 publications
