This application sets forth studies to examine the chronic relapsing EAE model in the mouse. The principal investigator has discovered that the SJL.B mouse, unlike the SJL, does nor develop a chronic relapsing EAE (CREAE) disease as does the SJL. This is reversed in the B10 mouse in which the B10.S gets CREAE while the normal B10 does not. This indicates to the principal investigator that in the H-2b there is a gene which might encode for resistance to relapses in CNS inflammation. In this set of studies he sets forth to discover the explanation for this phenomenon. His project is divided into three Specific Aims, some of which have subaims. In the first Specific Aim he will investigate recombinants of the B10 background in which the MHC is partially present. In this manner he hopes to narrow the area containing the locus that might control the CREAE phenotype. While a limited number of congenics exist, he will utilize those available and only in the extreme try to generate new ones of his own. The second Specific Aim is large an has five subaims. all are directed toward defining the cellular basis of the non-relapsing phenotype of the SJL.B. In (A) he will investigate the ability of the SJL.B to respond to PLP peptides and whole molecule. This might be relevant if the lack of relapses is due to failure of epitope spreading. In (B) he will further investigate if the non-relapsing phenotype is a lack of epitope spreading to other areas of the initiating antigen, MBP. In this he will use his thy1 congenic mice immunized with MBP and he will test proliferation and ELISPOT assays to define the ability of this mouse to respond to different areas of the MBP molecule first using cleavage fragments followed by synthetic peptides). In (C) he will determine if the absence of CREAE in SJL.B is because there is loss of the initial encephalitogenic (donor) cells or if these donor cells become inactivated or shift to Th2. The fourth subaim (D) will seek to learn if the SJL.B's resistance to CREAE can be corrected by manipulations of cytokines afforded by giving superantigens or antibodies against cytokines. In (E) he hopes to define if the level of resistance to CREAE resides in the encephalitogenic cells themselves or in the recipients tissues. He will do this by reciprocal T cell transfers. In the third and final aim, he hopes to determine if the initial administration of donor (encephalitogenic) T cells is responsible for or related to the CREAE phenomenon by remaining persistent and/or activated in the host. In subaims of this part he will (A) give the normal SJL Thy1 tagged pathogenic cells from an animal transgenic for an anti-MBP peptide TcR. These cells will be encephalitogenic, and also continuously detectable because of their distinct Thy1 molecule. In (B) he will as if these cells retain their pathogenicity and Th1 phenotype during active recurrence of EAE or remission. Part (C) are the donor encephalitogenic cells actually needed for relapses. He will delete them with antibodies against the encephalitogenic cells initially infused, thus eliminating them. Further relapses could not be due to their pathogenic influence. Finally (D) he will seek to discover if the initially infused T cells are expand or if their trafficking patterns (CNS vs. periphery -- spleen) change between remission and relapse. In this he will give BrdU to mice in remission and seek to discover if the cells found in the CNS during relapse are positive for the marker.
