Experimental allergic encephalomyelitis (EAE) is an autoimmune disease which shares many clinical and histological features with multiple sclerosis (MS). Following immunization of susceptible animals with myelin antigens (myelin basic protein or proteolipid protein (PLP)), T cells are generated which induce EAE. In this proposal we intend to study the role of the B7 costimulatory pathway in the induction and regulation of EAE. B7 costimulatory molecules provide a very important second signal in determining whether T cell recognition of antigen leads to T cell activation or unresponsiveness. The presence of multiple B7 molecules (B7-1 and B7-2), together with evidence for both positive and negative signaling through this pathway, indicate that this costimulatory pathway is complex and that additional insights are needed to manipulate it optimally. Our preliminary observations show that administration of anti-B7-1 antibody inhibits EAE whereas injection of anti-B7-2 exacerbates the disease, further supporting the complexity of the pathway in autoimmunity. Using B7-1 and B7-2 deficient mice generated by transgenic technologies, we will determine the role of this costimulatory pathway in the induction and effector phases of EAE. We propose to: I) study the mechanism by which costimulatory B7 molecules (B7-1 and B7-2) can either induce or inhibit EAE by a) using different protocols to generate T cell clones specific for the encephalitogenic PLP peptide 139-151 in the B7-1 and B7-2 deficient mice; b) test the cytokine profile and epitope specificity of these clones. ii) study the effect of B7-1 and B7-2 deficiency on spontaneous or actively induced EAE by interbreeding B7-1 and/or 2 deficient mice with MBP-TCR transgenic mice and determine incidence and severity of EAE in these mice. iii) determine the influence of B7- costimulatory molecules on the functional activity of altered peptide ligand (APL) generated by selectively changing TCR contact residues in the encephalitogenic PLP 139-151 peptide. The APL prevent and reverse EAE; we will analyze the potential contribution of B7 molecules in the functional activity of the APL by a) testing the effects of the APL on inhibiting EAE in the B7-1 and B7-2 deficient mice and b) testing the effect of the APL on the expression of B7-1 and B7-2 costimulatory molecules on the antigen-presenting cells in the periphery and in the target organ (brain) of the treated animals. These studies will provide broad basic information relevant to understanding the role of B7 costimulatory pathway in EAE and other autoimmune diseases, and on potential approaches for controlling autoimmune tissue injury.
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