Mechanisms by which individuals with systemic erythematosus (SLE) develop sustained autoantibody production remain largely undefined. In the NZB/NZW F1 mouse model of SLE, we have demonstrated that peptides derived from syngeneic anti-DNA monoclonal antibodies activate T cell help for autoantibody production, and modulate disease course. Normal mice, which are identical to NZB/NZW F1 at MHC class II, do not develop this autoreactivity spontaneously, but can be induced to develop such autoreactive T cells by immunization with self Ig. However, the normal immune responses are transient, and limited to a few determinants. In contrast, NZB/NZW F1 mice develop a persistent response to several determinants which spread over time to involve a large number of determinants all across the Ig molecule. The general objectives of this proposal are to develop novel strategies to modulate T cell autoreactivity, to understand the basis of differences in self-reactivity between lupus-prone and normal mice, and to ameliorate disease in lupus. Using our model of specific self antigenic stimulation by peptides derived from anti-DNA VH regions, we will attempt to alter antigen processing and presentation of self Ig peptides by administering them as mini-genes, and determine differences in self antigen presentation in BWF1 versus normal mice. The hypothesis to be tested is that altering in vivo antigen presentation of self Ig peptides, by administering them as mini-genes, will enhance or regulate peptide-specific responses in a way that down- regulates autoantibody responses and disease in lupus-susceptible mice. Specifically, we will construct recombinant adenovirus vectors and/or naked DNA designed to express the anti-DNA V region-derived T cell determinants, either singly or in tandem repeats. These peptide minigene expressing vectors will be tested for their ability to induce helper or regulatory CD4+ or CD8+ T cell activation, cytokine release, anti-peptide and anti-DNA antibodies, and to affect inherent abnormalities in T cell responses in lupus mice. Thus, this genetic approach to peptide delivery may help clarify abnormal T helper cell functions in lupus.
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