Systemic lupus erythematosus is a multi-system disease with significant morbidity and mortality. Current treatment is associated with significant side effects. This application pursues the novel hypothesis that cytotoxic T lymphocytes (CTL) are an important early mechanism that limits breaks in tolerance to nuclear antigens and prevents lupus development by eliminating activated autoreactive B cells. This hypothesis is tested using the parent-into-F1 model in which lupus-like disease is induced in normal F1 mice by the transfer of parental strain CD4+ T cells. Lupus is not observed with the transfer of both CD4+ and CD8+ T parental cells due to donor CD8+ CTL elimination of activated autoreactive host B cells. During the previous funding period, the Principal Investigator observed that perforin deficient donor cells result in impaired CTL elimination of host B cells leading to lupus long term. These results support a new paradigm in which defects in CTL killing are a final common pathway in lupus development due to incomplete elimination of activated autoreactive B cells which, in the setting of CD4 driven B cell activation, allows autoantibody production to persist and result in lupus. This paradigm is directly tested in this application. The long-term goal of the Principal Investigator is to develop a protocol for therapeutic induction of endogenous CTL which target and eliminate activated autoreactive B cells as treatment in lupus patients. This application will establish the underlying mechanisms required for this approach and test several promising strategies in the parent-into-F1 model.
Aim 1. Determine whether impaired elimination of autoreactive B cells by CTL is a final common pathway for the development of lupus regardless of the nature of the initial CTL defect. Sub-aims will evaluate whether perforin or Fas dominates.
Aim 2. Determine whether promoting CTL longevity by blocking downregulation will prevent lupus. The role of Fas, perforin, CD80, IL-2 and host T cells will be tested using knock out mice or mAb blockade.
Aim 3. Determine whether promoting CTL expansion by cytokine administration will prevent lupus. These experiments use an innovative method of TNF administration in the form of cytokine:anti-cytokine antibody complexes that prolongs biological activity in vivo. IL-15 will be tested as uncomplexed cytokine. Sub-aims will define the mechanisms by which TNF, IFN-g and IL-2 exert critical roles in the maturation of CTL effectors. Project Narrative Relevance. Systemic lupus erythematosus is an autoimmune disease that attacks major organ systems resulting in significant morbidity and mortality, particularly in women during their child bearing years. Current treatment is associated with significant side effects. This application examines a novel method of harnessing one's own immune system to help control disease.
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