This proposal focuses on lung disease in anti-RNP autoimmunity, the leading cause of death in Mixed Connective Tissue Disease, and a significant clinical issue in RNP+ lupus. Based on preliminary data in a murine model of anti-RNP autoimmunity and human studies, we hypothesize that a subset of CD11c+ CD11bhigh CD103- myeloid dendritic cells acting through TLR-inducible TRIF-mediated pathways play a central role in the pathogenesis of anti-RNP autoimmune lung disease. In this proposal, we will test this hypothesis with studies in animal models.
In Aim 1, we will assess the relevance of TRIF to anti-RNP lung disease by direct immunization and adoptive transfer studies with TRIF-/- mice.
In Aim 2, we will assess the relevance of CD11b+ mDC's to anti-RNP lung disease using depletion studies with clodronate or antibodies to DC surface markers, and we will test the therapeutic efficacy of a novel immunosuppressive therapeutic agent that targets CD11b-expressing cells in anti-RNP lung disease. These studies will lead to improved understanding and potentially to novel treatment approaches for a spectrum of autoimmune disease for which current treatments have not been efficacious.
Lung disease is the leading cause of death from Mixed Connective Tissue Disease, an autoimmune disease in which anti-RNP responses occur. We have recently observed that lupus patients with anti-RNP responses are also at high risk for serious lung disease. Current therapies are less effective for autoimmune lung disease than for other conditions (like lupus kidney disease). This proposal will examine how this form of autoimmune lung disease develops, and will test an innovative new approach to treat this condition, focusing on the role of a special kind of immune cell called lung-targeting dendritic cells. This work will show how dendritic cells become activated in the disease, and how this activation may be controlled. The results of this work may lead to improved treatments for this and additional forms of autoimmune lung disease.
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