Soluble mediators of relapse

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Abstract The most common event preceding relapse of primary glomerular diseases like Minimal Change Disease and Focal and Segmental Glomerulosclerosis is the common cold. Treatment of disease relapse is a lengthy process involving glucocorticoids and other immunosuppressive medications, some of which have multi-system toxicity. We hypothesized that relapse is induced by a “cytokine storm” that follows infection by common cold viruses like Rhinovirus. A “cytokine cocktail” was designed around the soluble Rhinovirus receptor and induces acute albuminuria after single intravenous injection in mice with low podocyte Zhx2 expression, a common feature in MCD and FSGS patients. This cytokine cocktail comprises of components of the innate and adaptive immune response that are necessary and sufficient to induce acute albuminuria. Exclusion of any member from the cytokine cocktail, or injection of individual members does not induce albuminuria. In this proposal, we will develop therapeutic strategies to prevent relapse of glomerular diseases after a common cold, by depleting soluble cytokines in the cytokine storm, or blocking their receptors in the glomerulus. In Aim 1, studies on cytokine depletion or receptor blockage in the podocyte will be conducted, and receptor dependent and independent mechanisms identified. In Aim 2, studies on cytokine depletion or receptor blockage in endothelial and mesangial cells will be conducted, and receptor dependent and independent mechanisms identified. In Aim 3, a therapeutic strategy that combines cytokine depletion with receptor blockage will be developed.