This is a proposal to develop novel therapeutic agents for preventing glomerular inflammation in lupus nephritis. The severity of renal involvement is variable among patients with lupus, and the detection of complement activation in a renal biopsy predicts progression of the disease Recent work has also shown that the complement regulatory protein factor H is critical for controlling complement activation within the glomerulus in lupus. The protein annexin A2 is specifically expressed within the glomeruli of patients and mice with lupus nephritis, and we have generated preliminary data demonstrating that annexin A2 blocks factor H from regulating complement within the glomerulus. We hypothesize, therefore, that annexin A2 is a critical factor in the development of renal inflammation and injury in patients with lupus. We will develop antagonists of the annexin A2-factor H interaction in order to prevent complement activation by annexin A2, and will test these agents in a model of lupus nephritis. Because annexin A2 expression within the glomerulus is specific for active lupus nephritis, antagonists of this interaction will have minimal effect in patients with quiescent disease. These agents will have fewer side effects than standard immunosuppressive drugs and will be safe for long-term administration,