Collaborative Project-Predicting LN flare and activity by an analysis of blood and urine

Feinstein Institute For Medical Research, Manhasset NY

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Abstract

PROJECT SUMMARY Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus (SLE) that can lead to irreversible renal impairment. Current immunosuppressive therapies fail to reverse disease in more than half of treated patients and only 2 new drugs have been approved treatment, both of which confer only modest improvement. Renal myeloid cells are involved in renal injury in LN, both in humans and animal models. Macrophages are highly plastic and can mediate both pro-inflammatory and reparative functions. Because there are so many subsets of myeloid cells and some of them change their function over time, analysis of single cells is crucial to the study of these cells. Initial studies in Phase 1 and early Phase 2 of the Accelerating Medicines Partnership-SLE (AMP-SLE), of which we are members, have shown that there are multiple subsets of macrophages in LN kidneys some of which are infiltrating and some of which are resident. By overlapping these data with data from several mouse models we have confirmed that some of these states are related to nephritis, independent of treatment and correlate with both histologic disease activity and chronicity. Study of kidney tissues in LN patients is hampered by the small size of the kidney biopsy and the infrequency of these biopsies in individual patients during their disease course. Therefore, a careful analysis of blood and urine from LN patients may allow non-invasive identification of both precursors and effector states of renal infiltrating cells. Our overall hypothesis is that we will identify early or precursor activated monocyte states in the blood of SLE patients prior to flare, and that this information will help identify new pathways for therapeutic intervention and direct personalized treatment. Our approach is focused on identifying myeloid cells and their intracellular pathways that associate with early tissue injury. In Aim 1 we will perform an integration of single cell RNAseq data from myeloid cells identified in several large PBMC datasets of SLE patients and healthy donors to map macrophage sub-populations that are SLE specific. We will integrate the data with that of renal and urine myeloid cells of 155 patients enrolled in AMP-SLE Phase 2 to determine which subsets might be precursors of renal infiltrating cells. Using legacy Autoimmunity Centers of Excellence samples already available to us we will then determine whether these subsets are increased in frequency during SLE flares, both renal and non-renal. In Aim 2, using a strategy to identify and enroll patients at high risk of flare we will design a longitudinal study to determine whether myeloid subsets of interest increase in the blood and/or urine prior to flare. Finally, we will begin to study the function of activated monocytes in SLE patients by analyzing their metabolic profiles and by culturing them in vitro. Our long-term goal is to design new therapeutic approaches to identify early disease and to modulate pathogenic myeloid cell subsets and thereby protect LN kidneys from disease progression, fibrosis, and end stage renal disease.