Modeling the Heterogeneity of Human LN in Mouse Models
Abstract
Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Immunosuppressive therapies fail to reverse disease in more than half of treated patients and the rate of progression to renal failure has plateaued in the USA in the past 20 years. This failure in part reflects disease complexity and heterogeneity. We have previously found in animal models that macrophages are involved in renal injury in LN. Macrophages are highly plastic and can mediate both pro-inflammatory and reparative functions. In human LN the presence of macrophages in renal biopsies correlates with poor prognosis. We propose to identify human-relevant myeloid cell subsets in lupus models that reflect differences in disease pathophysiology, disease stage and responsiveness to treatments; this information will help identify new pathways for therapeutic intervention and direct personalized treatment. In Aim 1 we will use single cell RNASeq analysis to define clusters of myeloid cells in 5 different models of LN and integrate these data with that from AMP Phase 2 to identify both shared and unique macrophage sub-populations and determine whether the presence of any of these correlates with responder status. In Aim 2 we will follow the fate of macrophages as they transition from the blood into the kidneys and harvest them at intervals in order to define how subsets are related to each other and the nephritis specific profile of each subset. In Aim 3 we will follow the fate of renal myeloid cells (in responder and non-responder strains and responder and non-responder mice within strains) in human-relevant mouse models treated with remission induction and to maintenance therapies. These studies are a necessary first step towards mechanistic studies aimed to promote novel approaches and therapies that prevent or treat LN.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1199280
Entities
People
- Anne Davidson
Organizations
- The Feinstein Institute for Medical Research