Modeling the Heterogeneity of Human LN in Mouse Models
Abstract
Rationale, Objective, and Aims: Lupus nephritis (LN) is a severe complication of lupus that affects between 30%-60% of adult lupus patients and up to 70% of children with lupus. Our current treatments for LN are not satisfactory, because they broadly suppress the immune system and more than half of patients fail to achieve a complete remission over a 12-month period. This results in irreversible kidney damage and progression requiring to dialysis or transplant in a significant proportion of patients. The goal of this proposal is to improve our understanding of what causes damage to the kidneys by studying a particular immune cell type that is found in the LN kidney called a macrophage. The presence of this cell type is associated with poor outcome when it is found in kidney biopsy tissue of patients with LN. Macrophages are highly dynamic cells that change their function to suit the environment that they are in. They can cause inflammation but can also help with tissue repair. Because there are so many subsets of macrophages and their function can change over time, new technologies that allow analysis of single cells is crucial to the study of these cells. Study of kidney tissues in LN patients is hampered by the small size of the kidney biopsy and the ability to biopsy patients only once or twice over the course of their disease. Therefore, animal models, when used carefully and rigorously are very useful for addressing hypotheses generated by examining human data. Our group has been part of a large national effort called the Accelerating Medicines Partnership in which human LN biopsies were collected across the country and single cell analyses of 160 of these tiny biopsies is being performed at the Broad Institute. Large numbers of cells from patients who responded and did not respond to treatment are being characterized, including a large cluster of macrophages and related cells. We have already identified at least four subsets of macrophages in the first 23 patients analyzed. Our plan is to first compare this information with single cell data from the kidneys of five diverse mouse models of LN in order to identify all the subsets of these cells that are present in humans and define which model has each cell type. Macrophages can change their functions over time and include both harmful and protective subsets. The function of each kidney subset is not yet known. In Aim 2 we will use the mouse models to follow the fate of macrophages as they enter the kidneys and define all the transition states of these cells. In Aim 3 we will treat several of our mouse models with both standard treatment and with a new successful drug, belimumab, and determine the treatment induced difference in macrophages between responders and non-responders. We will then determine whether there are similar characteristics in patients who are responders vs. non responders to treatment that might help predict either outcome or which therapy might be the best to use in each patient. Relationship of the Proposed Work to the Specific Focus Area: One reason for the difficulty in treating LN is the diversity of the disease both with respect to type of inflammation in the kidneys and the changes in each kidney that occur over time. Our study will address this diversity and use multiple mouse models to find the one that reflects both pathologic states that are shared by many LN patients and ones that are restricted to smaller subsets of individuals. Comparison of these states with the large human data set will teach us about differences between patients who respond and do not respond to treatment. Applicability of the Research: LN remains a huge unmet need in lupus patients, with more than 50% being unresponsive to current treatments and the failure of multiple clinical trials of new therapies over the last 20 years. Kidney damage is a major cause of poor quality of life and early death in patients with lupus. These are the patients we hope will
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110966
Entities
People
- Anne Davidson
Organizations
- The Feinstein Institute for Medical Research
- United States Army