Engineered immunological niche to monitor lupus nephritis

Aaron Morris, Ph.D., The Regents of the University of Michigan 

Many people with lupus are at risk of kidney inflammation (lupus nephritis (LN)), which can progress to end-stage kidney failure and require dialysis and/or a kidney transplant. Early diagnosis of LN is key to enable early treatment that can prevent kidney failure. However, blood and urine testing are typically not sensitive enough to diagnose early-stage LN, while surgical kidney biopsies are invasive, can lead to complications, and are not possible in some people with certain medical conditions. Improved technologies for monitoring LN that enable faster diagnosis, improved selection of the right treatment, and monitoring of treatment response without invasive biopsies are needed. Dr. Morris will develop a groundbreaking diagnostic tool that will provide insight into LN disease progression and treatment response in a less invasive way. 

Dr. Morris will engineer a diagnostic system made from FDA-approved biomaterials that will be implanted just under the skin. After implantation, the body will form an inflamed tissue like the inflamed tissue in LN but more easily accessed. The inflamed tissue, which can be collected by taking a sample of the implanted material rather than the kidney, will provide a wealth of information, including changes in cell types and their features. Additionally, analyses of how molecules in the tissue change over time can provide deep insight into how the disease progresses and how a person responds to treatment. Dr. Morris will test whether this system, which has shown promise in a mouse model of multiple sclerosis, can replicate what is seen in kidneys affected by LN and be used to monitor treatment response in mouse models of lupus. 

What this study means for people with lupus 

The lack of sensitive, non-invasive tools has hindered LN diagnosis, monitoring, and treatment. Findings from Dr. Morris’ study could improve our understanding of the development of LN, define key features that determine how an individual responds to treatment, and revolutionize the monitoring of people with this devastating complication. 

Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease that affects over 5 million people worldwide. Unfortunately, lupus nephritis (LN), a frequent complication of SLE, develops in up to half of SLE patients. Yet even in patients already diagnosed with SLE, monitoring for LN via urinalysis is simply not sensitive enough to catch LN at its early stages. Some patients receive kidney biopsies to monitor for LN, but this requires biopsy of a vital organ – an invasive procedure that precludes its repetitive use. Clinically, we know that early diagnosis is essential to allow intervention and prevent continued destruction of kidney tissue. Early and effective therapy is tissue sparing and can reduce progression to kidney failure. Yet, LN is a heterogeneous disease, reflected by variable patient response to therapy, with therapy selection an iterative process. Technologies for disease monitoring in SLE and LN could enable faster diagnosis, patient stratification to improve therapeutic selection, and monitoring of treatment response without any need for kidney biopsy. Longitudinally investigating tissue in LN may provide increased quantity and accuracy of information compared to biofluids, and thus improve our understanding of the pathogenic mechanisms, as well as identify targets for precision therapies.

We propose an entirely new approach to monitor LN that harnesses a simple biomaterial system to engineer an immunological niche (IN) in the subcutaneous space that can be readily and easily biopsied. We anticipate creating an implantable diagnostic tool that can provide molecular insight in disease pathogenesis reflective of changes within the kidney by completing the following aims:

Aim 1 will test the hypothesis that a biomaterial-based IN will replicate immune alterations in LN sufficient to monitor disease development/progression. To accomplish this, we will test the IN in two well-described LN mouse models using a combination of bulk RNA sequencing, single cell sequencing, and flow cytometry.

Aim 2 will evaluate the ability of the IN to monitor treatment response in LN. To accomplish this aim, we will test two treatments in the two LN mouse models. Analysis will be performed by bulk RNAseq and histology.

Toward individualized precision medicine approaches, the ultimate goal of this work is to create a diagnostic tool that can replace kidney biopsy as a facile method for identifying the development of LN in SLE patients. We anticipate the device will enable monitoring SLE and LN disease activity – predict disease flares and treatment response – more accurately than biofluids, a major quality of life improvement for people with lupus. Furthermore, immunological insights gained from longitudinal sampling of inflamed tissue may identify targets for novel therapeutic development.