Multiplexed single-cell imaging in pediatric lupus nephritis
Most kids with lupus develop kidney disease, but very few respond to currently available therapies. Grant support from the Lupus Research Alliance will allow Dr. Hsieh to use a new technology to map out individual immune cells in the kidneys of children with lupus—visual and quantitative guides of which immune cells are present and where they are. She plans to compare these two-dimensional maps with those from healthy children and those with other kidney diseases. Her hypothesis is that the kidneys of kids who have lupus and kidney disease have a unique structure. By mapping this structure, she hopes to understand how kidney disease develops in lupus so she can figure out how to treat children who develop kidney trouble. She’ll then correlate these kidney maps with the profiles of immune cells in blood, so that doctors will be able to do a simple blood test instead of invasive kidney biopsy to see how to determine which drugs to use.
What this study means for people with lupus
Dr. Hsieh’s goal of mapping what makes the structure of the lupus kidney unique, and how this uniqueness manifests in blood, should help researchers eventually develop better, more effective treatment options for children whose lupus leads to kidney failure.
Systemic lupus erythematosus (SLE) is a multi-organ rheumatologic disease with heightened disease severity in children. While a majority of pediatric SLE patients develop lupus nephritis (LN) only a small proportion achieve complete response to therapy, resulting in significant morbidity and mortality. Conventional clinical and laboratory parameters are not sufficiently sensitive or specific for detecting incipient renal disease or predict response to specific therapy, underscoring the need to better delineate the underlying immune changes that drive disease activity. A lack of knowledge regarding immune cellular dysregulation and altered renal immune architecture present in pediatric LN poses a significant hurdle in the effort to develop selective therapeutic agents and monitor disease activity. The objective of this proposal is to determine the precise phenotype of immune cells and their spatial localization in kidney tissue from pediatric LN patients, and correlate these features with detailed peripheral blood immunophenotyping. This deep immune profiling of matched kidney biopsies and peripheral blood will likely elucidate the relationship between tissue-specific LN immunopathology, peripheral blood biomarkers that correlate to renal disease, and response to treatment. To achieve this goal, we will use high-dimensional multiplexed ion beam imaging (MIBI) and mass cytometry (CyTOF) platforms, both of which offer single-cell analysis of over 40 parameters, for in situ (kidney) and in suspension (blood) cellular analysis, respectively. Our central hypothesis is that high-dimensional imaging analysis of kidney biopsies will reveal a renal immune architecture unique to LN; that is, specific spatial relationships between infiltrating immune cell subsets and renal stroma. Additionally, we posit that matched renal tissue and peripheral blood samples will share immunological parameters that will reliably serve as renal disease biomarkers. To test these hypotheses, we will perform MIBI on kidney biopsy samples from pediatric LN and inflammatory and non-inflammatory renal disease-control patients (Aim 1). We will also compare results of MIBI and CyTOF from the same LN patients for correlations between renal tissue and peripheral blood immunophenotype (Aim 2). This study is innovative in that it is the first of its kind to apply state-of-the-art single cell technology platforms to profile pediatric LN immunopathology in both renal tissue and peripheral blood cells, with the goal of identifying candidate immune pathways for patient-specific immunotherapy. The proposed research is significant because it will identify 1) candidate pathways of immune dysregulation that can be leveraged for therapeutic development, 2) novel insights into kidney immunopathology that will guide utilization of emerging targeted therapies, and 3) peripheral blood biomarkers that correlate with LN immunopathology, all of which will propel precision medicine in pediatric SLE.