IL-15 in Lupus
Abstract
Fiscal Year 2020 Lupus Research Program Focus Areas addressed include the following: 1. Determining the pathobiology of lupus disease in target human tissues 2. Understanding lupus disease heterogeneity, including understanding lupus disease mechanisms Three separate recent observations have led us to propose and test a novel hypothesis: (1) Out of several proteins we have interrogated in lupus patients’ urine using various screening platforms, one of the most predictive markers of active lupus nephritis is urine IL-15, a protein that drives the expansion and activation of one type of lymphocyte, the CD8 T-cell. (2) When multiple proteins were examined within lupus nephritis kidneys using a novel technology, patients with severe lupus nephritis exhibited increased numbers of CD8 T-cells. (3) Recent works by others show that in severe forms of nephritis (called crescentic glomerulonephritis), CD8 T-cells can infiltrate otherwise impenetrable locations within the kidneys, hence leading to clinical disease. Since “crescentic glomerulonephritis” is common in patients with lupus nephritis, we hypothesize that IL-15 is essential for the expansion and activation of intra-renal CD8 T-cells, CD8-mediated renal injury and clinical nephritis in lupus patients. Impact: Lupus afflicts approximately 50 per 100,000 individuals, including military personnel. Lupus Nephritis (LN) is prevalent among African Americans and Hispanics, both of whom are well represented in the military. Indeed, archived samples from the military have been instrumental in detailing the evolution of serological autoreactivity in lupus. The present proposal focuses on a form of lupus called lupus nephritis, where the kidneys are affected, and eventually damaged. Although lupus patients with a type of nephritis, called proliferative lupus nephritis, have a poorer longterm outcome, not all patients with proliferative lupus nephritis experience poor outcome. Only some patients progress to developing a unique pathology called “crescentic glomerulonephritis.” The mechanistic basis for this heterogeneity in disease is unknown. The proposed studies focus on a novel hypothesis and mechanism that may explain why only some lupus nephritis patients progress clinically. In addition, these studies may ascribe an important pathogenic role for CD8 T-cells and the cytokine IL-15 in the progression of lupus nephritis. Establishing this mechanistic link will not only clarify our understanding of how lupus nephritis progresses at the molecular level, this may also lead to novel disease biomarkers (such as urine IL-15) and novel therapeutic targets for lupus nephritis. Hence, this study may have a significant impact on lupus in three ways: (1) Augment our understanding of the pathogenic mechanisms underlying lupus nephritis, (2) lead to better biomarkers of lupus nephritis, and (3) pave the path toward a novel therapeutic target in lupus nephritis. Short-Term Impact: In the near term, these studies will confirm that IL-15 and CD8 T-cells are indeed responsible for severe forms of lupus nephritis, thus clarifying our basic understanding of how this disease progresses within the kidneys. These findings will then focus the limelight on IL-15 as a potential disease biomarker and therapeutic target. Long-Term Impact: Based on the results of this study, future studies will be planned in lupus patients to assess whether urine IL-15 can be used as a disease biomarker to predict disease flares and whether IL- 15 can be therapeutically targeted in patients. Studies will also be carried out to decipher the subcategories of lupus patients who may best respond to IL-15 targeting. The ability to track the underlying renal disease frequently and non-invasively can significantly simplify the diagnosis and monitoring of renal disease so that early treatment can be instituted promptly. Early detection and treatment of lupus nephritis can have a significant impact on healthcare cos
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110936
Entities
People
- Chandra Mohan
Organizations
- United States Army
- University of Houston