AKI Post Allogeneic Bone Marrow Transplantation: Disease Understanding and Targeted Nanomedicines
- AKI: Mechanisms - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Panagiotakopoulou, Magdalini, Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Jaimes, Edgar A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Van den brink, Marcel Mrm, Memorial Sloan Kettering Cancer Center, New York, New York, United States
- Heller, Daniel A., Memorial Sloan Kettering Cancer Center, New York, New York, United States
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a very effective treatment for a variety of hematologic malignancies, but also associated with serious complications, such as graft-versus-host-disease (GVHD), a severe immune condition that manifests in multiple organs including the kidneys. Kidney injury in the setting of allo-HCT has an incidence as high as 80% and leads to high patient morbidity and mortality, however, its progression and mechanisms remain poorly characterized. Moreover, no approved drugs for AKI of any etiology exist, as most experimental therapies have poor pharmacokinetic profiles and minimal efficacy in treating AKI in humans.
We used an MHC-disparate irradiation-conditioned murine model of GVHD to investigate the pathology, genetic and molecular signatures of GVHD-mediated AKI, via bulk RNA sequencing, immunohistochemistry and immunoassays. We have also used microfluidics to synthesize lipid nanoparticles that target overexpressed proteins in the GVHD kidneys.
Our transcriptome analysis in kidney lysates of GVHD mice indicated significant immune and inflammatory pathway upregulation (including TNF-NF-kB and JAK-STAT pathways) which persisted for 14 days after transplantation. We also saw a significant increase in genes associated with renal damage and pro-fibrotic cascades. Our histological analysis demonstrated increased T-cell infiltration, apoptosis and renal damage and abnormal renal function was confirmed by elevated serum and urine biomarkers. By designing lipid nanoparticles that target overexpressed proteins in GVHD kidneys, we achieved enhanced localization of nanoparticles to the kidneys in the GVHD model.
We have investigated the histological and molecular features of AKI in an established murine model of GVHD to assess its pathophysiology and progression as well as to identify potential therapeutic targets. GVHD results in AKI characterized predominantly by T-cell infiltration, tubular gene dysregulation, renal function impairment and activation of inflammatory pathways. We have also shown that targeting specific overexpressed proteins specifically localizes nanoparticles to GVHD-AKI kidneys. We plan to use those nanoformulations to deliver small-molecule inhibitors of dysregulated pathways to the kidneys.
- Other NIH Support