Kidney Week

Abstract: TH-OR102

Innate Immune Cells, Memory T Cells, and Interferon Gamma Responses Characterize Transplant Glomerulopathy of Chronic Antibody-Mediated Rejection

Session Information

• Transplantation: Basic and Translational Advances
  October 24, 2024 | Location: Room 25, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: Transplantation

• 2101 Transplantation: Basic

Authors

• Giarraputo, Alessia, Massachusetts General Hospital, Boston, Massachusetts, United States

Alessia Giarraputo, MS, PhD

• How, Ira Doressa Anne L., Massachusetts General Hospital, Boston, Massachusetts, United States

Ira Doressa Anne L. How, MD

• Pankaj, Amaya, Massachusetts General Hospital, Boston, Massachusetts, United States

Amaya Pankaj, MD

• Raabe, Michael, Massachusetts General Hospital, Boston, Massachusetts, United States

Michael Raabe

• Brousaides, Nicole Lauren, Massachusetts General Hospital, Boston, Massachusetts, United States

Nicole Lauren Brousaides

• Colvin, Robert B., Massachusetts General Hospital, Boston, Massachusetts, United States

Robert B. Colvin, MD

• Rosales, Ivy A., Massachusetts General Hospital, Boston, Massachusetts, United States

Ivy A. Rosales, MD

Group or Team Name

• Immunopathology Research Lab.

Background

Transplant glomerulopathy (TG) in chronic antibody mediated rejection (CAMR) portends poor graft survival and outcome. Despite many studies on CAMR using bulk mRNA analysis, the pathogenesis of TG remains unexplored. Here we used spatial transcript analysis on allograft biopsies to reveal potential pathogenetic mechanisms of glomerular injury in CAMR.

Methods

Five-micron sections from archived FFPE allograft biopsies with CAMR (n=10) and no evidence of rejection (NER, n=6) were mounted on slides and hybridized to the Whole Transcriptome Atlas Panel (Nanostring). Using the GeoMx Digital Spatial Profiler-NGS system (Nanostring, Illumina), slides were scanned and whole glomeruli regions of interest (ROI) were created. Oligo tags from ROIs were quantified and analyzed performing differential expression, pathway analysis, cell typing (Immune Cell Atlas) and cell deconvolution.

Results

Differential expression between 50 CAMR and 35 NER glomeruli showed enrichment of macrophage associated transcripts (C1QA, C1QB, C1QC), interferon-associated transcripts (IFITM1, STAT1, CXCL9) and increased Class II-associated transcripts (CD74, HLA-DRA, HLA-DRB1, HLA-DPA1) (FDR adjusted p-value <0.05) in CAMR, while the top significant pathways were related to MHC antigen presentation, complement system, cytokine mediated pathways and interferon-gamma response. Cell typing and deconvolution revealed increased proportions of macrophage, NK cells, CD8 and CD4 memory T cells together with neutrophils localized in CAMR glomeruli (Figure). These findings were associated with endothelial dedifferentiation (decreased EHD3, SOST; increased COL4A1) and decreased podocyte number.

Conclusion

Spatially resolved transcripts of TG in CAMR reveal immune cell-related pathways of glomerular endothelial injury, suggesting a novel interplay of endothelial dedifferentiation in the pathogenesis of TG.