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Updated: Jun 18, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Spatial Analysis Identifies Endothelial HLA-F as a Prognostic Marker in Antibody-mediated Rejection
Toshihito Hirai1, Tomokazu Shimizu2, Hironori Fukuda1
1Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
Background:
Microvascular injury (MVI) is a key histopathological feature required for the diagnosis of antibody-mediated rejection (ABMR) in kidney allografts. However, MVI alone is insufficient for definitive diagnosis or accurate prognostication. We previously demonstrated that interactions between cluster of differentiation 31 (CD31)+ endothelial cells and cluster of differentiation 68 (CD68)+ macrophages within the peritubular capillary (PTC) niche are associated with graft outcome. To further elucidate the molecular mechanisms underlying this cellular interplay, we performed spatial transcriptomic profiling focused on the PTCs niche using the GeoMx Digital Spatial Profiler.
Methods:
This study was conducted in 2 phases. In the discovery cohort, total RNA was extracted from CD31+ and CD68+ regions within the PTC niche from 3 ABMR and 3 T cell-mediated rejection (TCMR) samples, followed by sequencing using the whole-transcriptome atlas (WTA; >18 000 genes). For validation, 67 kidney allograft biopsy samples (42 ABMR and 25 non-ABMR) were analyzed by immunohistochemistry (IHC) for HLA-F, identified as a candidate spatial signature of ABMR in the PTC niche.
Results:
Preranked gene set enrichment analysis revealed a coordinated interferon-γ-driven transcriptional program across both CD31+ and CD68+ compartments in ABMR, with HLA-F emerging as a prominent feature. HLA-F expression was significantly associated with MVI severity and donor-specific antibody positivity. Among patients with active ABMR, higher HLA-F expression was associated with a greater decline in kidney function following biopsy.
Conclusion:
These findings identify HLA-F as a novel molecular marker linked to ABMR pathogenesis and prognosis, highlighting its potential utility as a spatially resolved biomarker within the PTC niche.
Insights
Human Leukocyte Antigen-F (HLA-F) is a novel biomarker for antibody-mediated rejection (ABMR) in kidney transplants. Its expression in the peritubular capillary niche correlates with rejection severity and predicts kidney function decline.
Area of Science:
- Immunology
- Transplantation Biology
- Genomics
Background:
- Microvascular injury (MVI) is crucial for diagnosing antibody-mediated rejection (ABMR) in kidney allografts but lacks prognostic value.
- Previous work linked CD31+ endothelial cells and CD68+ macrophages in the peritubular capillary (PTC) niche to graft outcomes.
- Understanding the molecular basis of this cellular interaction is key to improving ABMR diagnosis and management.
Purpose of the Study:
- To investigate the molecular mechanisms driving cellular interactions within the PTC niche in kidney allografts.
- To identify novel molecular markers associated with antibody-mediated rejection (ABMR) and its severity.
- To explore the potential of spatial transcriptomics for discovering biomarkers in kidney transplantation.
Main Methods:
- Spatial transcriptomic profiling using GeoMx Digital Spatial Profiler on CD31+ and CD68+ regions within the PTC niche.
- Discovery cohort analysis of 3 ABMR and 3 T cell-mediated rejection (TCMR) samples using whole-transcriptome atlas sequencing.
- Validation cohort analysis of 67 kidney allograft biopsies (42 ABMR, 25 non-ABMR) using immunohistochemistry for Human Leukocyte Antigen-F (HLA-F).
Main Results:
- A coordinated interferon-γ-driven transcriptional program was identified in both CD31+ and CD68+ cells in ABMR samples.
- Human Leukocyte Antigen-F (HLA-F) emerged as a prominent feature, significantly associated with MVI severity and donor-specific antibody positivity.
- Higher HLA-F expression in active ABMR patients correlated with a greater decline in kidney function post-biopsy.
Conclusions:
- Human Leukocyte Antigen-F (HLA-F) is identified as a novel molecular marker associated with ABMR pathogenesis.
- HLA-F expression within the PTC niche shows potential as a prognostic biomarker for kidney allograft outcomes.
- Spatially resolved analysis of the PTC niche offers valuable insights into ABMR mechanisms and biomarker discovery.
