Evidence map›Paper›PMID 40907721›Full record

ArticleTransplant immunology2025

IL-6 amplifies corneal transplant alloimmunity by inducing dysfunctional IFN-γ- secreting Treg through the VEGFA-VEGFR1 axis.

Seokjoo Lee, Akitomo Narimatsu, Neda Heydarian, Mark Krauthammer, Shilpy Bhullar, Yihe Chen, Sunil K Chauhan, Thomas H Dohlman, Reza Dana

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Transplant immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Seokjoo LeeLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Akitomo NarimatsuLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Neda HeydarianLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Mark KrauthammerLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Shilpy BhullarLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Yihe ChenLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Sunil K ChauhanLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Thomas H DohlmanLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Reza DanaLaboratory of Ocular Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: Reza_Dana@meei.harvard.edu.

Funding

MECHANISMS OF SENSITIZATION IN HIGH-RISK CORNEAL GRAFTSR01EY012963 · NEI · SCHEPENS EYE RESEARCH INSTITUTE · PI DANA, REZA · 2000 to 2025
$15.1M
NEI NIH HHS R01 EY012963
6 · The paper itself

Abstract

backgroundCorneal allografts generally exhibit high acceptance due to the immune-privileged ocular microenvironment. Regulatory T cells (Treg) promote graft tolerance; however, in a vascularized milieu, they may acquire a pro-inflammatory phenotype. We investigated how dysfunctional Treg contribute to graft rejection through the VEGFA-VEGFR1 axis.

methodsTreg were treated with IL-6 and VEGFA, and their phenotype-including FoxP3, IL-10, and IFN-γ-was evaluated with or without a VEGFR1 antagonist (αVEGFR1) using PCR, immunoblotting, ELISA, and flow cytometry. Suppressive function was assessed by T-cell proliferation assays, corneal cell death by Annexin V staining, and graft survival by adoptive transfer of dysfunctional Treg into a transplantation model.

resultsIL-6 reduced FoxP3 (p < 0.0001) and upregulated VEGFR1 (p < 0.001). IL-6 plus VEGFA further decreased FoxP3 (p < 0.0001) and IL-10 (p < 0.0001) while increasing IFN-γ (p < 0.0001). αVEGFR1 reversed these effects, restoring FoxP3 (p < 0.0001) and IL-10 (p < 0.05) while reducing IFN-γ (p < 0.001). Functionally, IL-6/VEGFA-pretreated Treg showed impaired suppression of effector T-cell proliferation (p < 0.0001), an effect partially rescued by αVEGFR1 (p < 0.001). In ex vivo assays, fresh Treg prevented, whereas dysfunctional IFN-γ-secreting Treg induced, corneal cell death (p < 0.0001). In vivo, grafts injected with dysfunctional Treg were rejected within 3-7 weeks, while those with αVEGFR1-treated Treg showed improved survival and reduced cell death (p < 0.0001).

conclusionIL-6 impairs Treg via VEGFR1 upregulation, driving IFN-γ secretion through the VEGFA-VEGFR1 axis and promoting corneal cell death and graft rejection.

Indexed as

Corneal TransplantationGraft RejectionInterleukin-6T-Lymphocytes, RegulatoryVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-1AnimalsCells, CulturedCorneaForkhead Transcription FactorsGraft SurvivalHumansInterferon-gammaMiceMice, Inbred BALB CMice, Inbred C57BLForkhead Transcription FactorsFoxp3 protein, mouseInterferon-gammaInterleukin-6Vascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-1Corneal transplantationDysfunctional TregIL-6 signalingImmune privilegeVEGFA–VEGFR1 axis

Identifiers

PMID40907721
PMCPMC12486648

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.