Evidence map›Paper›PMID 34099346›Full record

ArticleCytokine2021

Stable expression of the human thrombomodulin transgene in pig endothelial cells is associated with a reduction in the inflammatory response.

Hidetaka Hara, Hayato Iwase, Huy Nguyen, Yuko Miyagawa, Kasinath Kuravi, Jeremy B Foote, Will Eyestone, Carol Phelps, David Ayares, David K C Cooper

Open access · greenAbstract read
In one paragraph

Article in Cytokine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.0field-weighted citation impact, top 24% of its field
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

9 citing papers in PubMed, 11 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. [Research and application progress for liver xenotransplantation].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025
    Review
  5. Review
  6. Review
  7. Developments in kidney xenotransplantation.Frontiers in immunology · 2023
    Review
  8. Review
  9. Article
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

10 authors at 2 institutions in 1 country.

Hidetaka HaraXenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA; Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: harahjp@icloud.com.
Hayato IwaseXenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA; Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Huy NguyenXenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Yuko MiyagawaThomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Kasinath KuraviRevivicor, Blacksburg, VA, USA.
Jeremy B FooteDepartment of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL, USA.
Will EyestoneRevivicor, Blacksburg, VA, USA.
Carol PhelpsRevivicor, Blacksburg, VA, USA.
David AyaresRevivicor, Blacksburg, VA, USA.
David K C CooperXenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
University of Alabama at Birmingham · USUniversity of Pittsburgh · US

Funding

Prolonging life-supported pig kidney and heart graft survival in baboons by suppressing inflammationU19AI090959 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI COOPER, DAVID KC · 2010 to 2024
$26.3M
Nonhuman Primate Reagent ResourceU24AI126683 · NIAID · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Diogo Magnani · 2016 to 2026
$20.1M
Specific Pathogen Free Baboon Research Resource (SPFBRR) - Bridge Funding Administrative SupplementP40OD024628 · OD · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI WILLIAM D HOPKINS · 2017 to 2026
$15.7M
Resource CoreP40OD028116 · OD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Diogo Magnani · 2020 to 2026
$5.9M
Resource for Nonhuman Primate Cell Depleting AntibodiesR24OD010976 · OD · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ENGELMAN, KATHLEEN, MAGNANI, DIOGO · 2012 to 2019
$4.7M
NIAID NIH HHS U19 AI090959NIAID NIH HHS U24 AI126683NIH HHS P40 OD024628NIH HHS P40 OD028116NIH HHS R24 OD010976
6 · The paper itself

Abstract

backgroundXenotransplantation is associated with an inflammatory response. The proinflammatory cytokine, TNF-α, downregulates the expression of thrombomodulin (TBM), and induces coagulation dysfunction. Although human (h) TBM-transgenic pigs (p) have been developed to reduce coagulation dysfunction, the effect of TNF-α on the expression of hTBM and its functional activity has not been fully investigated. The aims of this study were to investigate (i) whether the expression of hTBM on pig (p) cells is down-regulated during TNF-α stimulation, and (ii) whether cells from hTBM pigs regulate the inflammatory response.

methodsTNF-α-producing T, B, and natural killer cells in blood from baboons with pig heart or kidney xenografts were investigated by flow cytometry. TNF-α staining in the grafts was detected by immunohistochemistry. Aortic endothelial cells (AECs) from GTKO/CD46 and GTKO/CD46/hTBM pigs were stimulated by hTNF-α, and the expression of the inflammatory/coagulation regulatory protein, TBM, was investigated.

resultsAfter pig organ xenotransplantation, there was a trend to increases in TNF-α-producing T and natural killer cells in the blood of baboons. In vitro observations demonstrated that after hTNF-α stimulation, there was a significant reduction in the expression of endogenous pTBM on pAECs, and a significant increase in the expression of inflammatory molecules. Blocking of NF-κB signaling significantly up-regulated pTBM expression, and suppressed the inflammatory response induced by hTNF-α in pAECs. Whereas the expression of pTBM mRNA was significantly reduced by hTNF-α stimulation, hTBM expression on the GTKO/CD46/hTBM pAECs was not affected. Furthermore, after hTNF-α stimulation, there was significant suppression of expression of inflammatory molecules on GTKO/CD46/hTBM pAECs compared to GTKO/CD46 pAECs.

conclusionsThe stable expression of hTBM in pig cells may locally regulate the inflammatory response. This will help suppress the inflammatory response and prevent coagulation dysregulation after xenotransplantation.

Indexed as

Gene ExpressionTransgenesAnimalsAnimals, Genetically ModifiedBlood CoagulationChemokine CCL2Endothelial CellsE-SelectinHumansImmunosuppression TherapyInflammationNF-kappa BSignal TransductionSwineThrombomodulinTransplantation, HeterologousChemokine CCL2E-SelectinNF-kappa BTHBD protein, humanThrombomodulinTumor Necrosis Factor-alphaVascular Cell Adhesion Molecule-1InflammationPig, genetically-engineeredThrombomodulinXenotransplantation

Identifiers

PMID34099346
PMCPMC8511266
OpenAlexW3169831641

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.