A chronic rejection model and potential biomarkers for vascularized composite allotransplantation

Background Chronic rejection remains the Achilles heel in vascularized composite allotransplantation. Animal models to specifically study chronic rejection in vascularized composite allotransplantation do not exist so far. However, there are established rat models to study chronic rejection in solid organ transplantation such as allogeneic transplantation between the rat strains Lewis and Fischer344. Thus, we initiated this study to investigate the applicability of hindlimb transplantation between these strains to imitate chronic rejection in vascularized composite allotransplantation and identify potential markers. Methods Allogeneic hindlimb transplantation were performed between Lewis (recipient) and Fischer344 (donor) rats with either constant immunosuppression or a high dose immunosuppressive bolus only in case of acute skin rejections. Histology, immunohistochemistry, microarray and qPCR analysis were used to detect changes in skin and muscle at postoperative day 100. Results We were able to demonstrate significant intimal proliferation, infiltration of CD68 and CD4 positive cells, up-regulation of inflammatory cytokines and initiation of muscular fibrosis in the chronic rejection group. Microarray analysis and subsequent qPCR identified CXC ligands 9–11 as potential markers of chronic rejection. Conclusions The Fischer344 to Lewis hindlimb transplantation model may represent a new option to study chronic rejection in vascularized composite allotransplantation in an experimental setting. CXC ligands 9–11 deserve further research to investigate their role as chronic rejection markers.

• Publication year

  2020

• Venue

  PLoS ONE

• Publication date

  2020-06-26

• Fields of study

  Medicine

• Identifiers
  DOI 10.1371/journal.pone.0235266PMID 32589662PMCID 7319338
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2015influential reference
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  2010influential reference
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  2009cited by this paper
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  2007cited by this paper
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  2005cited by this paper
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  2001cited by this paper
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  1969cited by this paper
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