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Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model
- Source :
- The American journal of pathology, vol 192, iss 7, Am J Pathol
- Publication Year :
- 2022
- Publisher :
- eScholarship, University of California, 2022.
-
Abstract
- Cardiac allograft vasculopathy (CAV) limits the long-term success of heart transplants. Generation of donor-specific antibodies (DSAs) is associated with increased incidence of CAV clinically, but mechanisms underlying development of this pathology remain poorly understood. Major histocompatibility complex–mismatched A/J cardiac allografts in B6.CCR5(−/−) recipients have been reported to undergo acute rejection with little T-cell infiltration, but intense deposition of C4d in large vessels and capillaries of the graft accompanied by high titers of DSA. This model was modified to investigate mechanisms of antibody-mediated CAV by transplanting A/J hearts to B6.CCR5(−/−) CD8(−/−) mice that were treated with low doses of anti-CD4 monoclonal antibody to decrease T-cell–mediated graft injury and promote antibody-mediated injury. Although the mild inhibition of CD4 T cells extended allograft survival, the grafts developed CAV with intense C4d deposition and macrophage infiltration by 14 days after transplantation. Development of CAV correlated with recipient DSA titers. Transcriptomic analysis of microdissected allograft arteries identified the Notch ligand Dll4 as the most elevated transcript in CAV, associated with high versus low titers of DSA. More importantly, these analyses revealed a differential expression of transcripts in the CAV lesions compared with the matched apical tissue that lacks large arteries. In conclusion, these findings report a novel model of antibody-mediated CAV with the potential to facilitate further understanding of the molecular mechanisms promoting development of CAV.
- Subjects :
- Graft Rejection
Transplantation
Heart Diseases
Animal
Regular Article
Organ Transplantation
Inbred C57BL
Allografts
Cardiovascular
Medical and Health Sciences
Antibodies
Pathology and Forensic Medicine
Mice
Heart Disease
Tooth Apex
Disease Models
Monoclonal
Pathology
Humans
Animals
Heart Transplantation
2.1 Biological and endogenous factors
Aetiology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The American journal of pathology, vol 192, iss 7, Am J Pathol
- Accession number :
- edsair.doi.dedup.....7bb51fd8d6ccaa1e56a79c8ba7976646