Session Name: Antigen Presentation / Allorecognition / Dendritic Cells
Session Type: Poster Abstract
Date: Sunday, June 5, 2022
Session Time: 7:00pm-8:00pm
Presentation Time: 7:00pm-8:00pm
Location: Hynes Halls C & D
*Purpose: Heart transplantation is currently the only treatment for advanced stage heart failure. While patient survival after transplantation has improved acutely, the same cannot be said years later. Immune mediated pathologies such as chronic allograft vasculopathy result in graft failure and significant morbidity from prolonged use of immunosuppressant medication including renal dysfunction and malignancy, continue to be experienced by patients. Thus, improved strategies to promote survival of the cardiac allograft are necessary. Conventional dendritic cell 1 cells (cDC1s) are powerful mediators of the immune response and have been shown as critical for the promotion of central tolerance, yet their role in solid organ transplantation or peripheral tolerance remains unknown. Using a murine model of heart transplant and genetic cellular knockouts, we investigated a role for cDC1s in prolongation of cardiac allograft survival.
*Methods: Recipient C57BL/6J and cDC1 knock out (KO) mice genetically deficient in cDC1s were subjected to a tolerization regimen of allo-infusion of donor Balbc splenocytes plus anti-CD40L costimulation blockade antibody (CoB) and heterotopic heart transplantation and monitored. To elucidate molecular mechanisms by which cDC1s were required, we performed single cell RNA sequencing (scSEQ) of dendritic cell enriched splenic cells from C57BL/6J mice that had received infusions of allogenic (Balbc) splenocytes + CoB compared to isogenic (C57BL/6J) splenocytes + CoB and saline controls.
*Results: We observed decreased survival of cardiac allografts in cDC1 deficient mice alongside impaired contractile function of the allograft measured by echocardiography. Additionally, assessment of the immunological environment acutely after exposure to alloantigen and CoB revealed a decrease in splenic regulatory T cells in cDC1 KO mice. scSEQ analysis of cDC1 transcriptional programming via gene ontology (GO) of differentially expressed genes following alloantigen and CoB exposure interestingly revealed upregulation of electron transport chain signaling pathways, implicating a novel role for mitochondrial signaling in the allo-response of cDC1s.
*Conclusions: These data imply a necessary role for cDC1s in cardiac allograft survival and reveal a metabolic shift towards electron transport chain signaling following cDC1 exposure to allo-infusion and costimulation blockade. Continued interrogation of cellular reprogramming may provide alternative avenues for therapeutic targets that could prolong cardiac allograft survival and minimize patient morbidity.
To cite this abstract in AMA style:Schroth SL, Thorp EB. cDC1-Mediated Prolongation of Cardiac Allograft Survival and Alloantigen Induced Transcriptional Programming [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/cdc1-mediated-prolongation-of-cardiac-allograft-survival-and-alloantigen-induced-transcriptional-programming/. Accessed February 27, 2024.
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