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Kerry J. Welsh, L. Maximilian Buja, Robert E. Brown, Sponsor: Amitava Dasgupta, 7: Increased Sirt1 Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target, American Journal of Clinical Pathology, Volume 143, Issue suppl_1, 1 May 2015, Page A005, https://doi.org/10.1093/ajcp/143.suppl1.006
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Objectives: Heart transplantation is an important treatment for many patients with end-stage heart disease. Rejection is a significant problem despite the considerable advances that have been made with immunosuppressants. Cardiac transplant rejection may occur as acute cellular rejection, antibody-mediated rejection, and allograft vasculopathy. Understanding the molecular mechanisms behind rejection is essential for developing targeted therapies to better prevent and control rejection. The goal of this investigation is to correlate cell type and expression of certain molecular markers with the state and grade of acute cellular rejection. Methods: Thirteen archived, endomyocardial biopsy specimens with acute cellular rejection were selected. First, the CD8/FoxP3 ratio was determined by immunohistochemical (IHC) stains. TIA-1, a marker of activated T-cells, and Sirt1 expression were also determined by IHC. Expression of Sirt1, an NAD+ histone deacetylase in the nuclei of the lymphocytic infiltrate can deacetylate and render coexpressed FoxP3 relatively inactive and vulnerable to degradation via the ubiquitin proteasome 26S pathway; we hypothesize that Sirt1 positive lymphocytes will be increased in cardiac allograft rejection. Image analysis was performed with the Nuance multispectral imaging system, which allows enumeration of cellular phenotypes in defined areas of pathology. Results: There were two cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, which coincided with myocardial injury and favored acute cellular rejection. TIA-1 expression, a marker of activated T-cells, corresponded with CD8 positive cells. Sirt1 expression was present in 61.8 ± 28.2% of lymphocytes; staining was also observed in cardiac myocytes. Conclusions: Immunosuppressant therapy can be potentially selected that could expand the FoxP3+ T suppressor cell population in cases with rejection and a low FoxP3 count. For example, histone deacetylase inhibitors that inhibit Sirt1, such as vorinostat, expand FoxP3 cells and can work collaboratively with rapamycin to reduce autoimmunity and theoretically graft rejection.
