title: Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target.
abstract: Cardiac allograft rejection remains a problem, despite advances with immunosuppressants. Understanding the mechanisms behind rejection is essential for developing targeted therapies. The goal of this investigation is to explore Sirtuin 1 (Sirt1) as a therapeutic target for cardiac allograft rejection. Thirteen endomyocardial biopsy specimens with acute cellular rejection (grade 2R or 3R) were selected. CD3, CD4, CD8, CD20, CD68, T-cell intracytoplasmic antigen (TIA-1), and Sirt1 expressions were determined by immunohistochemical stains. Comparison of Sirt1 expression was made with 10 cases of grade 0R and grade 1R. Quantitative image analysis was performed. There were 2 cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Sirtuin 1 expression was present in the majority of mononuclear cells (median percentage, 73.5; interquartile range, 51.2-100%); staining was also observed in cardiomyocytes. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, coinciding with acute cellular rejection. Sirtuin 1 expression in the nuclei of FoxP3+ cells can lead to deacetylation and inactivation of FoxP3 rendering the T-suppressor cells inactive and promoting acute cellular rejection. The use of a Sirt1 inhibitor may be a therapeutic option in expanding the functionality of the FoxP3+ T-suppressor cells and moderating the severity of such rejection.
authors.affiliation: From the Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Welsh
authors.forename: Bihong
authors.initials: B
authors.lastname: Zhao
authors.forename: L Maximilian
authors.initials: LM
authors.lastname: Buja
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
mesh_terms: D000208:Acute Disease; D006084:Graft Rejection / Q000209:etiology* / Q000628:therapy; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008214:Lymphocytes / Q000502:physiology*; D056564:Sirtuin 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D014184:Transplantation, Homologous
chemical_list: C447939:SIRT1 protein, human; D056564:Sirtuin 1