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.

The Landscape of Digital Pathology in Transplantation: From the Beginning to the Virtual E-Slide

“…Most of the studies (9/16, 56.3%) dealt with graft rejection and quantification of parameters that aid in grading the severity of rejection or help elucidate potential pathogenetic mechanisms. Features quantified with DIA software included myocyte diameter,[45] fibrosis with Masson's trichrome stain,[4546] microvasculature density with CD31[46] or CD34,[47] patterns of inflammatory and immunological cells,[48] monocytes and macrophage profiles,[49] expression of Sirt1, CD8, and FoxP3 on lymphocytes in rejection specimens,[50] and chromatin remodeling expressed as mean gray level. [51] In some publications, digital images were converted in formats adequate for fractal analysis to quantify the inflammatory infiltrate and signs of myocyte damage; it was shown that this kind of DIA can discriminate among different grades of rejection.…”

Regulation of Adaptive Immune Cells by Sirtuins

“…While advances have been made in long-term survival following transplantation, current immunosuppressive therapies are known to promote infections and cancer. There is speculation that SIRT1 inhibitors may enhance the function of Treg cells to support immune suppression and allograft tolerance (84). Additionally, SIRT1 inhibitors may also confer prolonged allograft survival through the suppression of Th17 activity, as evidenced by decreased IL-17A (85); however, these results are in direct opposition to the SIRT1-activating and anti-tumor properties of metformin described above (44), and further studies are needed.…”

Treatment of Multiple Myeloma in a Heart Transplant Recipient

“…In the process of acute cellular rejection, naive CD4 þ T helper (Th) cells under the influence of antigen and cytokine stimulation shift to Th1 and Th17 phenotypes with a concomitant decrease in T regulatory cells. 7 Lenalidomide, an analogue of thalidomide, is an immunomodulatory agent approved for clinical use in the treatment of some myelodysplastic syndromes and multiple myeloma. Its effects on the immune system are complex, as it demonstrates select anti-inflammatory properties by reducing release of pro-inflammatory cytokines tumor necrosis factor a, interleukin (IL) 1, IL-6, and IL-12 and stimulating an increase in IL-10, IL-2, and interferon (IFN) g involved with T-cell mediated immunity.…”