Correlations of lymphocyte subset infiltrates with donor-specific antibodies and acute antibody-mediated rejection in endomyocardial biopsies

Frank, Renee; Dean, Stephanie; Molina, María; Kamoun, Malek; Lal, Priti

doi:10.1016/j.carpath.2014.11.001

Cited by 11 publications

(5 citation statements)

References 25 publications

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“…Given that IFN‐γ and IL‐4 are of great importance in driving Mφ to M1 and M2 polarization and enhancing their activities, triptolide remarkably reduced mRNA expression levels of both IFN‐γ and IL‐4, implying that triptolide inhibits macrophage‐mediated responses by synergistically reducing their numbers as well as their functional enhancers. In addition, increased infiltration of CD8 + T cells in graft had also been documented to be correlated with AMR in heart grafts, with the ratio of CD4 + /CD8 + T cells significantly shifting to CD8 + T cells compared to cell‐mediated rejection, and CD4 + T cells played a key role in the AMR disease model . Accordingly, our results found in this model that the frequencies and numbers of CD8 + T cells and CD8 + IFN‐γ + cells and CD49b + NK cell numbers were significantly reduced in grafts with triptolide treatment.…”

Section: Discussionsupporting

confidence: 65%

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Zhao

Liao

et al. 2018

American Journal of Transplantation

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Donor-specific antibodies (DSAs) are major mediators of renal allograft injury, and strategies to inhibit DSAs are important in promoting long-term graft survival. Triptolide exhibits a wide spectrum of antiinflammatory and immunosuppressive activities, and in autoimmune diseases it inhibits autoantibody levels. In this study, we investigated the suppressive role of triptolide in the generation of DSAs in transplant recipients. We found that triptolide treatment of skin allograft recipients in mice significantly suppressed the development of circulating anti-donor-specific IgG and effectively alleviated DSA-mediated renal allograft injury, which led to prolonged allograft survival. In vitro studies revealed that triptolide inhibited the differentiation of B cells into CD138 CD27 plasma cells; reduced the levels of IgA, IgG, and IgM secreted by plasma cells; and repressed somatic hypermutation and class switch recombination of B cells. Moreover, triptolide-treated recipients showed reduced numbers of B cells, plasma cells, and memory B cells in spleens and decreased numbers of T, B, natural killer (NK) cells, and macrophages infiltrating grafts. These findings highlight the importance of triptolide in suppressing DSAs and establish triptolide as a novel therapeutic agent for antibody-mediated allograft rejection.

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Section: Discussionsupporting

confidence: 65%

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Zhao

Liao

et al. 2018

American Journal of Transplantation

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“…our data are limited by the small sample size and retrospective design. other studies have reported a CD4/ CD8 ratio of 1.49 in cases of acute cellular rejection in comparison with our ratio of approximately one 30 ; this may reflect the use of the objective, quantitative imaging used in our investigation or the small sample size. Nonetheless, our study highlights the potential of Sirt1 as a therapeutic target for cardiac allograft rejection and may serve as the basis for improved and less toxic immunosuppressant regimens.…”

Section: Discussioncontrasting

confidence: 75%

Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target

et al. 2016

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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.

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“…Detailed in vitro experiments must be performed to investigate the effects of MEK inhibition on B cells. Rejection after human lung transplantation is often associated with production of donor-specific antibodies (48,49), and this might be inhibited by trametinib.…”

Section: Discussionmentioning

confidence: 99%

Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Takahagi¹,

Shindo

Chen‐Yoshikawa³

et al. 2019

Am J Respir Cell Mol Biol

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Delayed immunological rejection after human lung transplantation causes chronic lung allograft dysfunction, which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells; however, its pathophysiology is not fully understood. The mitogen-activated protein kinase pathway is activated in T cells upon stimulation, and we previously showed that the MEK inhibitor, trametinib, suppresses graft-versus-host disease after murine bone marrow transplantation. We investigated whether trametinib suppresses graft rejection after two types of rat lung transplantation and analyzed its immunological mode of action. Major histocompatibility complex-mismatched transplantation from brown Norway rats into Lewis rats and minor histocompatibility antigen-mismatched transplantation from Fischer 344 rats into Lewis rats were performed. Cyclosporine (CsA) and/or trametinib were administered alone or consecutively. Acute and delayed rejection, lymphocyte infiltration, and pulmonary function were evaluated. Administration of trametinib after CsA suppressed delayed rejection, reduced inflammatory cell infiltration and fibrosis within the graft, and preserved pulmonary functions at Day 28. Trametinib suppressed functional differentiation of T and B cells in the periphery but preserved thymic T cell differentiation. Donor B cells within the graft disappeared by Day 14, indicating that delayed graft rejection at Day 28 was mainly due to indirect presentation by host antigen-presenting cells. Finally, trametinib administration without CsA preconditioning suppressed rejection after minor histocompatibility antigen-mismatched transplantation. Trametinib attenuates delayed rejection upon major histocompatibility complex-mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat chronic lung allograft dysfunction in humans.

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Correlations of lymphocyte subset infiltrates with donor-specific antibodies and acute antibody-mediated rejection in endomyocardial biopsies

Cited by 11 publications

References 25 publications

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Triptolide inhibits donor-specific antibody production and attenuates mixed antibody-mediated renal allograft injury

Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target

Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

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