Targeted depletion of PD-1-expressing cells induces immune tolerance through peripheral clonal deletion.

Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter.

Outcomes of Heart Transplantation From Donation After Circulatory Death: An Up-to-date Systematic Meta-analysis.

Background: Donation after circulatory death (DCD) heart transplantation (HTx) significantly expands the donor pool and reduces waitlist mortality. However, high-level evidence-based data on its safety and effectiveness are lacking. This meta-analysis aimed to compare the outcomes between DCD and donation after brain death (DBD) HTxs.

MEK1/2-PKM2 Pathway Modulates the Immunometabolic Reprogramming of Proinflammatory Allograft-infiltrating Macrophages During Heart Transplant Rejection.

Background: Emerging evidence has highlighted the role of macrophages in heart transplant rejection (HTR). However, the molecular signals modulating the immunometabolic phenotype of allograft-infiltrating macrophages (AIMs) during HTR remain unknown.

Methods: We analyzed single-cell RNA sequencing data from cardiac graft-infiltrating immunocytes to characterize the activation patterns and metabolic features of AIMs.

The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8 T-cell immunity.

Immune checkpoint blockade (ICB), including anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4), benefits only a limited number of patients with cancer. Understanding the in-depth regulatory mechanism of CTLA-4 protein stability and its functional significance may help identify ICB resistance mechanisms and assist in the development of novel immunotherapeutic modalities to improve ICB efficacy. Here, we identified that TNF receptor-associated factor 6 (TRAF6) mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of CTLA-4.

MTHFD2 ablation in T cells protects against heart transplant rejection by perturbing IRF4/PD-1 pathway through the metabolic-epigenetic nexus.

Background: One-carbon metabolism supports the activation, proliferation, and function of multiple immune cells. However, researchers have not clearly determined whether and how one-carbon metabolic enzymes contribute to heart transplant rejection.

Methods: We investigated the dynamic metabolic adaptation in grafts during heart transplant rejection by conducting transcriptomics, metabolomics and single-cell RNA sequencing studies of cardiac tissue from human and mouse heart transplant recipients.

Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection.

Background: PCSK9 (proprotein convertase subtilisin/kexin 9), which is mainly secreted by the liver, is not only a therapeutic target for hyperlipidemia and cardiovascular disease, but also has been implicated in the immune regulation of infections and tumors. However, the role of PCSK9 and the liver in heart transplant rejection (HTR) and the underlying mechanisms remain unclear.

Methods: We assessed serum PCSK9 expression in both murine and human recipients during HTR and investigated the effect of PCSK9 ablation on HTR by using global knockout mice and a neutralizing antibody.

Single-Cell RNA sequencing reveals immune cell dynamics and local intercellular communication in acute murine cardiac allograft rejection.

Transplant rejection is a major impediment to long-term allograft survival, in which the actions of immune cells are of fundamental importance. However, the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection are not completely clear. Here we performed single-cell RNA sequencing on CD45 immune cells isolated from cardiac grafts and spleens in a model of murine heterotopic heart transplantation.

Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells.

Background: Graft vascular disease (GVD), which limits the long-term survival of patients after solid-organ transplantation, is associated with both immune responses and nonimmune factors, including dyslipidemia. Recent studies have shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a U.S.

Erratum: Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation: Erratum.

[This corrects the article DOI: 10.7150/thno.43507.

Aspirin Attenuates Cardiac Allograft Rejection by Inhibiting the Maturation of Dendritic Cells the NF-κB Signaling Pathway.

Dendritic cells (DCs) serve as an important part of the immune system and play a dual role in immune response. Mature DCs can initiate immune response, while immature or semi-mature DCs induce immune hyporesponsiveness or tolerance. Previous studies have shown that aspirin can effectively inhibit the maturation of DCs.

Ablation of Survivin in T Cells Attenuates Acute Allograft Rejection after Murine Heterotopic Heart Transplantation by Inducing Apoptosis.

Although studies in oncology have well explored the pharmacological effects of , little is known about its role in allogeneic T-cell responses. Therefore, the present study used a mouse model of acute heart allograft rejection to investigate the protective effect and mechanism of conditional knockout of in T cells. Survivin (encoded by ) was up-regulated in T cells activated and .

IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation.

Regulatory T cells play a crucial role in orchestrating immune response and maintaining immune tolerance, and the expression of the Foxp3 gene is indispensable to the differentiation of regulatory T cells. IL-4 shows strong inhibitory effects on Foxp3 expression and regulatory T cells differentiation, but the detailed mechanisms are still unclear. Here, we revealed that epigenetic modulations are key to this process.

Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation.

: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown. : The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM).

PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation.

Chronic allograft dysfunction (CAD) resulting from fibrosis is the major limiting factor for long-term survival of lung transplant patients. Myofibroblasts promote fibrosis in multiple organs, including the lungs. In this study, we identified PLK1 as a promoter of myofibroblast differentiation and investigated the mechanism by which its inhibition alleviates transplant-associated obliterative bronchiolitis (OB) during CAD.

PKM2 Activator TEPP-46 Attenuates Thoracic Aortic Aneurysm and Dissection by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion.

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far.

Glibenclamide ameliorates transplant-induced arteriosclerosis and inhibits macrophage migration and MCP-1 expression.

Aims: Glibenclamide, a diabetes mellitus type 2 medication, has anti-inflammatory and autoimmune properties. This study investigated the effects of glibenclamide on transplant-induced arteriosclerosis as well as the underlying molecular events.

Methods: Male C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation.

Network-based analysis reveals novel gene signatures in the peripheral blood of patients with sporadic nonsyndromic thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA.