IL-6/IL-6R Signaling Blockade Alleviates Chronic Allograft Rejection by Modulating Germinal Center B Cells and Allograft Inflammation in Murine Cardiac Transplantation.

Introduction: The activation of B cells to produce donor-specific antibody (DSA) and the infiltration of T and macrophages in the allografts are important factors leading to chronic rejection (CR). Interleukin-6 (IL-6) is particularly important in immune responses, playing a crucial role in the activation of B, T, and macrophages. In this study, we investigate the preventive efficacy and underlying mechanism of IL-6/IL-6R signaling blockade.

Neuropilin-2 functions as a coinhibitory receptor to regulate antigen-induced inflammation and allograft rejection.

Coinhibitory receptors function as central modulators of the immune response to resolve T effector activation and/or to sustain immune homeostasis. Here, using humanized SCID mice, we found that neuropilin-2 (NRP2) is inducible on late effector and exhausted subsets of human CD4+ T cells and that it is coexpressed with established coinhibitory molecules including PD-1, CTLA4, TIGIT, LAG3, and TIM3. In murine models, we also found that NRP2 is expressed on effector memory CD4+ T cells with an exhausted phenotype and that it functions as a key coinhibitory molecule.

Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.

Introduction: Antibody-mediated rejection (ABMR) after allogeneic kidney transplantation is a substantial clinical problem for which there are no specific treatments. High endothelial venules (HEV) are specialized veins which are normally present only in lymph nodes (LN) facilitating immune cell entry. Here, we show that kidneys undergoing rejection develop HEV-like structures derived from host cells.

Follicular regulatory T cells restrain kidney allograft rejection in mice by suppressing alloreactive B cells.

Pathogenic antibodies produced by alloreactive B cells mediate antibody-mediated rejection after kidney transplantation, but the mechanisms remain poorly understood. Follicular regulatory T (Tfr) cells modulate follicular helper T cell-mediated B cell responses, but the functions of Tfr in controlling alloreactive antibody are unknown. Here we study the developmental signals and functions of Tfr cells in mouse allogeneic kidney transplantation models, and show that costimulatory blockade alters the development of Tfr cells disproportionately by decreasing germinal center (GC)-like Tfr cells but increasing follicular-like Tfr cells.

Progressively differentiated T13 cells are stabilized by JunB to mediate allergen germinal center responses.

Allergic diseases are common and affect a large proportion of the population. Interleukin-13 (IL-13)-expressing follicular helper T (T13) cells are a newly identified population of T cells that have been associated with high-affinity IgE responses. However, the origins, developmental signals, transcriptional programming and precise functions of T13 cells are unknown.

Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states.

Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies after vaccination or infection. Although the signals responsible for initiating Tfh differentiation from naïve T cells have been studied, the signals controlling sequential developmental stages culminating in optimal effector function are not well understood. Here we use fate mapping strategies for the cytokine IL-21 to uncover sequential developmental stages of Tfh differentiation including a progenitor-like stage, a fully developed effector stage and a post-effector Tfh stage that maintains transcriptional and epigenetic features without IL-21 production.

A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib-restricted CD8+ regulatory T cells.

Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression.

IL-21-producing effector Tfh cells promote B cell alloimmunity in lymph nodes and kidney allografts.

Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins, and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cells marked by previous IL-21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNA-Seq revealed that these lymph node (LN) effector Tfh cells have transcriptional and clonal overlap with IL-21-producing kidney-infiltrating Tfh cells, implicating common origins and developmental trajectories.

Single-nucleotide polymorphisms of matrix metalloproteinase genes are associated with graft fibrosis after kidney transplantation.

Background: Further research needs to be conducted on the role of genetic variables in kidney transplantation fibrosis. In this study, we used next-generation sequencing (NGS) to examine the relationship between matrix metalloproteinase (MMP) genes and single-nucleotide polymorphisms (SNPs) in renal allograft fibrosis.

Methods: This study comprised 200 patients, whose complete DNA samples were taken.

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival.

Transcriptionally Distinct B Cells Infiltrate Allografts After Kidney Transplantation.

Background: Following allogeneic kidney transplantation, a substantial proportion of graft loss is attributed to the formation of donor-specific antibodies and antibody-mediated rejection. B cells infiltrate kidney grafts during antibody-mediated rejection; however, the origins, repertoires, and functions of these intrarenal B cells remain elusive.

Methods: Here, we use murine allogeneic kidney transplant models to study the origins, transcriptional programming and B cell receptor repertoire of intragraft B cells, and in vitro stimulation assays to evaluate the ability of intragraft B cells to promote CD4+ T cell expansion.

Role of T follicular helper and T follicular regulatory cells in antibody-mediated rejection: new therapeutic targets?

Purpose Of Review: Antibody-mediated rejection (AbMR) after solid organ transplantation is tightly controlled by multiple cells of the immune system. Tfh and Tfr cells are essential controllers of antibody responses making them putative targets for therapeutics. However, the mechanisms of how Tfh and Tfr cells regulate B cell and antibody responses are not completely understood.

T cell depletion increases humoral response by favoring T follicular helper cells expansion.

Antibody-mediated rejection is a major cause of long-term graft loss in kidney transplant patients. T follicular helper (Tfh) cells are crucial for assisting B cell differentiation and are required for an efficient antibody response. Anti-thymocyte globulin (ATG) is a widely used lymphocyte-depleting induction therapy.

Everolimus Alleviates Renal Allograft Interstitial Fibrosis by Inhibiting Epithelial-to-Mesenchymal Transition Not Only Inducing Autophagy but Also Stabilizing IκB-α.

Chronic allograft dysfunction (CAD) is the major cause of late graft loss in long-term renal transplantation. In our previous study, we found that epithelial-mesenchymal transition (EMT) is a significant event in the progression of renal allograft tubulointerstitial fibrosis, and impaired autophagic flux plays a critical role in renal allograft fibrosis. Everolimus (EVR) has been reported to be widely used to prevent the progression of organ fibrosis and graft rejection.

Single Nucleotide Polymorphisms of IL-33 Gene Correlated with Renal Allograft Fibrosis in Kidney Transplant Recipients.

Background: Nowadays, renal allograft survival is confined by the development of allograft fibrosis. Previous studies have reported interleukin-33 (IL-33) upregulated significantly in patients with chronic renal allograft dysfunction, and it could induce renal tubular epithelial to mesenchymal transition (EMT), which eventually contributed to renal allograft fibrosis. Our study intended to detect the underlying association between single nucleotide polymorphisms (SNPs) of IL-33 gene and renal allograft fibrosis in kidney transplant recipients.

Efficacy and Safety of Iguratimod Supplement to the Standard Immunosuppressive Regimen in Highly Mismatched Renal Transplant Recipients: A Pilot Study.

Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China.

Combined Immunotherapy With Belatacept and BTLA Overexpression Attenuates Acute Rejection Following Kidney Transplantation.

Background: Costimulatory blockade provides new therapeutic opportunities for ensuring the long-term survival of kidney grafts. The adoption of the novel immunosuppressant Belatacept has been limited, partly due to concerns regarding higher rates and grades of acute rejection in clinical trials. In this study, we hypothesized that a combined therapy, Belatacept combined with BTLA overexpression, may effectively attenuate acute rejection after kidney transplantation.

Follicular T cells mediate donor-specific antibody and rejection after solid organ transplantation.

Following solid organ transplantation, a substantial proportion of chronic allograft loss is attributed to the formation of donor-specific antibodies (DSAs) and antibody-mediated rejection (AbMR). The frequency and phenotype of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells is altered in the setting of kidney transplantation, particularly in patients who develop AbMR. However, the roles of Tfh and Tfr cells in AbMR after solid organ transplantation is unclear.

Monitoring Strain Response of Epoxy Resin during Curing and Cooling Using an Embedded Strain Gauge.

The present work describes the monitoring system of the real-time strain response on the curing process of epoxy resin from the initial point of curing to the end, and the change in strain during temperature changes. A simple mould was designed to embed the strain gauge, thermometer, and quartz standard sample into the epoxy resin, so that the strain and the temperature were simultaneously measured and recorded. A cryogenic-grade epoxy resin was tested and the Differential Scanning Calorimetry (DSC) was used to analyse the curing process.

Highly Compressible, Thermally Conductive, yet Electrically Insulating Fluorinated Graphene Aerogel.

Carbon-based aerogels have drawn substantial attention for a wide scope of applications. However, the high intrinsic electrical conductivity limits their potential thermal management application in electronic packaging materials. Herein, a highly compressible, thermally conductive, yet electrically insulating fluorinated graphene aerogel (FGA) is developed through a hydrofluoric acid-assisted hydrothermal process.

Hypoxia-Inducible Factor-1: A Potential Target to Treat Acute Lung Injury.

Acute lung injury (ALI) is an acute hypoxic respiratory insufficiency caused by various intra- and extrapulmonary injury factors. Presently, excessive inflammation in the lung and the apoptosis of alveolar epithelial cells are considered to be the key factors in the pathogenesis of ALI. Hypoxia-inducible factor-1 (HIF-1) is an oxygen-dependent conversion activator that is closely related to the activity of reactive oxygen species (ROS).

The synergism of B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) attenuated acute T-cell mediated rejection and prolonged renal graft survival.

Background: Acute T-cell mediated rejection (TCMR) continues to be a major problem in the area of kidney transplantation. The B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) were recently found costimulatory molecules. The research aims to explore the inhibitory synergism of BTLA and CTLA-4 in TCMR.

The Double-Edged Sword of Immunosuppressive Therapy in Kidney Transplantation: A Rare Case Report of Pulmonary Mucormycosis Post-Transplant and Literature Review.

Immunosuppressive therapy is improving the graft survival of kidney transplant recipients and increasing the potential risk of infection. Pulmonary mucormycosis is a rare post-operative infection complication characterized with rapid deterioration and high mortality. In this case, a 33-year-old patient underwent a kidney transplantation with regular immunosuppressive therapy.