Epigenetic signature of human vitamin D3 and IL-10 conditioned regulatory DCs.

During differentiation of precursor cells into their destination cell type, cell fate decisions are enforced by a broad array of epigenetic modifications, including DNA methylation, which is reflected by the transcriptome. Thus, regulatory dendritic cells (DCregs) acquire specific epigenetic programs and immunomodulatory functions during their differentiation from monocytes. To define the epigenetic signature of human DCregs generated in vitamin D3 (vitD3) and IL-10 compared to immune stimulatory DCs (sDCs), we measured levels of DNA methylation by whole genome bisulfite sequencing (WGBS).

Early identification of children with Attention-Deficit/Hyperactivity Disorder (ADHD).

Signs and symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) are present at preschool ages and often not identified for early intervention. We aimed to use machine learning to detect ADHD early among kindergarten-aged children using population-level administrative health data and a childhood developmental vulnerability surveillance tool: Early Development Instrument (EDI). The study cohort consists of 23,494 children born in Alberta, Canada, who attended kindergarten in 2016 without a diagnosis of ADHD.

FCGR2C Q and FCGR3A V alleles jointly associate with worse natural killer cell-mediated antibody-dependent cellular cytotoxicity and microvascular inflammation in kidney allograft antibody-mediated rejection.

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of humoral allograft injury. FCGR3A V/F polymorphism influences ADCC activity. Additionally, NK cell FcγRIIc expression, dictated by the Q/STP polymorphism, was never investigated in kidney transplantation.

Six-year (2016-2022) longitudinal patterns of mental health service utilization rates among children developmentally vulnerable in kindergarten and the COVID-19 pandemic disruption.

Introduction: In the context of the COVID-19 pandemic, it becomes important to comprehend service utilization patterns and evaluate disparities in mental health-related service access among children.

Objective: This study uses administrative health records to investigate the association between early developmental vulnerability and healthcare utilization among children in Alberta, Canada from 2016 to 2022.

Methods: Children who participated in the 2016 Early Development Instrument (EDI) assessment and were covered by public Alberta health insurance were included (N = 23 494).

Donor-derived regulatory dendritic cell infusion modulates effector CD8 T cell and NK cell responses after liver transplantation.

Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant.

Interleukin-21 promotes Type-1 activation and cytotoxicity of CD56CD16 natural killer cells during kidney allograft antibody-mediated rejection showing a new link between adaptive and innate humoral allo-immunity.

The role of Natural killer (NK) cells during kidney allograft antibody-mediated rejection (ABMR) is increasingly recognized, but an in-depth characterization of mechanisms that contribute to such immune response is still under investigation. Here, we characterized phenotypic, functional, and transcriptomic profiles of peripheral blood circulating and allograft infiltrating CD56CD16 NK cells during anti-HLA donor-specific antibody (DSA)+ ABMR. Cross-sectional analyses performed in 71 kidney transplant recipients identified a unique phenotypic circulating CD56CD16 NK cell cluster expanded in DSA+ ABMR.

Distinct association between chronic Epstein-Barr virus infection and T cell compartments from pediatric heart, kidney, and liver transplant recipients.

Chronic Epstein-Barr virus (EBV) infection after pediatric organ transplantation (Tx) accounts for significant morbidity and mortality. The risk of complications, such as posttransplant lymphoproliferative disorders, in high viral load (HVL) carriers is the highest in heart Tx recipients. However, the immunologic signatures of such a risk have been insufficiently defined.

The IPTA Nashville consensus conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: II-consensus guidelines for prevention.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence.

Individualized Prospective Prediction of Opioid Use Disorder.

Objective: Opioid use disorder (OUD) is a chronic relapsing disorder with a problematic pattern of opioid use, affecting nearly 27 million people worldwide. Machine learning (ML)-based prediction of OUD may lead to early detection and intervention. However, most ML prediction studies were not based on representative data sources and prospective validations, limiting their potential to predict future new cases.

Activated-memory T cells influence naïve T cell fate: a noncytotoxic function of human CD8 T cells.

T cells are endowed with the capacity to sense their environment including other T cells around them. They do so to set their numbers and activation thresholds. This form of regulation has been well-studied within a given T cell population - i.

Adaptive immune cell responses as therapeutic targets in antibody-mediated organ rejection.

Humoral alloimmunity of organ transplant recipient to donor can lead to antibody-mediated rejection (ABMR), causing thousands of organ transplants to fail each year worldwide. However, the mechanisms of adaptive immune cell responses at the basis of humoral alloimmunity have not been entirely understood. In this review, we discuss how recent investigations have uncovered the key contributions of T follicular helper (T and B cells and their coordinated actions in driving donor-specific antibody generation and immune progression towards ABMR.

Concomitant loss of regulatory T and B cells is a distinguishing immune feature of antibody-mediated rejection in kidney transplantation.

Although considerable advances have been made in understanding the cellular effector mechanisms responsible for donor-specific antibody generation leading to antibody-mediated rejection (ABMR), the identification of cellular regulators of such immune responses is lacking. To clarify this, we used high dimensional flow cytometry to concomitantly profile and track the two major subsets of regulatory lymphocytes in blood: T regulatory (T) and transitional B cells in a cohort of 96 kidney transplant recipients. Additionally, we established co-culture assays to address their respective capacity to suppress antibody responses in vitro.

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection.

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation.

T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants.

Alloimmune responses driven by donor-specific antibodies (DSAs) can lead to antibody-mediated rejection (ABMR) in organ transplantation. Yet, the cellular states underlying alloreactive B cell responses and the molecular components controlling them remain unclear. Using high-dimensional profiling of B cells in a cohort of 96 kidney transplant recipients, we identified expanded numbers of CD27+CD21- activated memory (AM) B cells that expressed the transcription factor T-bet in patients who developed DSAs and progressed to ABMR.

Targeting T Follicular Helper Cells to Control Humoral Allogeneic Immunity.

Humoral allogeneic immunity driven by anti-HLA donor-specific antibodies and antibody-mediated rejection (AMR) significantly impede prolonged survival of organ allografts after transplantation. Although the importance of T follicular helper (TFH) cells in controlling antibody responses has been long established, their role in directing donor-specific antibody generation leading to AMR was only recently appreciated in the clinical setting of organ transplantation. In this review, we provide a comprehensive summary of the current knowledge on the biology of human TFH cells as well as their circulating counterparts and describe their pivotal role in driving humoral alloimmunity.

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation.

Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation.

Background: Although antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood.

Methods: Using high-dimensional flow cytometry, assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (T) cells and B cells during ABMR in 105 kidney transplant recipients.

Results: There were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients.

Regulatory dendritic cells for human organ transplantation.

Current immunosuppressive (IS) regimens used to prevent organ allograft rejection have well-recognized side effects, that include enhanced risk of infection and certain types of cancer, metabolic disorders, cardiovascular disease, renal complications and failure to control chronic allograft rejection. The life-long dependency of patients on these IS agents reflects their inability to induce donor-specific tolerance. Extensive studies in rodent and non-human primate models have demonstrated the ability of adoptively-transferred regulatory immune cells (either regulatory myeloid cells or regulatory T cells) to promote transplant tolerance.

Impact of Induction Therapy on Circulating T Follicular Helper Cells and Subsequent Donor-Specific Antibody Formation After Kidney Transplant.

Introduction: The cellular events that contribute to generation of donor-specific anti-HLA antibodies (DSA) post-kidney transplantation (KTx) are not well understood. Characterization of such mechanisms could allow tailoring of immunosuppression to benefit sensitized patients.

Methods: We prospectively monitored circulating T follicular helper (cT) cells in KTx recipients who received T-cell depleting (thymoglobulin,  = 54) or T-cell nondepleting (basiliximab,  = 20) induction therapy from pre-KTx to 1 year post-KTx and assessed their phenotypic changes due to induction and DSA occurrence, in addition to healthy controls ( = 13), for a total of 307 blood samples.

Characterization of eomesodermin and T-bet expression by allostimulated CD8 T cells of healthy volunteers and kidney transplant patients in relation to graft outcome.

Memory T cell (Tmem) responses play a critical role in the outcome of allo-transplantation. While the role of the T-box transcription factor Eomesodermin (Eomes) in the maintenance of antigen-specific Tmem is well studied, little is known about Eomes CD8 T cell responses after transplantation. We evaluated the phenotype and function of allo-reactive Eomes CD8 T cells in healthy volunteers and kidney transplant patients and their relation to transplant outcome.

High PD-L1/CD86 MFI ratio and IL-10 secretion characterize human regulatory dendritic cells generated for clinical testing in organ transplantation.

Human regulatory dendritic cells (DCreg) were generated from CD14 immunobead-purified or elutriated monocytes in the presence of vitamin D3 and IL-10. They exhibited similar, low levels of costimulatory CD80 and CD86, but comparatively high levels of co-inhibitory programed death ligand-1 (PD-L1) and IL-10 production compared to control immature DC (iDC). Following Toll-like receptor 4 ligation, unlike control iDC, DCreg resisted phenotypic and functional maturation and further upregulated PD-L1:CD86 expression.