Potential targeting of urokinase-type plasminogen activator receptor-formyl peptide receptor signaling to prevent recurrence in posttransplant primary podocytopathies.

Primary podocytopathies are a group of disorders characterized by nephrotic syndrome and frequent progression to kidney failure, with high rates of posttransplant recurrence. Increased expression of the urokinase-type plasminogen activator receptor (uPAR) has been associated with podocyte dysfunction in primary podocytopathies. uPAR can interact with formyl peptide receptors (FPRs) in podocytes, but the relevance of this signaling pathway in these diseases remains unclear.

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.

The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation.

Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh cell formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination.

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.

Pathophysiology of rejection in kidney transplantation.

Introduction: Rejection remains a major obstacle to successful kidney transplantation. The complex pathophysiology of rejection depends on a fine-tuned interplay between the innate and adaptive immune systems.

Areas Covered: This review provides a comprehensive analysis of the pathophysiology of rejection of kidney grafts, performed through careful selection of most relevant papers available on the topic in the PubMed database.

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.

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.

Ofatumumab in Rituximab-Resistant and Rituximab-Intolerant Patients With Primary Membranous Nephropathy: A Case Series.

Rationale & Objective: Rituximab is the first-choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population.

Role of complement in humoral immunity.

Purpose Of Review: Antibody-mediated rejection (AMR) after solid organ transplantation remains an unsolved problem and leads to poor early and late patient outcomes. The complement system is a well recognized pathogenic mediator of AMR. Herein, we review the known molecular mechanisms of disease and results from ongoing clinical testing of complement inhibitors after solid organ transplant.

Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome.

Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for adults. In these patients, treatment with rituximab allows safe discontinuation of steroids, but long-term efficacy is variable, and some patients experience NS relapses after B cell reconstitution.

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study.

Objectives: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab.

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.

Immune responses to SARS-CoV-2 in dialysis and kidney transplantation.

Despite progressive improvements in the management of patients with coronavirus disease 2019 (COVID-19), individuals with end-stage kidney disease (ESKD) are still at high risk of infection-related complications. Although the risk of infection in these patients is comparable to that of the general population, their lower rate of response to vaccination is a matter of concern. When prevention strategies fail, infection is often severe.

Sexual dimorphic response to rituximab treatment: A longitudinal observational study in a large cohort of patients with primary membranous nephropathy and persistent nephrotic syndrome.

Rituximab is one of the first-line therapies for patients with membranous nephropathy (MN) at high risk of progression towards kidney failure. We investigated whether the response to Rituximab was affected by sex and anti-PLAR antibody levels in 204 consecutive patients (148 males and 56 females) with biopsy-proven MN who were referred to the Nephrology Unit of the Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII from March 2001 to October 2016 and managed conservatively for at least 6 months. The primary outcome was a combined endpoint of complete (proteinuria <0.

Autophagy in lupus nephritis: A delicate balance between regulation and disease.

Autophagy is a highly regulated process wherein an unwanted cargo of damaged and dysfunctional cytoplasmic components is removed, delivered to lysosomes for degradation, and released back into the cytoplasm. Accumulating evidence suggests an important role of autophagy in the pathophysiology of systemic lupus erythematosus, with profound effects on both innate and adaptive immunity. Autophagy downregulation results in the inhibition of antigen presenting cells, reduced release of neutrophil extracellular traps and decreased activation of effector T and B cells, leading to reduced autoantibody production and attenuated type 1 interferon signaling.

Calciphylaxis after kidney transplantation: a rare but life-threatening disorder.

Calciphylaxis is a rare disorder characterized by vascular calcification and thrombosis of the subcutaneous microcirculation, leading to painful necrotic skin lesions and bearing a dreadfully high mortality rate. This syndrome is frequently also termed uraemic calcific arteriolopathy, since most cases are observed in patients with kidney failure. However, it is increasingly clear that calciphylaxis may also affect patients with normal or only slightly impaired renal function, including kidney transplant recipients.

Chimerism-Based Tolerance to Kidney Allografts in Humans: Novel Insights and Future Perspectives.

Chronic rejection and immunosuppression-related toxicity severely affect long-term outcomes of kidney transplantation. The induction of transplantation tolerance - the lack of destructive immune responses to a transplanted organ in the absence of immunosuppression - could potentially overcome these limitations. Immune tolerance to kidney allografts from living donors has been successfully achieved in humans through clinical protocols based on chimerism induction with hematopoietic cell transplantation after non-myeloablative conditioning.