Cardiac allograft tolerance can be achieved in nonhuman primates by donor bone marrow and kidney cotransplantation.

Long-term, immunosuppression-free allograft survival has been induced in human and nonhuman primate (NHP) kidney recipients after nonmyeloablative conditioning and donor bone marrow transplantation (DBMT), resulting in transient mixed hematopoietic chimerism. However, the same strategy has consistently failed in NHP heart transplant recipients. Here, we investigated whether long-term heart allograft survival could be achieved by cotransplanting kidneys from the same donor.

Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging.

Microglia, the brain's resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes.

Detectable plasma severe acute respiratory syndrome coronavirus 2 spike antigen is associated with poor antibody response following third messenger RNA vaccination in kidney transplant recipients.

Background: Kidney transplant recipients (KTRs) generate lower antibody responses to messenger RNA (mRNA)-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, yet precise mechanisms for this poor response remain uncertain. One potential contributor is suboptimal spike antigen (sAg) translation and expression owing to transplant immunosuppression, which might lead to insufficient exposure to develop humoral and/or cellular immune responses.

Methods: Within a single-arm clinical trial, 65 KTRs underwent ultrasensitive plasma sAg testing before, and 3 and 14 days after, the third mRNA vaccine doses.

The Promise of Complement Therapeutics in Solid Organ Transplantation.

Transplantation is the ideal therapy for end-stage organ failure, but outcomes for all transplant organs are suboptimal, underscoring the need to develop novel approaches to improve graft survival and function. The complement system, traditionally considered a component of innate immunity, is now known to broadly control inflammation and crucially contribute to induction and function of adaptive T-cell and B-cell immune responses, including those induced by alloantigens. Interest of pharmaceutical industries in complement therapeutics for nontransplant indications and the understanding that the complement system contributes to solid organ transplantation injury through multiple mechanisms raise the possibility that targeting specific complement components could improve transplant outcomes and patient health.

Imprinted immune abnormalities in liver transplant patients cured of hepatitis C with antiviral drugs.

Chronic HCV infection induces interferon and dysregulates immune responses through inflammation and chronic antigenic stimulation. Antiviral drugs can cure HCV, providing a unique opportunity to examine the immunological restoration that does and does not occur when a chronic viral infection is eradicated. We quantified blood cytokines levels and used mass cytometry to immunophenotype peripheral blood mononuclear cells before and after HCV cure in 2 groups of patients and controls.

p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation.

Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses, antigen-reactive naive and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond, whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood.

Advancing mouse models for transplantation research.

Mouse models have been instrumental in understanding mechanisms of transplant rejection and tolerance, but cross-study reproducibility and translation of experimental findings into effective clinical therapies are issues of concern. The Mouse Models in Transplantation symposium gathered scientists and physician-scientists involved in basic and clinical research in transplantation to discuss the strengths and limitations of mouse transplant models and strategies to enhance their utility. Participants recognized that increased procedure standardization, including the use of prespecified, defined endpoints, and statistical power analyses, would benefit the field.

Translating B cell immunology to the treatment of antibody-mediated allograft rejection.

Antibody-mediated rejection (AMR), including chronic AMR (cAMR), causes ~50% of kidney allograft losses each year. Despite attempts to develop well-tolerated and effective therapeutics for the management of AMR, to date, none has obtained FDA approval, thereby highlighting an urgent unmet medical need. Discoveries over the past decade from basic, translational and clinical studies of transplant recipients have provided a foundation for developing novel therapeutic approaches to preventing and treating AMR and cAMR.

T-cell receptor sequencing reveals selected donor-reactive CD8 T cell clones resist antithymocyte globulin depletion after kidney transplantation.

High frequencies of donor-reactive memory T cells in the periphery of transplant candidates prior to transplantation are linked to the development of posttransplant acute rejection episodes and reduced allograft function. Rabbit antithymocyte globulin (rATG) effectively depletes naïve CD4 and CD8 T cells for >6 months posttransplant, but rATG's effects on human donor-reactive T cells have not been carefully determined. To address this, we performed T cell receptor β-chain sequencing on peripheral blood mononuclear cells aliquots collected pretransplant and serially posttransplant in 7 kidney transplant recipients who received rATG as induction therapy.

Ultrasensitive ImmunoMag-CRISPR Lateral Flow Assay for Point-of-Care Testing of Urinary Biomarkers.

Rapid, accurate, and noninvasive detection of biomarkers in saliva, urine, or nasal fluid is essential for the identification, early diagnosis, and monitoring of cancer, organ failure, transplant rejection, vascular diseases, autoimmune disorders, and infectious diseases. We report the development of an Immuno-CRISPR-based lateral flow assay (LFA) using antibody-DNA barcode complexes with magnetic enrichment of the target urinary biomarkers CXCL9 and CXCL10 for naked eye detection (ImmunoMag-CRISPR LFA). An intermediate approach involving a magnetic bead-based Immuno-CRISPR assay (ImmunoMag-CRISPR) resulted in a limit of detection (LOD) of 0.

Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.

The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention.

Understanding the heterogeneity of alloreactive natural killer cell function in kidney transplantation.

Human Natural Killer (NK) cells are heterogeneous lymphocytes regulated by variegated arrays of germline-encoded activating and inhibitory receptors. They acquire the ability to detect polymorphic self-antigen via NKG2A/HLA-E or KIR/HLA-I ligand interactions through an education process. Correlations among HLA/KIR genes, kidney transplantation pathology and outcomes suggest that NK cells participate in allograft injury, but mechanisms linking NK HLA/KIR education to antibody-independent pathological functions remain unclear.

Letter to the editor: "hook" (prozone) effect in sars-cov-2 anti-spike binding antibody levels following vaccination, infection, or monoclonal antibody in solid organ transplant recipients.

Anti-spike binding antibody (Ab) levels are used by some providers to inform COVID-19 risk assessment for solid organ transplant recipients (SOTRs). As has been observed with other Ab assays, in the setting of high binding Ab, quantitative results may demonstrate artifactually low values (i.e.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBD; n = 42 anti-RBD), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBD remained seronegative; 5% KTRs developed BA.

Cutting Edge: Neutrophil Complement Receptor Signaling Is Required for BAFF-Dependent Humoral Responses in Mice.

T cell-independent (TI) B cell responses to nonprotein Ags involve multiple cues from the innate immune system. Neutrophils express complement receptors and activated neutrophils can release BAFF, but mechanisms effectively linking neutrophil activation to TI B cell responses are incompletely understood. Using germline and conditional knockout mice, we found that TI humoral responses involve alternative pathway complement activation and neutrophil-expressed C3a and C5a receptors (C3aR1/C5aR1) that promote BAFF-dependent B1 cell expansion and TI Ab production.

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial.

Background: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes.

Methods: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.

Blood Transcriptomes of SARS-CoV-2-Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to Severity.

Background: Among patients with COVID-19, kidney transplant recipients (KTRs) have poor outcomes compared with non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort.

Methods: We ascertained clinical data by chart review.

Effects of the complement system on antibody formation and function: implications for transplantation.

Purpose Of Review: In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate complement also modulates development of humoral immune responses. Herein we review recent data that describes how complement affects antibody formation and we discuss therapeutic implications.

Mannan-Binding Lectin Promotes Murine Graft-versus-Host Disease by Amplifying Lipopolysaccharide-Initiated Inflammation.

Conditioning regimens used for hematopoietic stem cell transplantation (HCT) can escalate the severity of acute T cell-mediated graft-versus-host disease (GVHD) by disrupting gastrointestinal integrity and initiating lipopolysaccharide (LPS)-dependent innate immune cell activation. Activation of the complement cascade has been associated with murine GVHD, and previous work has shown that alternative pathway complement activation can amplify T cell immunity. Whether and how mannan-binding lectin (MBL), a component of the complement system that binds mannose as well as oligosaccharide components of LPS and lipoteichoic acid, affects GVHD is unknown.