In utero human cytomegalovirus infection expands NK-like FcγRIII+CD8+ T cells that mediate Fc antibody functions.

Human cytomegalovirus (HCMV) profoundly impacts host T and NK cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III-expressing (FcγRIII-expressing) CD8+ T cells following HCMV exposure in utero. Most FcγRIII+CD8+ T cells express the canonical αβ T cell receptor (TCR), but a proportion express noncanonical γδ TCR.

Mitigation of supply chain challenges in cell therapy manufacturing: perspectives from the cord blood alliance.

Cellular therapies rely on highly specialized supply chains that often depend on single source providers. Public cord blood banks (CBB) manufacturing the first cell therapy to be highly regulated by the FDA and related international agencies are a prime example of being subject to this phenomenon. In addition to banking unrelated donor cord blood units for transplantation, CBBs also source and characterize starting materials for supply to allogeneic cell therapy developers that often employ customized technologies offered by just a small number of manufacturers.

Impact of FDA's HCT/P ZIKV Recommendations on Cord Blood Unit Eligibility and Utilization in a Large Public Cord Blood Bank.

Background: Cord blood units (CBUs) that are ineligible for licensure due to incomplete compliance with FDA recommendations may be used for hematopoietic stem cell transplantation under urgent medical need and an Investigational Drug Application. The largest reason for CBU donor ineligibility is Zika virus (ZIKV) risk. The study's objective was to analyze the impact of current FDA recommendations for ZIKA risk on a large public cord blood bank and propose updated recommendations.

Newborn Screening for Krabbe Disease: Status Quo and Recommendations for Improvements.

Krabbe disease (KD) is part of newborn screening (NBS) in 11 states with at least one additional state preparing to screen. In July 2021, KD was re-nominated for addition to the federal Recommended Uniform Screening Panel (RUSP) in the USA with a two-tiered strategy based on psychosine (PSY) as the determinant if an NBS result is positive or negative after a first-tier test revealed decreased galactocerebrosidase activity. Nine states currently screening for KD include PSY analysis in their screening strategy.

Mural cells interact with macrophages in the dura mater to regulate CNS immune surveillance.

The central nervous system (CNS) tightly regulates access of circulating immune cells. Immunosurveillance is therefore managed in the meninges at the borders of the CNS. Here, we demonstrated that mural cells, which include pericytes and smooth muscle cells, decreased coverage around blood vessels in the dura, the outermost layer of the meninges, and upregulated gene pathways involved in leukocyte migration in presymptomatic experimental autoimmune encephalomyelitis (EAE).

A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.

Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center.

Mesenchymal stromal cells suppress microglial activation and tumor necrosis factor production.

Background Aims: White matter diseases are commonly associated with microglial activation and neuroinflammation. Mesenchymal stromal cells (MSCs) have immunomodulatory properties and thus have the potential to be developed as cell therapy for white matter disease. MSCs interact with resident macrophages to alter the trajectory of inflammation; however, the impact MSCs have on central nervous system macrophages and the effect this has on the progression of white matter disease are unclear.

Improving thymus implantation for congenital athymia with interleukin-7.

Objectives: Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.

Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial.

Various types of cellular injection have become a popular and costly treatment option for patients with knee osteoarthritis despite a paucity of literature establishing relative efficacy to each other or corticosteroid injections. Here we aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI). The study was a phase 2/3, four-arm parallel, multicenter, single-blind, randomized, controlled clinical trial with 480 patients with a diagnosis of knee osteoarthritis (Kellgren-Lawrence II-IV).

In utero human cytomegalovirus infection expands NK cell-like FcγRIII-expressing CD8+ T cells that mediate antibody-dependent functions.

Human cytomegalovirus (HCMV) profoundly modulates host T and natural killer (NK) cells across the lifespan, expanding unique effector cells bridging innate and adaptive immunity. Though HCMV is the most common congenital infection worldwide, how this ubiquitous herpesvirus impacts developing fetal T and NK cells remains unclear. Using computational flow cytometry and transcriptome profiling of cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify major shifts in fetal cellular immunity marked by an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells (FcRT) following HCMV exposure in utero.

A Pilot Phase I Trial of Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells in Neonates With Hypoxic-Ischemic Encephalopathy.

Hypoxic ischemic encephalopathy (HIE) in neonates causes increased mortality and long-term morbidity in surviving babies. Hypothermia (HT) has improved outcomes, however, mortality remains high with ~half of surviving babies developing neurological impairment in their first years. We previously explored the use of autologous cord blood (CB) to determine if CB cells could lessen long-term damage to the brain.

The potential cost-effectiveness of novel cord blood therapies in children with autism spectrum disorder.

Objective: To model the long-term clinical and economic outcomes of potential cord blood therapy in autism spectrum disorder (ASD).

Study Design: Markov microsimulation of ASD over the lifespan was used to compare two strategies: 1) standard of care (SOC), including behavioral and educational interventions, and 2) novel cord blood (CB) intervention in addition to SOC. Input data reflecting behavioral outcomes included baseline Vineland Adaptive Behavior Scale (VABS-3), monthly VABS-3 changes, and CB intervention efficacy on adaptive behavior based on a randomized, placebo-controlled trial (DukeACT).

Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome.

Background: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking.

Materials And Methods: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells).

Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials.

Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide.

Unrelated Donor Cord Blood Transplantation in Children: Lessons Learned Over 3 Decades.

Four decades ago, Broxmeyer et al. demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al.

Changes in the geometry and robustness of diffusion tensor imaging networks: Secondary analysis from a randomized controlled trial of young autistic children receiving an umbilical cord blood infusion.

Diffusion tensor imaging (DTI) has been used as an outcome measure in clinical trials for several psychiatric disorders but has rarely been explored in autism clinical trials. This is despite a large body of research suggesting altered white matter structure in autistic individuals. The current study is a secondary analysis of changes in white matter connectivity from a double-blind placebo-control trial of a single intravenous cord blood infusion in 2-7-year-old autistic children (1).

Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: An open-label, randomized trial.

Aim: To evaluate safety and motor function after treatment with allogeneic umbilical cord blood (AlloCB) or umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in children with cerebral palsy (CP).

Method: Ninety-one children (52 males, 39 females; median age 3 years 7 months [range 2-5 years]) with CP due to hypoxic-ischemic encephalopathy, stroke, or periventricular leukomalacia were randomized to three arms: (1) the AlloCB group received 10 × 10 AlloCB total nucleated cells (TNC) per kilogram at baseline (n = 31); (2) the hCT-MSC group received 2 × 10 hCT-MSC at baseline, 3 months, and 6 months (n = 28); (3) the natural history control group received 10 × 10 AlloCB TNC per kilogram at 12 months (n = 31). Motor function was assessed with the Gross Motor Function Measure-66 (GMFM-66) and Peabody Developmental Motor Scale, Second Edition.

Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and antiviral functions in paired maternal and cord blood sera from HCMV-seropositive transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads identified via a large, US-based, public cord blood bank.