Allostimulation leads to emergence of a human B cell population with increased expression of HLA class I antigen presentation-associated molecules and the immunoglobulin receptor FcRL5.

In the extensive literature characterizing lymphocyte contributions to transplant-related pathologies including allograft rejection and graft-versus-host disease, T cell-focused investigation has outpaced investigation of B cells. Most B cell-related reports describe regulatory and antibody-producing functions, with less focus on the potential role of antigen-presenting capacity. Using in vitro human mixed lymphocyte reactions (MLRs) to model allostimulation, we analyzed responder B cells using transcriptional analysis, flow cytometry, and microscopy.

Donor antigen-specific regulatory T cell administration to recipients of live donor kidneys: A ONE Study consortium pilot trial.

Regulatory T cells (Tregs) can inhibit cellular immunity in diverse experimental models and have entered early phase clinical trials in autoimmunity and transplantation to assess safety and efficacy. As part of the ONE Study consortium, we conducted a phase I-II clinical trial in which purified donor antigen reactive (dar)-Tregs (CD4CD25CD127) were administered to 3 patients, 7 to 11 days after live donor renal transplant. Recipients received a modified immunosuppression regimen, without induction therapy, consisting of maintenance tacrolimus, mycophenolate mofetil, and steroids.

Expanded HCT-CI Definitions Capture Comorbidity Better for Younger Patients of Allogeneic HCT for Nonmalignant Diseases.

Allogeneic hematopoietic cell transplantation (HCT) can cure many nonmalignant conditions, but concern for morbidity and mortality remains. To help physicians estimate patient-specific transplant mortality risk, the HCT comorbidity index (HCT-CI) is used. However, pediatric physicians use the HCT-CI less frequently than adult counterparts.

Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade.

The potential of adoptive cell therapy with regulatory T cells (Tregs) to promote transplant tolerance is under active exploration. However, the impact of specific transplant settings and protocols on Treg manufacturing is not well-delineated. Here, we compared the use of peripheral blood mononuclear cells (PBMCs) from patients before or after liver transplantation to the use of healthy control PBMCs to determine their suitability for Treg manufacture using ex vivo costimulatory blockade with belatacept.

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.

Background: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.

Methods: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up).

Use of Crowd Innovation to Develop an Artificial Intelligence-Based Solution for Radiation Therapy Targeting.

Importance: Radiation therapy (RT) is a critical cancer treatment, but the existing radiation oncologist work force does not meet growing global demand. One key physician task in RT planning involves tumor segmentation for targeting, which requires substantial training and is subject to significant interobserver variation.

Objective: To determine whether crowd innovation could be used to rapidly produce artificial intelligence (AI) solutions that replicate the accuracy of an expert radiation oncologist in segmenting lung tumors for RT targeting.

Alloanergization Method for Inducing Allospecific Hyporesponsiveness in PBMC Exposed to Allostimulation In Vitro in the Context of Costimulatory Molecule Blockade.

Alloantigen-specific hyporesponsiveness can be induced in alloreactive T cells contained within the whole peripheral blood mononuclear cell (PBMC) population by stimulating these responder cells ex vivo with HLA-mismatched stimulator PBMC as the antigen presenting cell (APC) source, in the presence of a CD28 costimulation blocking agent. As a result of this approach, specific alloreactivity is markedly decreased (by 1-2 logs), but third-party alloresponses and in vitro responses relying on the activation of pathogen- and tumor-associated antigen T-cell functional activities are not globally impinged upon (Guinan et al. N Engl J Med 340(22):1704-1714, 1999, Davies et al.

Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model.

Background: Fanconi anemia is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Currently, no interventions to prevent or delay the formation of solid tumors are available.

Procedure: Two of the most important hallmarks of Fanconi anemia are inflammation and oxidative stress.

The Open Translational Science in Schizophrenia (OPTICS) project: an open-science project bringing together Janssen clinical trial and NIMH data.

Clinical trial data are the gold standard for evaluating pharmaceutical safety and efficacy. There is an ethical and scientific imperative for transparency and data sharing to confirm published results and generate new knowledge. The Open Translational Science in Schizophrenia (OPTICS) Project was an open-science initiative aggregating Janssen clinical trial and NIH/NIMH data from real-world studies and trials in schizophrenia.

Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.

rBPI (Opebacan) Promotes Rapid Trilineage Hematopoietic Recovery in a Murine Model of High-Dose Total Body Irradiation.

The complexity of providing adequate care after radiation exposure has drawn increasing attention. While most therapeutic development has focused on improving survival at lethal radiation doses, acute hematopoietic syndrome (AHS) occurs at substantially lower exposures. Thus, it is likely that a large proportion of such a radiation-exposed population will manifest AHS of variable degree and that the medical and socioeconomic costs of AHS will accrue.

Three sides to a story: Child, parent, and nurse perspectives on the child's experience during hematopoietic stem cell transplantation.

Background: The experience of children undergoing hematopoietic stem cell transplantation (HSCT), including the ways in which different participants (ie, children, parents, and nurses) contribute to the overall picture of a child's experience, is poorly characterized. This study evaluated parent, child, and nurse perspectives on the experience of children during HSCT and factors contributing to interrater differences.

Methods: Participants were enrolled in a multicenter, prospective study evaluating child and parent health-related quality of life over the year after HSCT.

Looking Across and Looking Beyond the Knowledge Frontier: Intellectual Distance, Novelty, and Resource Allocation in Science.

Selecting among alternative projects is a core management task in all innovating organizations. In this paper, we focus on the evaluation of frontier scientific research projects. We argue that the "intellectual distance" between the knowledge embodied in research proposals and an evaluator's own expertise systematically relates to the evaluations given.

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies.

Parent Outlook: How Parents View the Road Ahead as They Embark on Hematopoietic Stem Cell Transplantation for Their Child.

Pediatric hematopoietic stem cell transplantation (HSCT) offers cure for high-risk malignancies and other conditions, but carries a risk of complications. Parental outlook regarding their child's transplantation course and future health has been largely unexplored. This report presents the Parent Outlook Scale, describes its properties, and examines the outlook of parents embarking on their child's transplantation course and the associated variables.

The impact of pediatric blood and marrow transplant on parents: introduction of the parent impact scale.

Background: Parents often experience stress-related complications when their child requires blood and marrow transplant (BMT). Previous studies have described the emotional toll BMT places on parents during the acute phase of care and within the context of clinical complications. In this paper we introduce the Parent Impact Scale (PARimpact), designed to capture physical and emotional challenges of the child's health on the parent.

Bone loss and vitamin D deficiency in children undergoing hematopoietic cell transplantation.

Background: Hematopoietic cell transplantation (HCT) may be detrimental to bone health and vitamin D status in children.

Procedure: We conducted a prospective, multicenter cohort study to identify changes in bone health markers during the first 100 days after allogeneic HCT in 26 children. Bone mineral density (BMD), bone mineral content (BMC), and serum 25-hydroxyvitamin D (25OHD) concentrations were measured at baseline, 30 days, and 100 days after HCT.

Changing factors associated with parent activation after pediatric hematopoietic stem cell transplant.

Purpose: To identify factors associated with parent activation in parents of children undergoing pediatric hematopoietic stem cell transplant (HSCT) in the 6 months following HSCT, and to address if their association with parent activation changes over time.

Methods: Measures for this analysis, including the Parent-Patient Activation Measure (Parent-PAM), were completed by parents (N = 198) prior to their child's HSCT preparative regimen and again at 6 months post-HSCT. Clinical data were also collected.

Aplastic anemia in adolescents and young adults.

Adolescent and young adult patient presentations of aplastic anemia require a particular perspective on both diagnosis and treatment. This unique age group necessitates a thorough diagnostic evaluation to ensure the etiology, acquired or inherited, is sufficiently determined. The treatment options include human leukocyte antigen-identical sibling hematopoietic cell transplantation or immunosuppressive therapy, and both require attention to the specific medical and social needs of these adolescents and young adults.

Serum citrulline as a biomarker of gastrointestinal function during hematopoietic cell transplantation in children.

Objectives: We sought to determine whether serum citrulline (CIT), an amino acid produced by small bowel enterocytes, was associated with clinical and biochemical markers of gastrointestinal function in children undergoing hematopoietic cell transplantation (HCT).

Methods: We conducted a multicenter, prospective cohort study of 26 children to define time-related changes in serum CIT during the course of HCT. Markers of gastrointestinal function including oral energy intake, emesis, stool volume, presence of graft-versus-host disease (GVHD), oral mucositis severity, and cytokine and neurohormone levels were measured.

Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin.

Hematopoietic cell transplant (HCT) is a life-saving therapy for many malignant and non-malignant bone marrow diseases. Associated morbidities are often due to transplant-related toxicities and infections, exacerbated by regimen-induced immune suppression and systemic incursion of bacterial products. Patients undergoing myeloablative conditioning for HCT become endotoxemic and display blood/plasma changes consistent with lipopolysaccharide (LPS)-induced systemic innate immune activation.

Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia.

Purpose: Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed.

Patients And Methods: We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007.