International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

Objectives: This study sought to characterize HCT outcomes in APDS.

Methods: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.

WD Repeat Domain 1 (WDR1) Deficiency Presenting as a Cause of Infantile Inflammatory Bowel Disease.

Infantile and very early onset inflammatory bowel disease (VEOIBD) are a rare phenomenon wherein patients develop intestinal inflammation with typical IBD symptoms before ages 2 and 6, respectively. In recent years, there has been an increasing number of monogenetic immunological disorders identified that lead a child to develop VEOIBD. We present a case of an infant boy who presented with hematochezia and thrombocytopenia in the first week of life and developed IBD by the age of 1 month.

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft-versus-host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor-specific tolerance results in improved outcomes remains unanswered. We collected follow-up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper-matched living-donor renal transplantations from the Austrian dialysis and transplant registry.

Calcineurin and mTOR Inhibitor-Free Post-Transplantation Cyclophosphamide and Bortezomib Combination for Graft-versus-Host Disease Prevention after Peripheral Blood Allogeneic Hematopoietic Stem Cell Transplantation: A Phase I/II Study.

Graft-versus-host disease (GVHD) hampers the utility of allogeneic hematopoietic stem cell transplantation (AHSCT). The purpose of this study was to determine the feasibility, safety, and efficacy of a novel combination of post-transplantation cyclophosphamide (PTC) and bortezomib for the prevention of GVHD. Patients undergoing peripheral blood AHSCT for hematological malignancies after reduced-intensity conditioning with grafts from HLA-matched related or unrelated donors were enrolled in a phase I/II clinical trial.

Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. Although current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor, possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD.

Pulmonary Arteriovenous Malformations in Dyskeratosis Congenita.

Pulmonary arteriovenous malformations (PAVMs) are rare lesions known to cause cyanosis due to abnormal communication between the pulmonary arteries and veins. They are commonly seen in association with hereditary hemorrhagic telangiectasia, congenital heart disease, hepatopulmonary syndrome, and portopulmonary shunting, but rarely in patients with dyskeratosis congenita (DC). We describe a patient previously diagnosed with DC confirmed to have microscopic PAVMs after bone marrow transplantation and discuss possible pathogenic mechanisms.

Short Course of Post-Transplantation Cyclophosphamide and Bortezomib for Graft-versus-Host Disease Prevention after Allogeneic Peripheral Blood Stem Cell Transplantation Is Feasible and Yields Favorable Results: A Phase I Study.

An effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells.

Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease.

Cyclophosphamide's lack of hematopoietic stem cell toxicity and its unique effects on the immune system have prompted several investigators to explore its potential for the prevention of graft-versus-host disease (GVHD). In haploidentical hematopoietic stem cell transplants, post-transplant cyclophosphamide together with standard prophylaxis reduces the incidence of GVHD to acceptable rates without the need for T cell depletion. In matched related and unrelated donor settings, cyclophosphamide alone has produced encouraging results.

Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.

Importance: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births.

Risk factors associated with pediatric intensive care unit admission and mortality after pediatric stem cell transplant: possible role of renal involvement.

Background: Hematopoietic stem-cell transplant (HSCT) is associated with many risk factors for life-threatening complications. Post-transplant critical illness often requires admission to the pediatric intensive care unit (PICU).

Methods: A retrospective analysis was made on the risk factors associated with PICU admission and mortality of all HSCT patients at Helen DeVos Children's Hospital from October 1998 to November 2008.

Performance of Interleukin-6 and Interleukin-8 serum levels in pediatric oncology patients with neutropenia and fever for the assessment of low-risk.

Background: Patients with chemotherapy-related neutropenia and fever are usually hospitalized and treated on empirical intravenous broad-spectrum antibiotic regimens. Early diagnosis of sepsis in children with febrile neutropenia remains difficult due to non-specific clinical and laboratory signs of infection. We aimed to analyze whether IL-6 and IL-8 could define a group of patients at low risk of septicemia.

Pneumococcal conjugate vaccine provides early protective antibody responses in children after related and unrelated allogeneic hematopoietic stem cell transplantation.

Following allogeneic hematopoietic stem cell transplantation (alloHSCT), children are at risk of life-threatening pneumococcal infections. Whereas vaccination with polysaccharide vaccines fails to elicit protective immunity in most alloHSC transplant recipients, pneumococcal conjugate vaccines may effectively prevent invasive disease by eliciting T-cell-dependent antibody responses. Here, we report safety and immunogenicity in 53 children immunized with a regimen of 3 consecutive doses of a heptavalent pneumococcal conjugate vaccine (7vPCV) in monthly intervals starting 6 to 9 months after alloHSCT.

A severe form of human combined immunodeficiency due to mutations in DNA ligase IV.

DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and alphabeta T cells 10-fold, whereas gammadelta T cells were normal.

A variant of SCID with specific immune responses and predominance of gamma delta T cells.

We describe here a patient with a clinical and molecular diagnosis of recombinase activating gene 1-deficient (RAG1-deficient) SCID, who produced specific antibodies despite minimal B cell numbers. Memory B cells were detected and antibodies were produced not only against some vaccines and infections, but also against autoantigens. The patient had severely reduced levels of oligoclonal T cells expressing the alphabeta TCR but surprisingly normal numbers of T cells expressing the gammadelta TCR.

Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia.

Chimaerism analysis was performed by polymerase chain reaction amplification of short-tandem repeat markers in 30 children following haematopoietic stem cell transplantation for juvenile myelomonocytic leukaemia (JMML). Fourteen patients always had complete chimaerism (CC); one of them relapsed after the discontinuation of the study and 13 continued in complete remission (CR). Mixed chimaerism (MC) was noted in 16 patients.

Intact-protein-based high-resolution three-dimensional quantitative analysis system for proteome profiling of biological fluids.

The substantial complexity and vast dynamic range of protein abundance in biological fluids, notably serum and plasma, present a formidable challenge for comprehensive protein analysis. Integration of multiple technologies is required to achieve high-resolution and high-sensitivity proteomics analysis of biological fluids. We have implemented an orthogonal three-dimensional intact-protein analysis system (IPAS), coupled with protein tagging and immunodepletion of abundant proteins, to quantitatively profile the human plasma proteome.

Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively.

Blockade of CXCR3 receptor:ligand interactions reduces leukocyte recruitment to the lung and the severity of experimental idiopathic pneumonia syndrome.

Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication after allogeneic stem cell transplantation (allo-SCT) that responds poorly to standard immunosuppressive therapy. The pathophysiology of IPS involves the secretion of inflammatory cytokines including IFN-gamma and TNF-alpha along with the recruitment of donor T cells to the lung. CXCR3 is a chemokine receptor that is expressed on activated Th1/Tc1 T cell subsets and the expression of its ligands CXCL9 (monokine induced by IFN-gamma (Mig)) and CXCL10 (IFN-gamma-inducible protein 10 (IP-10)) can be induced in a variety of cell types by IFN-gamma alone or in combination with TNF-alpha.

Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease.

Alloantigen expression on host APCs is essential to initiate graft-vs-host disease (GVHD); however, critical APC subset remains to be elucidated. We compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD by an add-back study of MHC class II-expressing APCs (II(+/+)) into MHC class II-deficient (II(-/-)) mice that were resistant to CD4-dependent GVHD. Injection of host-derived, but not donor-derived, II(+/+) DCs or host-derived II(+/+) B cells, was sufficient to break GVHD resistance of II(-/-) mice and induced lethal acute GVHD.

A critical role for CCR2/MCP-1 interactions in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.

Idiopathic pneumonia syndrome (IPS) is a major complication after allogeneic bone marrow transplantation (allo-BMT) and involves the infiltration of donor leukocytes and the secretion of inflammatory cytokines. We hypothesized that leukocyte recruitment during IPS is dependent in part upon interactions between chemokine receptor 2 (CCR2) and its primary ligand monocyte chemoattractant protein-1 (MCP-1). To test this hypothesis, IPS was induced in a lethally irradiated parent --> F1 mouse BMT model.

Role of CXCR3-induced donor T-cell migration in acute GVHD.

Objective: The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8(+) T cells against minor histocompatibility antigens. METHODS; Lethally irradiated C3H.

Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation.

We have recently shown that early administration of interleukin 18 (IL-18) after bone marrow transplantation (BMT) attenuates acute graft-versus-host disease (GVHD) in a lethally irradiated parent into F1 (B6-->B6D2F1) BMT model. In this study, we investigated whether IL-18 can maintain graft-versus-leukemia (GVL) effect in this context. B6D2F1 mice received transplants of T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either syngeneic (H2(b/d)) or allogeneic B6 (H2(b)) donors.

Stem cell transplantation for paroxysmal nocturnal haemoglobinuria in childhood.

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic disorder characterized by chronic or intermittent intravascular haemolysis, variable cytopenia and an increased risk of thrombosis. Stem cell transplantation (SCT) is a curative therapeutic option, but its risks must be carefully weighed against the natural course of PNH. World-wide experience with SCT for PNH in the paediatric age group is scarce.