Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor.

Humoral Immune Reconstitution Kinetics after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Maturation Block of IgM Memory B Cells May Lead to Impaired Antibody Immune Reconstitution.

Although T cell immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been well studied, long-term B cell immune reconstitution remains less characterized. We evaluated humoral immune reconstitution among 71 pediatric allo-HSCT recipients. Although tetanus toxoid antibody levels were normal at 1 year after allo-HSCT, antipolysaccharide carbohydrate antibodies remained persistently low for up to 5 years.

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (GVHD) is the leading cause of late, nonrelapse mortality and disability in allogeneic hematopoietic cell transplantation recipients and a major obstacle to improving outcomes. The biology of chronic GVHD remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report.

Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, or of a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include the following: (1) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity; (2) prognostic risk to develop chronic GVHD; and (3) prediction of response to therapy.

Immunologic resolution of human chronic graft-versus-host disease.

To determine the role of regulatory T lymphocytes (Tregs) in the pathogenesis of human chronic graft-versus-host disease (GVHD) and its clinical resolution, we evaluated long-term recipients of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). Seventy-one recipients were evaluated, 30 of whom had a history of chronic GVHD, including 16 with active chronic GVHD and 14 with resolved chronic GVHD. There were no significant clinical differences and no differences in the frequency of Tregs (CD4(+), CD127(-), CD25(+)) between the recipients with active chronic GVHD and those with resolved chronic GVHD.

Primary Immune Deficiency Treatment Consortium (PIDTC) report.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects.

T lymphocyte abnormalities in juvenile systemic sclerosis patients.

Multi-center evaluations of pediatric patients with juvenile systemic sclerosis (jSSc) have suggested that the pathogenesis of jSSc may differ from that of systemic sclerosis (SSc) in adult patients. Therefore, we undertook to identify abnormalities in the T lymphocytes of jSSc patients and to determine if they differed from the abnormalities reported in the T lymphocytes of adult SSc patients. We identified decreases in the frequency of resting regulatory T lymphocytes and an increased frequency of CD45RA expressing effector memory (EMRA) CD4 T lymphocytes, which were characterized by an increased frequency of CCR7 protein expressing cells.

A 2-hit model for chronic GVHD.

In this issue of Blood, Dertschnig and colleagues1 demonstrate in mice that acute graft-versus-host disease (GHVD) results in a marked reduction of autoimmune receptor–expressing medullary thymic epithelial cells (Aire1 mTEC) and a decrease in the diversity of Aire-dependent tissue-restricted peripheral selfantigens (TRAs) required for effective negative thymic selection. Both of these abnormalities are reversed by the peritransplant administration of the epithelial protectant drug, fibroblast growth factor 7(Fgf7).

Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.

Anti-CD52 antibody-mediated immune ablation with autologous immune recovery for the treatment of refractory juvenile polymyositis.

Autologous hematopoietic stem cell transplantation (HSCT) has been used for the treatment of both adult and pediatric autoimmune diseases. However, HSCT has significant side effects (neutropenia, thrombocytopenia, infertility, cardiotoxicity) and costs (HSC collection/harvesting, blood product support). In an attempt to avoid the toxicities and costs associated with HSCT, we investigated whether immune ablation similar to that achieved following myeloablative HSCT could be achieved by the intensive administration of an anti-CD52 antibody (Campath-1H antibody).

Hematopoietic stem cell transplantation for severe combined immune deficiency or what the children have taught us.

It is now more than 40 years since the first successful allogeneic hematopoietic stem cell transplantation (HSCT) for a child with severe combined immunodeficiency (SCID). In the succeeding years, HSCT for SCID patients have represented only a small portion of the total number of allogeneic HSCT performed. Nevertheless, the clinical and biologic importance of the patients transplanted for SCID has continued.

Patients beware: commercialized stem cell treatments on the web.

A report by the International Society for Stem Cell Research (ISSCR)'s Task Force on Unproven Stem Cell Treatments outlines development of resources for patients, their families, and physicians seeking information on stem cell treatments.

Hematopoietic stem cell transplantation for severe combined immune deficiency or what the children have taught us.

It is now more than 40 years since the first successful allogeneic hematopoietic stem cell transplantation (HSCT) for a child with severe combined immunodeficiency (SCID). In the succeeding years, HSCT for SCID patients have represented only a small portion of the total number of allogeneic HSCT performed. Nevertheless, the clinical and biologic importance of the patients transplanted for SCID has continued.

Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs.

Allogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible.

Pre- and post-natal treatment of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare autosomal recessive disorder of infancy and childhood that is invariably fatal if not treated. We report on the first patient to receive post-natal HSCT for HLH after receiving in utero chemotherapy for disease stabilization.

Long-term neurocognitive function of pediatric patients with severe combined immune deficiency (SCID): pre- and post-hematopoietic stem cell transplant (HSCT).

Background: Hematopoietic stem cell transplantation (HSCT) is the only cure for patients with severe combined immunodeficiency (SCID). The purpose of this study was to evaluate long-term neurodevelopment of patients with SCID following myeloablative chemotherapy and HSCT.

Materials And Methods: Sixteen pediatric patients diagnosed with SCID were tested using the Bayley Scales of Infant Development and the validated Vineland Adaptive Behavior Scales (VABS) pre- and 1-year post-HSCT.

Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies.

Neurocognitive function of pediatric patients is of great concern after hematopoietic stem cell transplantation (HSCT). We evaluated the neurocognitive function of pediatric patients pre-HSCT, 1, 3, and 5 years post-HSCT. All patients had a hematologic malignancy and received therapy to their central nervous system.

Antigen-specific immunity following hematopoietic stem cell transplantation.

Most studies evaluating immune reconstitution following hematopoietic stem cell transplantation (HSCT) have focused on immunophenotypic analysis and the capacity of the immune system to respond to mitogenic stimulation. However, protection against infectious pathogens and potentially anti-tumor responses correlate with the presence of antigen-specific immunity, not the immunophenotypic presence of T lymphocytes. Antigen-specific T lymphocytes present after HSCT can be derived from donor antigen-specific T lymphocytes present in the transplantation inoculum if it is not T cell depleted.

The effects of Campath 1H upon graft-versus-host disease, infection, relapse, and immune reconstitution in recipients of pediatric unrelated transplants.

Graft-versus-host disease (GVHD) is a cause of serious morbidity and mortality in >50% of recipients of unrelated hematopoietic stem cell transplantation (HSCT). We performed a trial using Campath 1 H pre- and post-HSCT in an attempt to decrease the incidence of GVHD without increasing the risk of infection or relapse. Patients were retrospectively compared to a population of patients who received antithymocyte globulin (ATG) pre- and post-HSCT.

Antigen-specific T-lymphocyte function after cord blood transplantation.

It has not been possible to determine the singular contribution of naive T lymphocytes to antigen-specific immunity after hematopoietic stem cell transplantation (HSCT), because of the confounding effects of donor-derived antigen-specific T lymphocytes present in most hematopoietic stem cell (HSC) products. Because umbilical cord blood contains only naive T lymphocytes, we longitudinally evaluated the recipients of unrelated cord blood transplantation (UCBT) for the presence of T lymphocytes with specificity for herpesviruses, to determine the contribution of the naive T lymphocytes to antigen-specific immune reconstitution after HSCT. Antigen-specific T lymphocytes were detected early after UCBT (herpes simplex virus on day 29; cytomegalovirus on day 44; varicella zoster virus on day 94).

Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.

A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40.

Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is established therapy for selected patients with acute leukemia. After transplantation, antileukemic immune responses are believed to eliminate residual leukemia cells and decrease the likelihood of relapse. However, the clinical effect of successful antigen-specific immune reconstitution after HSCT on the likelihood of leukemic relapse and overall survival is not known.

Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B.

Histocompatible hematopoietic stem cell transplantation (HSCT) was conducted on a 4.5-year-old girl with Niemann-Pick disease type B. The donor was her unaffected brother.