Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management

Successful Treatment of Acute Lymphoblastic Leukemia in a Child with Trisomy 21 and Complex Congenital Heart Disease with Mechanical Prosthetic Valve

A 10-year-old girl with trisomy 21 and complex congenital heart disease presented with acute lymphoblastic leukemia. Her chemotherapy required modifications due to poor baseline cardiac status and a mechanical prosthetic heart valve that was dependent on anticoagulation. We describe our management including the use of low-molecular-weight heparin as anticoagulation for a mechanical heart valve, the safe delivery of intrathecal chemotherapy included bridging with unfractionated heparin, and the use of fluoroscopic guidance to minimize the risk of bleeding. Adjustments were made to avoid anthracyclines. The child tolerated therapy well without complications and remains relapse free five years after diagnosis

Immunophenotypic, Cytotoxic, Proteomic and Genomic Characterization of Human Cord Blood vs. Peripheral Blood CD56Dim Nk Cells

Unrelated cord blood (CB) is an excellent alternative as an allogeneic donor source for stem cell transplantation. CB transplantation is associated with lower incidence of severe acute graft versus host disease (GVHD) and chronic GVHD but similar rates of malignant relapse compared with other unrelated donor cell transplants. NK cells are critical innate immune components and the comparison of CB vs. peripheral blood (PB) NK cells is relatively unknown. NK cell receptor expression, cell function, and maturation may play a role in the risk of relapse after CB transplant. We investigated CB vs. PB NK cell subset cytotoxicity, function, receptor expression, and genomic and proteomic signatures. The CB CD56(dim) compared with PB CD56(dim) demonstrated significantly increased expression of NKG2A and NKG2D, respectively. CB vs. PB CD56(dim) NK cells had significantly decreased in vitro cytotoxicity against a variety of non-Hodgkin lymphoma targets. Various proteins were significantly under- and over-expressed in CB vs. PB CD56(dim) NK cells. Microarray analyses and qRT-PCR in CB vs. PB CD56(dim) demonstrated significantly increased expression of genes in cell regulation and development of apoptosis, respectively. In summary, CB vs. PB CD56(dim) NK cells appear to be earlier in development, have decreased functional activity, and increased capacity for programmed cell death, suggesting that CB NK cells require functional and maturational stimulation to achieve similar functional levels as PB CD56(dim) NK cells

Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways.

BACKGROUND: Chronic active Epstein-Barr virus (CAEBV) presents with high levels of viral genomes in blood and tissue infiltration with Epstein-Barr virus (EBV)-positive lymphocytes. The pathogenesis of CAEBV is poorly understood. METHODS: We evaluated 2 patients with natural killer (NK) cell CAEBV and studied their NK cell phenotype and signaling pathways in cells. RESULTS: Both patients had increased numbers of NK cells, EBV predominantly in NK cells, and immature NK cells in the blood. Both patients had increased phosphorylation of Akt, S6, and STAT1 in NK cells, and increased total STAT1. Treatment of 1 patient with sirolimus reduced phosphorylation of S6 in T and B cells, but not in NK cells and did not reduce levels of NK cells or EBV DNA in the blood. Treatment of both patients\u27 cells with JAK inhibitors in vitro reduced phosphorylated STAT1 to normal. Patients with T- or B-cell CAEBV had increased phosphorylation of Akt and S6 in NK cells, but no increase in total STAT1. CONCLUSIONS: The increase in phosphorylated Akt, S6, and STAT1, as well as immature NK cells describe a new phenotype for NK cell CAEBV. The reduction of STAT1 phosphorylation in their NK cells with JAK inhibitors suggests a novel approach to therapy