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Transplantation of T- and B-cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome ( n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation ( SCT). Toxicity-reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 109/l leucocytes, >20 × 109/l platelets and >0·1 × 109/l T-cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft-versus-host disease (Gv HD) grade II and III- IV occurred in 20% and 7%, chronic Gv HD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant-related mortality ( TRM) was 8% at one year and 20% at 5 years. Event-free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [ CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor. [ABSTRACT FROM AUTHOR]

Current therapeutic regimens for acute myeloid leukaemia ( AML) are still associated with high rates of relapse. Immunotherapy with T-cells genetically modified to express chimeric antigen receptors ( CARs) represents an innovative approach. Here we investigated the targeting of the interleukin three receptor alpha ( IL3 RA; CD123) molecule, which is overexpressed on AML bulk population, CD34+ leukaemia progenitors, and leukaemia stem cells ( LSC) compared to normal haematopoietic stem/progenitor cells ( HSPCs), and whose overexpression is associated with poor prognosis. Cytokine-induced killer ( CIK) cells were transduced with SFG-retroviral-vector encoding an anti- CD123 CAR. Transduced cells were able to strongly kill CD123+ cell lines, as well as primary AML blasts. Interestingly, secondary colony experiments demonstrated that anti- CD123. CAR preserved in vitro HSPC s, in contrast to a previously generated anti- CD33. CAR, while keeping an identical cytotoxicity profile towards AML. Furthermore, limited killing of normal monocytes and CD123-low-expressing endothelial cells was noted, thus indicating a low toxicity profile of the anti- CD123. CAR. Taken together, our results indicate that CD123-specific CARs strongly enhance anti- AML CIK functions, while sparing HSPCs and normal low-expressing antigen cells, paving the way to develop novel immunotherapy approaches for AML treatment. [ABSTRACT FROM AUTHOR]

Perforin is critical for cytotoxicity mediated by granules present in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Perforin-deficient mice have impaired cytotoxicity by NK cells and CTLs, resulting in failure to control infections with certain viruses or bacteria. Infection of perforin-deficient mice with lymphocytic choriomeningitis virus results in haemophagocytic lymphohistiocytosis and elevated levels of pro-inflammatory cytokines. Mutations throughout the perforin gene have been identified in patients with familial haemophagocytic lymphohistiocytosis (FHL) type 2. These patients present with fever, hepatosplenomegaly, pancytopenia, have marked elevations of T-helper type 1 and type 2 cytokines, and have impaired NK cell and CTL cytotoxicity. A number of infectious pathogens have been implicated as triggering the onset of disease. Identification of mutations in perforin as the cause of FHL should allow prenatal diagnosis of the disorder. While stem cell transplantation is curative, gene therapy might be effective in the future. [ABSTRACT FROM AUTHOR]

Focuses on the management of children with hemophagocytic lymphohistiocytosis (HLH), an autosomal recessive disease. Conditions leading to HLH; Cardinal symptoms of familial HLH; Genetic markers for HLH; Pathophysiology of HLH; Diagnostic management; Therapeutic management; Restoration of immune function; Problem of EBV-associated HLH; Immunochemotherapy for familial HLH; Bone marrow transplantation.

Focuses on eosinophilias, including the idiopathic hypereosinophilic syndrome. Disease history; Causes; Single-organ eosinophil infiltration without blood eosinophilia; Diagnosis of persistent unexplained eosinophilia.

A letter to the editor is presented that discusses the detection of WT1-specific T cells in paediatric acute lymphoblastic leukaemia patients in first remission.

Autologous transplantation of lymphocyte-depleted peripheral blood stem cells (PBSC) has been proposed for treatment of patients with severe autoimmune disease. However, several patients have been reported to achieve only transient remissions. We report on a child with thalassaemia intermedia and immune-mediated haemolytic anaemia, given an autologous lymphocyte-depleted PBSC transplant, who relapsed 7 weeks after transplant. A complete remission, lasting 18 months to date, was obtained with allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. This experience indicates that, in selected cases, allogeneic BMT may be the treatment of choice for life-threatening autoimmune disease. A graft-versus-autoimmunity effect may favour the eradication of the recipient autoaggressive lymphocytes. [ABSTRACT FROM AUTHOR]