We found a lineage switch of human postmitotic neutrophils into macrophages in culture. When CD¹⁵ CD14^-cells, the majority of which are band neutrophils, were cultured with GM-CSF, TNF-α, IFN-γ, and IL-4, and subsequently with M-CSF, they obtained morphologic, cytochemical, phenotypic, genotypic, and functional features of macrophages. Postmitotic neutrophils can give rise to macrophages as well as polymorphonuclear neutrophils.GM-CSF and TGF-β1 are produced in the skin. Notch ligand Delta-1 is expressed by skin resident epidermal stem cells which are surrounded by keratinocytes. In the presence of GM-CSF, TGF-β1, and Notch ligand Delta-1, human blood CD 14⁺ monocytes differentiated into cells that had Langerhans cell markers : CDla, Langerin, cutaneous lymphocyte-associated antigen, CCR6, E-cadherin, and Birbeck granules. Blood monocytes become not only macrophages anddendritic cells but also Langerhans cells. These data suggest that human band neutrophils and monocytes, both of which are lineage-committed mature blood cells, retain the multipotentiality and are capable of generating more types of mature cells than is generally accepted.

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In recent years, with the rapid advance in the investigation of Natural Killer (NK) receptors and their ligands, it has become possible to explain unequivocally an immune phenomenon related to NK cells in hematopoietic cell transplantation. NK cells mainly possess a binary function of cellular cytotoxicity and cytokine production, and they play an important role in rejection, GVHD, and GVL in hematopoietic cell transplantation. Those immune phenomena may reduce complications and improve survival in hematopoietic cell transplantation when we understand and employ the action of a particularly inhibitory NK receptor. Thus, it is with a beneficial outcome of hematopoietic cell transplantation as functional weapon in mind that we evaluate the degree of concordance between NK receptor and HLA-C in terms of donor choice.

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Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the gene encoding the WAS protein (WASP). WASP is predominantly expressed in hematopoietic cells and regulates the reorganization of actin cytoskeleton in response to cell stimulation including T cell receptor signaling. WASP is localized at the immunological synapses between T cells and antigen-presenting cells. Regulation of WASP functions by its binding molecules, the molecular basis of immunological defects and prediction of clinical outcome in WAS patients have been revealed recently, based on recent basic and clinical research. I have reported the significance of WASP-interacting protein, WIP, as a molecular chaperone for WASP. WIP plays significant roles in the regulation of WASP functions, mechanism of recruitment of WASP to immunological synapses and stability of WASP protein. Protection of WASP by WIP from protein degradation links to the reason why most WASP missense mutations in WAS patients are accumulated in the WIP-binding site. In this article, I review these recent advances, discuss the possibility of an autosomal type of WAS and recent basic approaches to clinical gene therapy for WAS.

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Invasive fungal infections (IFI) are a significant cause of morbidity and mortality after stem cell transplantation (SCT). We analyzed effect of micafungin on prevention of IFI during neutropenia in pediatric patients undergoing stem cell transplantation. One hundred sixty-one patients were administered oral amphotericin B 100 mg/kg (AMPH group), and 36 patients were administered drip infusion of micafungin 1 mg/kg (MCFG group) for prevention of IFI. IFI was seen in 12 out of 146 patients (7.4%) in the AMPH group. However, there was no patient with an occurrence of IFI in the MCFG group. In patients with graft failure, 3 out of 9 patients were complicated with IFI and died in the AMPH group. On the other hand, no patient with graft failure was complicated with IFI, and all patients survived in the MCFG group (3 patients). Micafungin was thought to be useful for prevention of IFI in pediatric patients with stem cell transplantion.

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Recently, several studies suggest that pediatric intensive treatment can produce an excellent outcome in adolescent ALL. We evaluated safety and feasibility of pediatric chemotherapy on adolescents with ALL (B-precursor ALL 3, T-ALL 3) between sixteen and nineteen years old who entered our hospital after initial chemotherapy administered by adult hemato-oncologists in their hospital. Grade 3 and 4 adverse events were as follows : neutropenia, anemia, thrombocytopenia, and infection (including two fungal pneumoniae). Osteonecrosis occurred in two patients during maintenance therapy. Two patients in whom therapy was delayed due to fungal pneumoniae relapsed in central nervous system, but they achieved 2nd complete remission. Now all six patients are alive and disease free with a median follow-up time of three and half years. Pediatric chemotherapy regimen can be applied to adolescents without increased risk of serious adverse events except for high incidence of infection and osteonecrosis secondary to steroids. Pediatric chemotherapy regimen appears promising for adolescent ALL to produce better outocome without stem cell transplantation.

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Megaloblastic anemia is caused by deficiency of folate or cobalamin (vitamin B 12), and is a relatively rare disease in childhood. Here we report a pediatric case of megaloblastic anemia following intestinal tube feeding for 6 years. The patient was a 14-year-old boy. At 7 months of age, he was transported to our hospital in a cardiopulmonary arrest state due to idiopathic gastric rupture, and he developed severe hypoxic-ischemic encephalopathy. At 6 years of age, he was placed a stomach tube because of frequent gastroesophageal reflux. However, the symptoms did not improve. At 8 years of age, he was placed on a intestinal tube for enteral feeding, and gastric juice was drained from a stomach tube. At 14 years of age, he was admitted to our hospital because of edema of the limbs end and gingival bleeding. Laboratory examination on admission revealed pancytopenia and decreased levels of vitamin B 12. He was diagnosed with megaloblastic anemia caused by deficiency of vitamin B 12. He was treated with cyanocobalamin intramuscularly and the blood corpuscle abnormality improved immediately. The clinical course suggests that megaloblastic anemia developed due to the loss of gastric juice containing an intrinsic factor from the gastric tube.

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We report an 11-year-old girl with essential thrombocythemia in association with acquired von Willebrand disease. Platelet count at presentation was 343.6 × 10⁴/μl, and she developed subcutaneous hematoma at thesite of bone marrow aspiration. Platelet aggregation studies revealed the response to collagen, epinephrine and ristocetin to be absent, and that to ADP decreased. VWF : RCo markedly decreased and the analysis of multimetric pattern of VWF showed diminished large VWF multimer. Platelet-lowering treatment with busulfan resulted in prompt disappearance of bleeding symptoms. 10 months after the start of treatment, VWF : RCo mildly rose and an increase of largeVWF multimer was observed. But, 22 months later, though platelet count fell below 40 × 10μl, large VWF multimer decreased again and low VWF : RCo persisted.

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Transient pancytopenia associated with bone marrow aplasia rarely develops to acute lymphoblastic leukemia (ALL) 3 to 6 months later. We present a 3-year-old girl who developed ALL 10 months after the onset of aplastic anemia. The patient showed pancytopenia without hepatosplenomegaly in May 2005. The bone marrow was very hypoplastic and did not contain leukemic or dysplastic cells. We diagnosed her as having an aplastic anemia. An immunosuppressive therapy achieved a good response and was transfusion-free. In February 2006, she complained of recurrent leg pain, and in March, she had anemia and thrombocytopenia. Leukemic cells were found in 94% of bone marrow cells. She was diagnosed with B-precursor ALL. A hyperdiploid karyotype abnormality found in overt ALL was the same as that in aplastic anemia. We propose that we should carefully observe a development to ALL in aplastic anemia with an abnormal karyotype for long periods when immunosuppressive therapy was effective.

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A 15-year-old boy with acute mixed-lineage leukemia (AMLL) developed fungal appendicitis and abdominal fungal abscess during re-induction therapy. The appendectomy and the surgical drainage of the abscess improved the abscess temporarily. However, the abscess relapsed with a cecum perforation just before BMT. Reduced intensity stem cell transplantation (RIST) from an unrelated donor was carried out under the condition of the continuous drainage from the abdominal cavity. BMT was successfully done without any severe complications such as sepsis or panperitonitis by a simultaneous administration of the antifungal combination therapy. Antifungal combination therapy and RIST may enable the patients with severe fungal infection or bowel perforation to undergo BMT.

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Hemophagocytic lymophohistiocytosis (HLH) is a hyperinflammatory condition resulting from an uncontrolled ineffective immune response, where proliferation of activated T-lymphocytes and macrophages is caused by dysfunctional cytotoxic T cells. HLH occurs in association with inherited (genetic or familial) diseases or with various non-hereditary diseases, termed as primary or secondary HLH. Among primary HLH, familial hemophagocytic lymphohistiocytosis (FHL) is most common, of which subtypes (FHL2, 3, 4) can now be molecularly diagnosed. The disease develops mostly in infancy except for rare late-onset cases and is fatal if not appropriately treated. Secondary HLH may develop associated with infections, malignancies and autoimmune disorders, the outcome of which varies. In clinical practice, HLH has been recognized as distinct clinical entity over the past 20 years; however, clarification of unidentified genetic defects explaining the pathogenesis in half of FHL cases remains as a challenging problem. This report briefly summarizes the recent progress in this field and emphasizes that the disease heterogeneity needs to be considered in the diagnosis and treatment in the patients with HLH.

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A report of hemophagocytic lymphohistiocytosis (HLH) in the neonatal period is rare. I was able to find 26 neonatal HLH cases from a medical magazine web in Japan and I analyzed them. The cause of the disease was not identified in more than half of the patients. However, herpes virus or enterovirus that was regarded as infection from the mother was identified in ten patients. No fever was recorded in premature infants. Thrombocytopenia, elevated AST, LDH and hyperferritinemia were useful markers for an early diagnosis of HLH. There were few cases that measured soluble interleukin-2 receptor or urine β2-microglobuline, which, however, rose in almost all cases. About half of the infants lived, but the survival for the eight patients that satisfied diagnostic criteria of HLH-2004 was only two. Improvement of the prognosis may be obtained by early diagnosis followed by chemo-immunotherapy such as HLH-2004. As it is very likely that a serious infectious disease may develop after chemo-immunotherapy, the prevention of such an infection is necessary and we must keep an eye on it.

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Hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (HPS/HLH) is a hypercytokinemic syndrome which is characterized by fever, hepatosplenomegaly, disseminated intravascular coagulopathy and bone marrow hemophagocytosis. Half of the patients with primary HLH carry the mutation of responsible genes associated with cytotoxic granules governing the immune homeostasis, which explains the rationale for allogeneic hematopoietic stem cell transplantation (HSCT) as the sole curative treatment. On the other hand, there remain many problems concerning the appropriate time and method of HSCT since HLH infants have considerable transplantation-related mortality. Reemerging HLH and central nervous system disease during the course of HSCT are the challenge inherent in the disease. The treatment modality should be individualized for patients with atypical presentation including adult onset HLH or lymphoma. Because of the small number of refractory cases with Epstein-Barr virus associated HLH that require allogeneic HSCT, the application and method of transplantation have not been established. We herewith review the recent advances and pressing problems concerning HSCT in patients with primary HLH or EBV-HLH.

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Langerhans cell histiocytosis (LCH), a most common histiocytic disease, consists of single-system disease (affecting only one organ/system) or multi-system (with involvement of two or more organs/systems). The incidence ratio of single-system to multi-system disease is about 2 to 1. The single system disease occurs, as either single or multiple lesions, in the bones, skin, lymph nodes or lungs, but the majority (90%) is found in the bones. Currently, the multi-focal single system disease is a candidate for systemic chemotherapeutic treatment, where it isessential to increase the cure rate by reducing the high incidence of reactivation and permanent sequelae, such as diabetes insipidus (DI), central nervous system dysfunction and orthopedic disabilities. Regardless of systemic chemotherapy, the patients with multi-focal bone disease are known to inter reactivation of about 40% and DI of about 10%during the treatment. In particular, care must be taken for patients with craniofacial bone lesions, both for single and multi-focal diseases, because of the high incidence of DI and/or neurological sequelae. In this review, we overview the various issues in relation to the treatment of single-system LCH.

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Langerhans cell histiocytosis (LCH) is a rare disease and its clinical manifestations vary from single system disease to severe and sometimes life-threatening multisystem disease (MS-LCH). Multi-agent chemotherapy is indicated for patients with multisystem involvement. Results of previous studies revealed that 1) under 2 yearsof age, 2) multiorgan involvement, especially in case of a high-risk organ such as bone marrow, liver/spleen and lung, or 3) poor responder to therapy at 6 weeks, were the predictors of poor prognosis. Current salvage protocols include 2-chlorodeoxyadenosine/cytarabine and allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-nine patients with infantile LCH, who received HSCT during 1992 and 2003, and additional 10 patients who received reduced intensity hematopoietic stem cell transplantation (RIST) were reviewed in this article. Despite the mixed chimerism after RIST, long-term remission of LCH was achieved in several patients. It could be presumed that not an eradication of the pathologic cell clone, but rather a strong immunomodulating influence, probably mainly exerted by allogeneic T-cells (graft versus LCH effect), plays a role. The approach of less-toxic RIST with antibodies to the CD52, TNF-α and CD1a will be promising for the patients with progressive or refractory LCH in the near future.

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There is considerable variation in the incidence of the late effects after Langerhans cell histiocytosis (LCH), however, about half of the children with LCH (22-64%) have some late sequelae. The most common late effects are endocrinological problems including central diabetes insipidus (15-50%) and growth hormone deficiency (5-20%). Other common effects were skeletal defects in 15% (2.5-42%) of LCH, dental problems in 3-30%, hearing loss in 3-16%, and other central nervous system dysfunction including cognitive dysfunction and cerebellar involvement in 2-14%. Health-related quality of life was adversely affected in > 50% of patients with multi-system LCH. The association of LCH and malignancy has been described in many reports before today. According to the Malignancy Registry of the Histiocytosis Society, 157 LCH-malignancy cases have been registered. Organ damage from LCH causes long term morbidity extending into adolescent and adult life. Carefully planned, multidisciplinary followup is essential to ensure early recognition of problems with appropriate interventions to reduce the impact on patients' quality of life.

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