[show abstract][hide abstract] ABSTRACT: Because immune responses simultaneously defend and injure the host, the immune system must be finely regulated to ensure the host's survival. Here, we have shown that when injected with high Toll-like receptor ligand doses or infected with lymphocytic choriomeningitis virus (LCMV) clone 13, which has a high viral turnover, inflammatory monocyte-derived dendritic cells (Mo-DCs) engulfed apoptotic erythroid cells. In this process, called hemophagocytosis, phosphatidylserine (PS) served as an "eat-me" signal. Type I interferons were necessary for both PS exposure on erythroid cells and the expression of PS receptors in the Mo-DCs. Importantly, hemophagocytosis was required for interleukin-10 (IL-10) production from Mo-DCs. Blocking hemophagocytosis or Mo-DC-derived IL-10 significantly increased cytotoxic T cell lymphocyte activity, tissue damage, and mortality in virus-infected hosts, suggesting that hemophagocytosis moderates immune responses to ensure the host's survival in vivo. This sheds light on the physiological relevance of hemophagocytosis in severe inflammatory and infectious diseases.
[show abstract][hide abstract] ABSTRACT: Transformation to acute myeloid leukemia (AML)
frequently occurs in patients with myelodysplastic syndrome
(MDS), and genetic evolution probably plays a critical role in
this transformation. However, lateappearance of the Philadelphia (Ph)
chromosome during the course of transformed MDS is extremely
rare. We report a 77-year-old man with transformed MDS and
an acquired Ph chromosome. He was initially diagnosed with
refractory anemia with 45,XY,del(5)(q?),-7,-14,-17,+mar1,+mar2
[7/20] as the major clone. After 4 months, hematological studies
showed progression of anemia with increased number of blast cells.
Conventional chromosome analysis revealed 45,XY,del(5)(q?),-7,
t(9;22)(q34;q11.2),-14,-17,+mar1,+mar2 [20/20], a subclone with
an acquired Ph chromosome derived from a stem clone observed
at MDS diagnosis. RT-PCR results were positive for major BCRABL
transcript. Although a comparison of whole-genome sequences
between original and transformed clones would be informative,
the acquired Ph chromosome probably played a role as a “class-I
mutation,” which increasescellproliferation intransformed MDS.
[show abstract][hide abstract] ABSTRACT: We herein present a case of concurrent chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Two different clones, a Philadelphia (Ph) clone and a CLL clone with a 13q deletion, were identified using fluorescent in situ hybridization. Dasatinib was administered to inhibit Bcr-Abl and Lyn kinase. The patient exhibited a molecular response for CML and a partial response for CLL. To our knowledge, this is the first report to describe the occurrence of a gradual increase in the Bcr-Abl transcript level prior to the diagnosis of Ph-positive CML in an individual with CLL who was successfully treated with dasatinib as the first-line therapy.
Internal Medicine 01/2013; 52(22):2567-71. · 0.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Liposomal amphotericin B (L-AmB) is recommended as an empirical antifungal treatment for patients at increased risk of fungal infections although renal toxicity remains a clinical problem. We therefore conducted a pilot study to evaluate the safety and efficacy of low-dose L-AmB as an empirical antifungal therapy for patients with prolonged neutropenia. METHODS: High-risk patients with hematological malignancies were eligible to enroll in this study provided they had: exhibited neutropenia for at least 1 week; suffered from high-grade fever for 4 days despite treatment with a broad-spectrum antibacterial; and no identified fever-causing pathogen. Low-dose L-AmB (1 mg/kg) was administrated as empirical antifungal therapy. RESULTS: Sixteen patients were registered and, of these, data from the13 patients who did not receive allogeneic stem cell transplantation were analyzed. The median duration of low-dose L-AmB treatment was 8 days. Hypokalemia was seen in one patient: administration of potassium supplements for 10 days restored potassium levels to the normal range. A two-fold increase in creatinine levels was not found in any patients even those taking concomitant nephrotoxic drugs (e.g., amynoglycoside) during the study. One patient stopped receiving the drug due to an infusion-related adverse event. No patients showed breakthrough fungal infections or died during therapy or within 7 days after the end of the study. Increase in the L-AmB dose was necessary due to persistent fever in three patients who withdrew from the study. The satisfactory response rate for low-dose L-AmB was 69 %. CONCLUSION: This study suggests that low-dose L-AmB may be an effective option as empirical antifungal therapy for high-risk patients with febrile neutropenia.
International Journal of Clinical Oncology 10/2012; · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent studies have shown that anemia is commonly observed after exposure to pathogens or pathogen-derived products, which are recognized via Toll-like receptor 9 (TLR9). In the current study, we demonstrate that CpG oligodeoxynucleotide-2006, a TLR9 ligand with phosphodiester (PO; 2006-PO) but not with the phosphorothioate backbone, selectively inhibits the erythroid growth derived from human CD34(+) cells. The 2006-PO was internalized by the erythroid progenitors within 30 minutes; however, expression of TLR9 mRNA was not detected in these cells. The 2006-PO directly inhibited burst-forming unit-erythroid growth, resulted in the accumulation of cells in S and G(2)/M phases, and increased cell size and frequency of apoptotic cells. These features were similar to those observed in erythroid progenitors infected with human parvovirus B19 that causes pure red cell aplasia. The consensus sequence of 2006-PO was defined as 5'-GTTTTGT-3', which was located in the P6-promoter region of B19 and inhibited erythroid growth in a sequence-specific manner and down-regulated expression of erythropoietin receptor (EPOR) mRNA and EPOR. B19 genome extracted from serum also inhibited erythroid growth and down-regulated expression of EPOR on glycophorin A(+) cells. These results provide a possible insight into our understanding of the mechanisms of human parvovirus B19-mediated inhibition of erythropoiesis.
[show abstract][hide abstract] ABSTRACT: We have developed a method that cells exhibiting typical dendritic cell (DC) characteristics are generated from human CD34(+) cells and phagocytose cogenerating erythroid progenitor cells in the presence of tumor necrosis factor-alpha (TNF-alpha), interleukin-3, stem cell factor and erythropoietin. Using this system, we titrated the effects of TNF antagonists, etanercept and infliximab, on TNF-alpha activity. We found that 1 microg/ml etanercept dramatically inhibited the generation of CD11c(+) cells accompanying with a complete recovery of the generation of erythroid progenitors. Infliximab at 200 microg/ml exhibited a similar effect to that observed for etanercept. The delayed addition of etanercept to this culture system at day five resulted in significant inhibitory effects on the generation of CD11c(+), CD4(+) and CD86(+) cells. These results indicate that TNF antagonists administered at a concentration that is achievable in vivo, neutralize the biologic effects of TNF-alpha in generating CD11c(+) cells and that a delay in the administration of these antagonists for as long as 5 days partially inhibits the biologic activity of TNF-alpha. These findings may contribute to a great understanding of anti-TNF therapy in patients with an overproduction of cytokines such as hemophagocytic syndromes.
International journal of hematology 12/2009; 91(1):61-8. · 1.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: We describe a 69-year-old woman with bilateral adrenal hemorrhage complicated with antiphospholipid syndrome (APS). She was hospitalized with nausea and vomiting in September 2003. Laboratory data demonstrated hyponatremia, hypoglycemia and prolongation of activated partial thromboplastin time (aPTT). Abdominal computed tomography showed bilateral adrenal enlargement. In October 2003, she demonstrated altered mental status with progressive hyponatremia, a high level of ACTH, and a low level of serum cortisol. She also showed thrombocytopenia, anti-cardiolipin IgG antibody, anti-beta2GPI antibody, and lupus anticoagulants. After four months, anti-cardiolipin IgG antibody was still positive. Based on these findings, she was diagnosed as having APS complicated with adrenal insufficiency due to hemorrhagic infarction. After treatment with corticosteroid, a low dose of aspirin and normal saline infusion, her condition quickly improved. Platelet counts and aPTT were also normalized. To our knowledge, this is the second Japanese case of APS complicated with bilateral adrenal hemorrhage. APS should be considered an important underlying cause of adrenal insufficiency.
Internal Medicine 02/2006; 45(16):963-6. · 0.97 Impact Factor