致死性アデノウイルス感染症の病態解析に関する研究: 骨髄移植後の再活性化を中心に

金沢大学附属病院最近の造血幹細胞移植では、より強化された免疫抑制剤を用いてHLA不一致の移植を行うことも可能となってきた。その場合、移植の成功を規定する因子として免疫抑制状態下での感染症、特にウイルスの再活性化による致死的感染症が問題となる。以前は、サイトメガロウイルス(以下CMV)か、再活性化を代表する病原体であったが、抗ウイルス剤とγ-グロブリン製剤の効果的使用により発症頻度は減少した。本研究では、今後より強い免疫抑制状態下で発症頻度が増加すると予想される、アデノウイルス(ADV)、BKウイルス(BKV)、水痘帯状庖疹ウイルス(VZV)、CMV、Ebstein-Barrウイルス(EBV)の5種類のウイルス再活性化状態をリアルタイムPCRを用いて定量的にウイルス再活性化状態を評価した。造血幹細胞移植を施行された15名の患児を対象とした。患児の状態に変化がないときは、2週間毎に血清を採取した。発熱、血尿、GVHDの悪化した場合は、その都度検体を採取した。総検体数256の検討から、以下の結論が導かれた。(小児造血幹細胞移植において)1.CMVウイルス再活性化は、4/256で臨床上問題とならなかった。(いわゆる感染症)CMVに関しては、現在の予防法で十分と考えられた。2.ADV、ADVの再活性化は、対象患者15名中それぞれ1例のみであった。致死性にはいたらなかったが両ウイルス共に長期に渡り検出された。臨床的には出血性膀胱炎の様相を呈していたが、ウイルス学的にはウイルス血症であり常に、重篤化する可能性が考えられた。3.5/15名で帯状疱疹が発症した。通常帯状疱疹は、神経節に潜伏していたVZVの再活性化によるもので、支配神経領域に一致した局所疾患と考えられているが、PCR法によりウイルス血症であることが証明された。確かに免疫抑制状態下での全身VZV感染症は致死的となるので、今後この方法を用いてのウイルス量の詳細な検討により全身感染症へのリスクの層別化が可能と考えられる。研究課題/領域番号:14770350, 研究期間(年度):2002-2003出典：「致死性アデノウイルス感染症の病態解析に関する研究: 骨髄移植後の再活性化を中心に」研究成果報告書　課題番号14770350（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14770350/)を加工して作

Modeling of the inherence of feedback regulation and stem cell behavior in granulopoiesis

金沢大学医学部附属病院小児科Long-standing controversies in hematopoiesis are the mechanisms of self-maintenance and differentiation commitment of the hematopoietic stem cells (HSC), and regulation of the peripheral control of hematopoiesis. In the present study, we have applied a threedimensional cellular automaton (CA) model to granulopoiesis in order to identify the internally generative theoretical relationship between microscopic mechanisms and macroscopic behavior of hematopoietic processes. The number of mitotic event of the cells in a proliferating phase, the transit time of each of 15 differential stages from HSC to mature cells (designated as Tl to Tl 5, and Tdup for HSC duplication time), and the neighborhood rules for HSC self-renewal were incorporated in this model system as analytical parameters. Homeostatic granulopoiesis was achieved when the following inequalities for the transit times were fulfilled: Tl > Z Tn (n = 2 to 15) and Tdup > 1/2 Tl. Importantly, stabilization of the cell production was induced in a negative feedback manner following external perturbation of the peripheral granulocyte numbers. The Tdup of individual HSC was dramatically fluctuated to produce the offspring responding to this perturbation. A single cell kinetic analysis demonstrated that symmetrical or asymmetrical cell division of the HSC was recruited in a transitional manner resulting in generation of the regulatory effect on the lineage-commitment processes. The inherence of feedback regulation would be a characteristic feature of the emergent dynamical property in the hematopoietic system. The CA modeling will provide the framework to analyze the behavior of HSC and to understand abnormal kinetics of the cells such as minimal residual disease in the treatment of leukemias

Treatment of primary central nervous system lymphoma with induction of complement-dependent cytotoxicity by intraventricular administration of autologous-serum-supplemented rituximab

医薬保健研究域医学系We describe an immunocompetent 19-year-old man with CD20-positive primary central nervous system (CNS) lymphoma refractory to chemotherapy and irradiation. After intraventricular administration of rituximab, a chimeric anti-CD20 monoclonal antibody, supplemented with autologous serum, a remarkable response developed to the CNS parenchymal lymphoma. Cytotoxicity assays showed that untreated patient\u27s serum with rituximab, but not that of heat-inactivated patient\u27s serum with rituximab or rituximab alone, induced potent rituximab-mediated cytotoxicity against tumor cells in the patient\u27s cerebrospinal fluid, suggesting induction of complement-dependent cytotoxicity against CNS lymphoma. © 2006 Japanese Cancer Association

Epstein-Barr virus-associated leukemic lymphoma after allogeneic stem cell transplantation

Leukemic Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative diseases (PTLD) following allogeneic hematopoietic stem cell transplantation are extremely rare. We can successfully treat an EBV-associated leukemic lymphoma patient with rituximab, cidofovir, and donor lymphocyte infusion (DLI). In the present case, EBV-specific T cells that were present in the peripheral blood before rituximab administration treatment rapidly increased after DLI in association with a decrease in the EBV-DNA load. © 2016 Elsevier B.V.Embargo Period 12 month

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type 2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8+ T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8+ T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum pro-inflammatory cytokines in five patients with FHL2. All patients showed significantly increased subpopulations of activated CD8+ T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vβ repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8+ T cells may serve as a useful marker of dysregulated T cell activation and proliferation in FHL2. © 2013 American Society for Histocompatibility and Immunogenetics