Fumimaro Takaku

EFFECT OF MATCHING OF CLASS I HLA ALLELES ON CLINICAL OUTCOME AFTER TRANSPLANTATION OF HEMATOPOIETIC STEM CELLS FROM AN UNRELATED DONOR

BACKGROUND The requirements with respect to HLA compatibility and the relative importance of matching for individual class I and class II HLA alleles in the transplantation of hematopoietic stem cells from unrelated donors have not yet been established. METHODS We performed retrospective DNA typing of alleles at 11 polymorphic loci of HLA genes in 440 recipients of hematopoietic stem cells from unrelated donors who were serologically identical with their respective recipients for HLA-A, B, and DR antigens. Of these recipients, 80 percent had leukemia; the rest had lymphoma, marrow failure, or a congenital disorder. RESULTS Multivariate analysis showed that incompatibility for HLA-A alleles and incompatibility for HLA-C alleles were independent risk factors for severe acute graft-versus-host disease (GVHD) (HLA-A, P=0.006; HLA-C, P=0.001). Mismatching of HLA-A, but not of HLA-C, alleles was an independent risk factor for death (P<0.001). Matching [corrected] of HLA-C alleles was a significant risk factor for relapse of leukemia (P=0.035). HLA-B disparity was a significant risk factor for both GVHD and death in the univariate analysis, but not in multivariate analysis. Disparities in class II HLA alleles of the DRB1, DQA1, DQB1, DPA1, and DPB1 loci were not identified as significant risk factors for acute GVHD or death in the multivariate analysis. CONCLUSIONS Genomic typing of class I HLA alleles adds substantially to the success of transplantation of hematopoietic stem cells from unrelated donors, even if the donors are serologically identical to their recipients with respect to HLA-A, B, and DR antigens.

A case of lung cancer associated with granulocytosis and production of colony-stimulating activity by the tumour.

A case of lung cancer associated with granulocytosis and production of colony-stimulating activity by the tumour

Influence of leukaemic cells on the colony formation of human bone marrow cells in vitro

IN ACUTE leukaemia, mature granulocytes are usually reduced in peripheral blood and bone marrow. In such cases it could be considered that normal haemopoietic stem cells are merely replaced by leukaemic cells in haemopoietic organs or that normal haemopoietic stem cells are suppressed by leukaemic cells through such mechanisms as cell-to-cell interaction, humoral factors produced by leukaemic cells and so on. Therefore, we wished to check the effects of leukaemic cells on non-leukaemic bone marrow cells when the two were cultured by the soft agar culture technique. Suppressive effects of leukaemic cells on non-leukaemic marrow cell colony formation were clearly observed.

Influence of leukaemic cells on the colony formation of human bone marrow cells in vitro II. Suppressive effects of leukaemic cell extracts

The influence of leukaemic cells on the colony formation of human bone marrow cells was studied in vitro as an extension of our previous work (Chiyoda et al., 1975). An extract of leukaemic bone marrow cells significantly suppressed colony forming ability of the normal bone marrow cells, whereas an extract of normal bone marrow cells did not suppress it except in two cases. The suppressive effect of normal bone marrow cells, however, was obviously less intense than that of leukaemic cells. This suppressive effect was dose dependent and was fairly stable to heat treatment. These results suggest that leukaemic bone marrow cells contain factor(s) which suppress normal colony formation.

Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes.

Abstract A study to evaluate WT1 mRNA expression levels in peripheral blood (PB) and bone marrow aspirate (BM) was conducted in 172 patients, including 115 with myelodysplastic syndromes (MDS), in Japan. The level of WT1 mRNA expression was evaluated according to the French–American–British (FAB) and World Health Organization (WHO) classifications (2001, 2008) and using the International Prognostic Scoring System and the WHO Prognostic Scoring System scales. WT1 mRNA expression levels in PB and BM were well correlated (r = 0.85), and they tended to increase with disease stage progression and in those at higher risk of leukemic transformation. WT1 mRNA expression can be a useful marker for the diagnosis and risk evaluation of MDS.

Differences in blast immunophenotypes among disease types in myelodysplastic syndromes: A multicenter validation study

We conducted a multicenter, flow cytometry study to validate differences in immunophenotypes among disease types in melodysplastic syndromes (MDS). The data obtained from 115 patients were combined into three groups according to disease grade, i.e., low-grade MDS, refractory anemia with excess blasts, and acute leukemia transformed from MDS (AL-MDS). The data comparison showed that with the progression of disease grade, the immunophenotypes of CD34(+) myeloblasts were more immature, with an increase and a decrease in CD7 and CD15 expression, respectively, and the percentages of CD34(+) B-progenitors among total CD34(+) cells and the granularity of granulocytes decreased. Logistic regression analyses showed that, in addition to myeloblast percentages, the expression of CD7 and B7-H1 on myeloblasts was independently associated with AL-MDS patients.

Activation and priming of human monocyts by monocyte chemotactic and activating factor.

Both monocyte chemotactic and activating factor (MCAF) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) stimulated an increase in cytoplasmic free Ca2+ ( [Ca2+] i) and changes in intracellular pH (pHi) in human monocytes in parallel at lower concentrations, and stimulated superoxide (O-2) release and changes in transmembrane potential in parallel at higher concentrations. The changes in pHi were characterized by initial rapid acidification followed by sustained alkalinization, and the changes in transmembrane potential were characterized by initial depolarization followed by partial repolarization. The time-courses of all responses stimulated by MCAF and FMLP were similar to each other, although the magnitude of all responses was less in MCAF-stimulated cells. MCAF by itself was a very weak stimulus for inducing O-2 release. However, MCAF primed monocytes and enhanced O-2 release stimulated by FMLP. The priming effect of MCAF was maximal within 5 min of preincubation, and the doseresponse curves for priming were identical to those for triggering of an increase in [Ca2+] i and intracellular acidification. Intracellular acidification was induced at lower concentration than O-2 release by MCAF stimulated monocytes. MCAF further potentiated FMLP-induced O-2 release in tumor necrosis factor (TNF) -, granulocyte-macrophage colony-stimulating factor (GM-CSF) -or IL-3-primed monocytes.These findings suggest that MCAF, alone or in concert with other cytokines, primes monocytes for enhanced release of O-2, and that stimulus induced acidification is closely associated with an increase in [Ca2+] i, but not O-2 release.

Erythropoietin titers in patients on maintenance dialysis determined by a new radioimmunoassay technique

遺伝子組換えヒトエリスロポエチンを用いた放射免疫測定法を新たに開発し, 特異性, 感度, 再現性ともに優れた臨床応用可能な血中エリスロポエチン (EPO) 濃度の測定系を確立した. その容量反応曲線は3-250mU/mlの範囲で直接測定が可能であり, 最小測定限界は5mU/mlであった.本法によって測定したEPOは長期透析患者428例において16.1±8.6mU/ml (m±SD), 正常人86例において17.1±7.2mU/mlであり, 両群間に有意差を認めなかった. 透析患者のEPOは貧血の程度に比して相対的に極めて低値と考えられ, またEPOとHtとの間には相関を認めなかった. 大量の輸血を受けた患者群と非輸血群のEPOはほぼ同値であったが, 一部の高度貧血患者では低値の傾向があり, 輸血を繰り返す必要があった. 正常人, 透析患者ともにEPOは加齢にともなって増加する傾向があったが, 正常人では70歳以上でやや減少した. 透析期間が長いほどHtが高い症例が増加する傾向があるが, 透析期間とEPOの間には有意の相関を認めなかった. 腎不全の原因疾患別にみると, 多発性骨髄腫のEPDは他疾患の患者群よりも有意に高値であった. 多発性嚢胞腎では貧血は軽度であり, EPOはやや高値の傾向を示した. なお, 蛋白同化ステロイド・鉄剤投与の有無, 網状赤血球数, 血液尿素窒素, 血清クレアチニン, 血清鉄, 血清フェリチンとEPOとの間には, 相関を認めなかった.

Hemopoietic Stem Cells in Experimental Hypoplastic Marrow Failure of the Mouse

Aplastic anemia is a syndrome characterized by a failure of the supply of erythrocytes, leukocytes, and platelets to the peripheral blood, owing to a decreased production of these cells. In this disease, the number of hemopoietic cells in the bone marrow usually fall, and they are replaced by fatty cells.