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OBJECTIVE B cells lacking RP105 produce autoantibodies in patients with SLE. Expression of B-cell activating factor (BAFF) binding receptors (BBRs) and survival of RP105(-) B cells from SLE patients were examined. METHODS Detection of difference of gene expression between RP105(-) and RP105(+) B cells was done by DNA microarrays. Surface expression was confirmed by flow cytometry. The contribution of BAFF, a proliferation-inducing ligand (APRIL) and monomers/trimers of sCD40L to survival of RP105(-) and RP105(+) B cells was examined. RESULTS Gene expression of B-cell maturation antigen (BCMA) was different among BBRs in RP105(-) and RP105(+) B cells in SLE. Preferential expression of BCMA on RP105(-) B cells was confirmed compared with RP105(+) B cells by flow cytometry, although BAFF receptor (BAFF-R) expression on RP105(-) B cells was significantly lower. Additionally, relative ratios of BCMA/BAFF-R expression on RP105(-) B cells were increased significantly in SLE patients compared with normal subjects. Stimulation by sCD40L decreased the number of surviving RP105(-) and RP105(+) B cells in vitro. RP105(+) B cells were not rescued from sCD40L-induced cell death by BAFF and/or APRIL. In contrast, either BAFF or APRIL maintained the survival of RP105(-) B cells due to avoidance of cell death. Activated RP105(-) B cells reduced BAFF-R and increased BCMA levels. CONCLUSIONS RP105(-) B cells from SLE patients showed more preferential expression of BCMA compared with BAFF-R than normal subjects, and were possibly regulated by BAFF/APRIL. Our results provide a new insight of BCMA and their ligands in B cells from SLE patients.

To assess the effects of disease activity of systemic lupus erythematosus (SLE) and high-dose corticosteroids on endothelial injuries, the significance of soluble endothelial cell protein C receptor (sEPCR) and soluble thrombomodulin (sTM) was analyzed. Serum levels of sEPCR and sTM were measured by enzyme-linked immunosorbent assay (ELISA) cross-sectionally in 97 SLE patients, 49 patients with other rheumatic diseases and 22 normal subjects. The changes in these levels upon corticosteroid treatment were also analyzed in 41 patients. The levels of sEPCR and sTM were both higher in SLE and other rheumatic disease patients than in normal subjects. When low-dose corticosteroids were used, both the level of sEPCR and the ratio of positive tests for sEPCR were significantly higher in active SLE patients than in inactive patients [median 2.30 ng/ml (range 0.00–147.10 ng/ml) vs 0.00 ng/ml (0.00–58.90 ng/ml) and 53.5 vs 13.0%, respectively] (P < 0.005). Moreover, the ratio of positive tests for sEPCR was higher after corticosteroid treatment in 9 of 19 (47.3%) SLE patients compared to other rheumatic diseases (3/22; 13.6%). Although the mean level of sTM was significantly higher in active SLE patients than in inactive patients, the ratio of positive tests for sTM was not affected by disease activity or corticosteroids. In conclusion, the positive test for sEPCR is a more sensitive biomarker than that for sTM in reflecting endothelial injuries caused by active disease and often by corticosteroids in SLE.

Inducible costimulator (ICOS) is a costimulatory molecule expressed in activated T cells and plays an important role in T-cell-dependent immune responses. We investigated the role of ICOS in the development of autoimmune diseases in MRL/Mpj-lpr/lpr (MRL/lpr) mice. ICOS was expressed on CD4+ T cells from adult MRL/lpr mice. ICOS-deficient MRL/lpr mice showed mild lymphoadenopathy and a decreased memory type CD4+ T cells in the spleen. The anti-dsDNA antibody levels were decreased. CD4+ T cells from ICOS-deficient MRL/lpr mice showed less of a bias to Th1 and an enhanced production of IL-4 in response to anti-CD3 antibody in comparison to those from wild-type MRL/lpr mice. Although ICOS-deficiency abrogated renal vasculitis completely, the severity of glomerulonephritis was not altered. ICOS is considered to play a role in CD4+ T cell activation, autoantibody production, and renal vasculitis. However, it is not essentially required in the development of glomerulonephritis.

Although osteonecrosis of femoral head (ONF) is one of the serious complications in systemic lupus erythematosus (SLE) associated with corticosteroid therapy, there has been few trials of prevention of ONF described. We aimed to prevent ONF in steroid-treated SLE patients using anticoagulant, warfarin, conducting a multicenter prospective study. Sixty newly diagnosed SLE patients requiring 40 mg/day or more prednisolone were alternately assigned to either of two groups; a warfarin group and a control one. Warfarin (1 ∼ 5 mg/day) was started together with the beginning of steroid therapy and continued at least for three months. Patients were observed for the development of silent ONF by magnetic resonance imaging (MRI) and symptomatic ONF by plain radiography for over five years. The warfarin group consisted of 31 patients (62 hips) and the control one 29 patients (58 hips). Silent ONF developed in 13 hips (21%) and 19 hips (33%) in the warfarin group and the control group, respectively ( P = 0.13). On the other hand, warfarin tended to prevent symptomatic ONF; only three hips of 62 (4.8%) in the warfarin group and eight hips of 58 (14%) in the control group ( P = 0.08) developed silent ONF. It was also found that silent ONF developed, if it did, very early; within three months in 16 of 18 patients (89%). Among risk factors for silent ONF, steroid pulse therapy was most outstanding and it seemed to overcome the effect of warfarin. Taken together, for the time being, anticoagulant therapy, if not significantly sufficient, may be of use for the prevention of steroid-induced ONF in SLE. We consider that this study added to important evidence for the pathogenesis and prevention of ONF.

Objectives To investigate the relationship between the production of Th1/Th2 cytokines and cell kinetics, cell division and proliferation in patients with Behcet's disease (BD). Methods Peripheral venous blood was drawn from patients with BD (n = 24; 10 patients with active and 14 patients with inactive BD) and normal subjects (n = 22). Peripheral blood mononuclear cells were separated immediately and were cultured with concanavalin A (Con A) followed by phorbol 12-myristate 13-acetate and ionomycin (PMA+Ion). Intracellular cytokine production of interferon-gamma (IFN-gamma) (Th1) and IL-4 (Th2) in CD4(+) T cells was determined by flow cytometry. Furthermore, CD4(+) T cells labelled with CFSE [5 (and 6) carboxyfluorescein diacretate, succinimidyl ester] were stimulated and the cells were analysed for entry into the cytokine production effector pathway during cell division in active BD and normal subjects. Results In active BD, enhanced entry into the Th1 response effector pathway of CD4(+) T cells was observed after stimulation with Con A followed by PMA+Ion. Analysis of CD4(+) T cells at an identical cell division number in response to Con A followed by PMA+Ion revealed that IFN-gamma-producing cells were increased in active BD patients compared with normal subjects. These results suggest that the Th1 response of dividing CD4(+) T cells is predominantly operating in active BD. Dividing CD4(+) T cells stimulated with Con A followed by PMA+Ion showed a phenotype of activated effector memory T cells (CD45RA(low), CD45RO(+), CD69(high)). Conclusions Cell kinetics play a crucial role in Th1 cell differentiation and pathophysiology in BD.

安定した血液透析を施行するためには, 良好なブラッドアクセスを維持することが必要である. 最近, PTAをはじめとする各種interventional techniqueが発達し, ブラッドアクセスの長期開存に寄与しているものの血管のqualityの問題で急性閉塞をきたすこともしばしばみられる. 今回, 我々は人工血管使用による内シャントの急性閉塞に対してパルススプレー法による血栓溶解を試みた.症例は74歳男性で慢性腎炎による慢性腎不全のため平成3年から慢性維持透析を受けている.度重なるシャントトラブルのため左上腕動静脈間ならびに左鎖骨下静脈と上大静脈間に人工血管を使用し内シャントとしていた. 平成8年6月14日透析のため来院するもシャントが閉塞しており, 血管造影施行後にパルススプレー法による血栓溶解療法を行った. ウロキナーゼを合計60万単位使用にて治療後約1時間で血流は再開し, 以後の透析で使用可能であった.今後, 高齢者, 糖尿病ならびに長期透析患者の増加が予想され, シャントトラブルも増すものと思われる. その場合シャントの再建が困難なことも少なくない. したがって今回の症例のような急性閉塞に対して, パルススプレー法は比較的簡便でかつ安全で成功率も高いことから, 試みてみるべき方法の一つであると考える.

Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and other exogenous and endogenous molecules, and is thought to contribute to defense mechanisms against infections. Our objective was to elucidate the clinical significance of TLR4 in acute infectious diseases by analyzing its sequential expression on CD14+ monocytes. Peripheral blood samples were obtained from 36 patients with acute infectious diseases on admission and after treatment within certain intervals. The TLR4 expression on CD14+ monocytes was analyzed using flow cytometry and was presented as a mean fluorescence intensity (MFI). TLR4 expression during the acute phase of infection was highly enhanced compared to that of normal subjects (MFI: 22.1 vs 8.5). TLR4 expression was promptly reduced to normal levels in parallel with the disease improvement. In patients who died despite treatment, the enhancement of TLR4 expression during the acute phase was less prominent compared to those who survived (MFI: 14.6 vs 23.5) and its sequential change was also subtle. These results indicate that monocytes respond to acute infections by the induction of TLR4 expression and that a poor response may be associated with a poor prognosis.

We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenalpha1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-beta1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-gamma mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-gamma levels rather than the effect on TGF-beta1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.

B cells lacking RP105 molecule, a member of the Toll-like receptor family, were increased in the peripheral blood of 2 patients with antinuclear antibody (ANA) negative systemic lupus erythematosus (SLE). The increased proportion of RP105-lacking B cells was associated with disease activity in patients with ANA-negative SLE. When there are no significant serological markers for SLE, analysis of expression of RP105 may be helpful in evaluation of activity in ANA-negative SLE. We describe a new approach, using phenotyping of B cells, to evaluate activity of ANA-negative SLE.

A multicenter cooperative study of docetaxel (60 mg/m2) combined with cisplatin (60 mg/m2) was performed in stage III and IV patients with inoperable non-small cell lung cancer from March 1998 to September 1999. Of 37 patients enrolled, 36 patients were eligible. One patient obtained a complete response (CR) and nine patients had a partial response (PR). The overall response rate in 36 patients was 28.6%. The median survival time was 360 days. The response rates of stage III and stage IV patients were 36.8% and 18.7%, respectively. The median survival times of stage III and stage IV patients were 502 days and 286 days, respectively. The major toxicities were grade 3 leukopenia (16.2%), grade 3 neutropenia (32.4%), and grade 4 neutropenia (10.8%).

We investigated the features and the usefulness of gallium scintigraphy in the diagnosis and the assessment of Adult Still's disease (ASD) by retrospective case review. Gallium scintigraphy have been done for 11 cases of ASD (3 males and 8 females) and 4 females were positive. Among these, 67 Ga-citrate was accumulated to the bone marrow in all 4 cases and to the major joints in 2 cases. Positive cases were rather serious and administered more immunosuppressants than negative cases. In order to characterize gallium scintigraphy findings of ASD, i.e. bone marrow accumulation, we analyzed 130 cases of collagen vascular diseases. Although 101 cases (77.7%) were positive, only 7 cases (5.4%) showed the accumulation of 67Ga-citrate to the bone marrow. These include 3 cases with ASD, and 1 case with systemic lupus erythematosus, polyarteritis nodosa, Wegener's granulomatosis and Sjögren's syndrome. We also accumulated 18 patients who exhibited bone marrow accumulation of 67Ga-citrate, and found that 7 patients had collagen vascular and their related diseases. In conclusion, bone marrow accumulation in gallium scintigraphy is a specific feature of collagen vascular diseases, especially ASD, and it is suggested that cases with positive gallium scintigraphy in ASD can be serious and resistant to treatment.

Directional atherectomy (DA) was developed as a new therapeutic modality for coronary artery disease. For the past 3 years, we have applied DA intervention to vascular access failure with either poor blood flow rate or high venous pressure. DA intervention was performed on 27 lesions of 16 hemodialyzed patients. A reduction of stenosis to less than 20% of that before treatment was judged a technical success, and the rate of technical success was 84%. All patients showed adequate blood flow rates after DA intervention, indicating initial success. Although restenotic events occurred frequently, repeated DA interventions could be performed successfully. The patency rate at 1 month after DA intervention was 100%, at 3 months 93%, at 6 months 92% and at 12 months 75%. The short-term patency rate of DA was more satisfactory than the results of percutaneous transluminal angioplasty as reported by several investigators. Regarding the site of stenosis, restenotic events were relatively fewer in the lesions occurring at the native vein compared to those at graft-venous anastomotic sites. Eccentric-type stenosis was also associated with fewer restenotic events than circumferential-type stenosis. These results suggest that eccentric-type stenosis at the native vein is the most suitable lesion for the application of DA intervention in terms of long-term patency. As no severe complications occurred after DA intervention, this would appear to be a useful therapeutic modality for the correction of vascular access failure.