Biomedical subjects

Takao Koike

Publications and source records attributed to Takao Koike.

At least 55 records · Page 3Linked to original sources

PubMed2004

Unexpected role of TNF-alpha in graft versus host reaction (GVHR): donor-derived TNF-alpha suppresses GVHR via inhibition of IFN-gamma-dependent donor type-1 immunity.

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, leading to significant morbidity and mortality. Host-derived TNF-alpha play a role in the induction of allo-reactive donor T cell activation and the pathogenesis of GVHD. On the other hand, the precise role of donor-derived TNF-alpha in GVHD remains unclear. To elucidate this issue, we designed an acute GVHD model using (B6 x D2) F1 recipient mice transferred with spleen cells derived from either wild-type or TNF-alpha(-/-) C57BL/6 mice. Surprisingly, we found that spleen cells from TNF-alpha(-/-) mice induce more severe graft versus host reaction (GVHR) than wild-type spleen cells upon transfer into B6D2F1 mice. Transplantation of TNF-alpha(-/-) mouse spleen cells was associated with enhanced anti-host CTL generation and augmented deletion of host cells. Moreover, mice receiving TNF-alpha(-/-) cells showed significantly higher levels of serum IFN-gamma, which was mainly produced by donor CD8+ T cells. We also demonstrated that TNF-alpha deficiency in donor spleen cells caused a marked elevation of TNF-alpha producing capacity by LPS-stimulated host macrophages. Such enhanced GVHR was completely prevented by using TNF-alpha(-/-)IFN-gamma(-/-) splenic cells. Our findings demonstrate, for the first time, that donor-derived TNF-alpha suppress GVHR by inhibiting IFN-gamma-dependent donor type-1 immunity which is essential for host TNF-alpha elevation.

Animals↗

PubMed2004

Diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis.

Our objective in this study was to explore the diagnostic value of antiagalactosyl IgG antibodies in rheumatoid arthritis (RA). The study comprised 266 Japanese patients with systemic autoimmune diseases, including 60 with RA. Human agalactosyl IgG was prepared enzymatically, and the serum levels of antiagalactosyl IgG antibodies were determined using a lectin enzyme immunoassay. Serum IgG and IgM rheumatoid factors (RF) were measured using laser nephelometry for IgM (LN-RF) and an enzyme-linked immunosorbent assay for IgG (IgG-RF). Antiagalactosyl IgG antibodies were significantly more common in patients with RA than in those without (78% vs. 18%, odds ratio (OR) 16.51, 95% confidence interval (CI) 8.12-33.58, p<0.0001). Patients with RA also had a higher frequency of LN-RF than those without RA (75% vs. 28%, OR 7.81, 95% CI 3.91-15.58, p< 0.001). The specificity of antiagalactosyl IgG antibodies for RA was significantly higher than that of LN-RF (82% vs. 72%, p<0.0011). There was a significant correlation between titers of antiagalactosyl IgG antibodies and C-reactive protein levels. Antiagalactosyl IgG antibodies are more specific markers for RA than conventional LN-RF, and may provide useful information for the diagnosis of RA.

Antibodies↗

PubMed2004

Gain-of-function polymorphism in mouse and human Ltk: implications for the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex-type tissue inflammation, most prominently in the kidney. Evidence suggests that genetic factors predisposing to aberrant proliferation/maturation of self-reactive B cells initiate and propagate the disease. In SLE-prone New Zealand Black (NZB) mice and their F1 cross with New Zealand White (NZW) mice, B cell abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Our genome-wide scans to search for susceptibility genes for aberrant activation of B1 cells in these mice showed evidence that the gene, Ltk, encoding leukocyte tyrosine kinase (LTK), is a possible candidate. LTK is a receptor-type protein tyrosine kinase, belonging to the insulin receptor superfamily, and is mainly expressed in B lymphocyte precursors and neuronal tissues. Sequence and functional analyses of the gene revealed that NZB has a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). SLE patients also had this type of Ltk polymorphism with a significantly higher frequency compared with the healthy controls. Our findings suggest that these polymorphic LTKs cause up-regulation of the PI3K pathway and possibly form one genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.

Adult↗

PubMed2004

Nicked beta2-glycoprotein I: a marker of cerebral infarct and a novel role in the negative feedback pathway of extrinsic fibrinolysis.

BEta(2)-glycoprotein I (beta(2)-GPI) is proteolytically cleaved by plasmin in domain V (nicked beta(2)-GPI), being unable to bind to phospholipids. This cleavage may occur in vivo and elevated plasma levels of nicked beta(2)-GPI were detected in patients with massive plasmin generation and fibrinolysis turnover. In this study, we report higher prevalence of elevated ratio of nicked beta(2)-GPI against total beta(2)-GPI in patients with ischemic stroke (63%) and healthy subjects with lacunar infarct (27%) when compared to healthy subjects with normal findings on magnetic resonance imaging (8%), suggesting that nicked beta(2)-GPI might have a physiologic role beyond that of its parent molecule in patients with thrombosis. Several inhibitors of extrinsic fibrinolysis are known, but a negative feedback regulator has not been yet documented. We demonstrate that nicked beta(2)-GPI binds to Glu-plasminogen with K(D) of 0.37 x 10(-6) M, presumably mediated by the interaction between the fifth domain of nicked beta(2)-GPI and the fifth kringle domain of Glu-plasminogen. Nicked beta(2)-GPI also suppressed plasmin generation up to 70% in the presence of tissue plasminogen activator, plasminogen, and fibrin. Intact beta(2)-GPI lacks these properties. These data suggest that beta(2)-GPI/plasmin-nicked beta(2)-GPI controls extrinsic fibrinolysis via a negative feedback pathway loop.

Aged↗

PubMed2004

Identification of a functional peroxisome proliferator-activated receptor responsive element within the murine perilipin gene.

Perilipin, a family of phosphoproteins located around lipid droplets in adipocytes, is essential for enlargement of lipid droplets and lipolytic reaction by hormone-sensitive lipase. Thiazolidinediones, peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been shown to increase perilipin expression in fully differentiated adipocytes. However, the precise mechanism of transcriptional regulation of murine perilipin gene heretofore remains unclear. We determined the transcription start site of murine perilipin gene by RNA ligase-mediated rapid amplification of the cDNA ends method. We generated luciferase reporter gene constructs containing various lengths of the 5'-flanking region of the murine perilipin gene and assayed promoter/enhancer activities using differentiated 3T3-L1 adipocytes. We identified a functional PPAR-responsive element (PPRE) in the murine perilipin promoter, and this was confirmed by gel EMSAs using nuclear extracts from differentiated 3T3-L1 adipocytes. Furthermore, point mutations of the identified functional PPRE markedly reduced both the reporter gene activity in differentiated 3T3-L1 adipocytes and PPARgamma/thiazolidinedione-induced transactivation in NIH-3T3 fibroblasts. Real-time RT-PCR revealed that thiazolidinedione up-regulates endogenous perilipin mRNA levels. We propose that PPARgamma plays a significant role in the transcriptional regulation of murine perilipin gene via the PPRE in its promoter.

Adipocytes↗

PubMed2004

A randomized open-label comparative study of conventional therapy versus mizoribine onlay therapy in patients with steroid-resistant nephrotic syndrome (postmarketing survey).

BACKGROUND: A previous double-blind 24-week clinical trial of mizoribine (MZ) vs placebo in steroid-resistant primary nephrotic syndrome (SRPNS) showed that MZ was more effective than placebo in reducing the rate of deterioration of renal function. The present study was conducted to evaluate the efficacy and safety of MZ in patients with SRPNS after 2 years' treatment. METHODS: A multicenter randomized open-label controlled trial in patients with SRPNS was conducted as a 2-year prospective postmarketing study. RESULTS: There was a significant imbalance in the baseline serum albumin level (s-Alb) between the conventional therapy (CT) and MZ onlay therapy groups. Early dropouts were more frequent in the subset of patients in the CT group having a baseline s-Alb < or =3 g/dl. Therefore, the primary analysis (urinary protein level (UP)-improving effect) was performed using a mixed-effects model, with stratification according to the baseline s-Alb value. The analysis revealed that, in the subset of 34 patients with membranous nephropathy (MN) within the stratum of patients with baseline s-Alb < or =3 g/dl (n = 52), the rate of change (slope of change in the UP level/month), in terms of the log (UP+0.2), was -0.0577 in those allocated to the MZ group and -0.0227 in those allocated to the CT group (P = 0.058). In the stratum of patients with a baseline s-Alb >3 g/dl (n = 97), there were no significant differences in the UP between the two treatment groups. Hence, MZ onlay therapy was not considered to be efficacious in this group of patients. No serious adverse reactions to the drug were observed. CONCLUSIONS: The present study yielded significant results, in that it suggested the possibility that long-term MZ therapy may afford further reduction of the UP, in addition to that obtained following CT, in particular, in MN patients in a severe nephrotic state.

Adult↗

PubMed2004

Steroid-sensitive nephrotic syndrome associated with positive C1q immunofluorescence.

A 21-year-old woman showed heavy proteinuria and edema. A light microscopic study of a renal biopsy specimen showed diffuse mild mesangial expansion, with borderline mesangial hypercellularity. An immunofluorescence study revealed dominant positive staining (3+) of C1q in the glomerular mesangium. Stainings for C3, C4, IgG, and IgM were weak or 1+. Staining for IgA was negative. Electron-dense deposits were present in the mesangial area. There was significant fusion of foot processes. There was no serological or clinical evidence of collagen disease. She was treated with oral prednisolone (initially, 40 mg/day). The proteinuria was alleviated and the patient remains in complete remission. The histopathological studies were compatible with C1q nephropathy, although the clinical outcome differed in a number of aspects. The clinical picture in the current patient appears to represent a very rare phenotype of nephritis.

Adult↗

PubMed2004

Lupus mortality in Japan.

Systemic lupus erythematosus (SLE)-related mortality has significantly declined in Japan during the past four decades. Decrease in number of deaths due to renal failure has considerably improved the prognosis of SLE. The adequate use of steroid therapy, the new advances in the second-line therapies including immunosuppressants, plasmapheresis and hemodialysis, and the appropriate control of infectious complications are the major reasons of the reduction of SLE-related mortality. The establishment of a nation-wide registration system of SLE in Japan will allow us to improve our strategy to control the disease.

Cohort Studies↗

PubMed2004

Antiprothombin antibodies and the diagnosis of antiphospholipid syndrome.

The preliminary classification criteria for definite antiphospholipid syndrome (APS) include the presence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA) as laboratory criteria. However, antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies comprising also antibodies against phospholipid-binding proteins or their complexes with phospholipids. Prothrombin is one of the antigen recognized by aPL. In the last decade, there has been increasing interest in antibodies against prothrombin alone and those against phosphatidylserine-prothrombin complex. The latter, phosphatidylserine-dependent antiprothrombin antibodies (aPT), have been closely associated with APS and LA. In this paper, we review the properties of antiprothrombin antibodies.

Animals↗

PubMed2004

Phosphatidylserine-dependent antiprothrombin antibodies are not useful markers for high-risk women with recurrent miscarriages.

To determine the possible association between antiprothrombin antibodies and conventional antiphospholipid antibody (aPL) 1 (1.0%), 2 (2.0%) and 17 (17.0%) were found to be positive for phosphatidylserine-dependent antiprothrombin antibody (aPS/PT) IgG, beta2glycoprotein I-dependent anticardiolipin antibody, and lupus anticoagulant by activated partial thromboplastin time (LA), respectively, in 100 recurrent aborters. Because patients with aPS/PT were included in the 17 with LA, we should not add aPS/PT measurement to routine testing in addition to conventional aPL for patients with recurrent miscarriage.

Abortion, Habitual↗

PubMed2004

Beta2-glycoprotein I, anti-beta2-glycoprotein I, and fibrinolysis.

Beta2-glycoprotein-I (beta2GPI) is a phospholipid-binding plasma protein that consists of five homologous domains. Domain V is distinguished from others by bearing a positively charged lysine cluster and hydrophobic extra C-terminal loop. Beta2GPI has been known as a natural anticoagulant regulator. Beta2GPI exerts anticoagulant activity by inhibition of phospholipid-dependent coagulation reactions such as prothrombinase, tenase, and factor XII activation. It also binds factor XI and inhibits its activation. On the other hand, beta2GPI inhibits anticoagulant activity of activated protein C. According to the data from knockout mice, beta2GPI may contribute to thrombin generation in vivo. Phospholipid-bound beta2GPI is one of the major target antigens for antiphospholipid antibodies present in patients with antiphospholipid syndrome (APS). Binding of pathogenic anti-beta2GPI antibodies increases the affinity of beta2GPI to the cell surface and disrupts the coagulation/fibrinolysis balance on the cell surface. These pathogenic antibodies activate endothelial cells via signal transduction events in the presence of beta2GPI. Impaired fibrinolysis has been reported in patients with APS. Using a newly developed chromogenic assay, we demonstrated lower activity of intrinsic fibrinolysis in euglobulin fractions from APS patients. Addition of monoclonal anti-beta2GPI antibodies with beta2GPI also decreased fibrinolytic activity in this assay system. beta2GPI is proteolytically cleaved by plasmin in domain V (nicked beta2GPI) and becomes unable to bind to phospholipids, reducing antigenicity against antiphospholipid antibodies. This cleavage occurs in patients with increased fibrinolysis turnover. Nicked beta2GPI binds to plasminogen and suppresses plasmin generation in the presence of fibrin, plasminogen, and tissue plasminogen activator (tPA). Thus, nicked beta2GPI plays a role in the extrinsic fibrinolysis via a negative feedback pathway loop.

Animals↗

PubMed2004

Antiprothrombin antibodies--are they worth assaying?

According to the preliminary classification criteria of the antiphospholipid syndrome (APS) (Sapporo Criteria), beta2-glycoprotein I (beta2GPI)-dependent anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) are the only laboratory tests considered as criteria for the classification of the APS. Recently, antibodies against phosphatidylserine-prothrombin complex (aPS/PT) have been detected and these antibodies, rather than antibodies against prothrombin alone, are closely associated with APS and LA. We assessed the sensitivity and specificity of aPS/PT for the diagnosis of APS in our population of patients with a variety of autoimmune disorders and investigated whether aPS/PT could be used as diagnostic test in patients suspected of having APS. The study population comprised 219 patients with autoimmune diseases including 82 patients with APS and 137 without APS (55 systemic lupus erythematosus, 32 rheumatoid arthritis, 10 primary Sjogren's syndrome, 8 scleroderma, 5 Behcet's disease and 27 other rheumatic diseases). IgG/M aPS/PT were measured by ELISA using phosphatidylserine-prothrombin complex as antigen immobilized on ELISA plates in the presence of CaCl2. IgG/M aCL were measured by standard methods and LA was detected by clotting assays. aPS/PT, aCL and LA were more frequently found in patients with APS (47, 46 and 69, respectively) than in those without APS (11, 19 and 29, respectively) (OR 95% [CI]; 15.4 [7.2-32.7], 7.9 [4.1-15.2, 19.8 [9.6-40.6], respectively]. The sensitivity of each assay for the diagnosis of APS was 57%, 56% and 86% with a specificity of 92%, 86% and 79%, respectively. aPS/PT and aCL have similar diagnostic value for APS, therefore, we propose that aPS/PT should be further explored, not only for research purposes, but also as a candidate of one of the laboratory criteria for the classification of the APS.

Antibodies, Antiphospholipid↗

PubMed2004

Effective high-dose chemotherapy combined with CD34+-selected peripheral blood stem cell transplantation in a patient with cutaneous involvement of nasal NK/T-cell lymphoma.

The prognosis of nasal natural killer (NK)/T-cell lymphoma with cutaneous involvement especially is morbid despite intensive chemotherapy and radiotherapy. We treated a 52-yr-old Japanese woman with cutaneous dissemination of nasal NK/T-cell lymphoma. Six cycles of chemotherapy, irradiation to skin lesion were administered and complete remission (CR) was attained. High-dose chemotherapy (HDC; etoposide 750 mg/m(2) x 2 d, cyclophosphamide 60 mg/kg x 2 d, total body irradiation 12 Gy two daily fractions x 3 d) followed by CD34(+)-selected autologous peripheral blood stem cell transplantation (CD34(+)-APBSCT) was then prescribed. Complete remission (CR) was obtained and she has been free of disease for 34 months since CD34(+)-APBSCT. We suggest that marrow-ablative chemotherapy facilitated by autologous stem cell transplantation should be considered part of the primary therapy for subjects with a poor prognosis for nasal NK/T-cell lymphoma with cutaneous involvement.

Antigens, CD34↗

PubMed2004

Rheumatoid factors induce signaling from B cells, leading to Epstein-Barr virus and B-cell activation.

B-cell antigen receptor signaling is initiated upon binding of the antigen to membrane-bound immunoblobulin (Ig), and the anti-Ig antibody (Ab) mimics this signaling. In B cells latently infected with Epstein-Barr virus (EBV), the same signals induce virus activation. We examine here whether rheumatoid factors (RFs), autoantibodies directed against the Fc portion of IgG, induce EBV and B-cell activation. As a source of RFs, RF-producing lymphoblastoid cell line (LCL) clones were isolated from peripheral blood mononuclear cells (PBMC) and synovial cells from patients with rheumatoid arthritis (RA) by EBV transformation. Burkitt's lymphoma-derived Akata cells, which are highly responsive to EBV activation by anti-Ig Abs, were used for the assay of EBV activation. Akata cells expressed IgG3 as membrane-bound Ig. RFs from a synovium-derived LCL were directed to IgG3 and induced EBV activation in 16 to 18% of Akata cells, whereas RFs from another synovium-derived LCL were directed to IgG1 and did not induce EBV activation. Pretreatment of RFs with the purified Fc fragment of human IgG completely abolished EBV activation. Furthermore, B-cell activation was assessed by incorporation of [3H]thymidine. RFs from synovium-derived LCLs efficiently induced B-cell activation, and the addition of CD40 ligand had a synergistic effect. On the other hand, RFs from PBMC-derived LCLs were polyreactive, had a lower affinity to IgG, and did not induce EBV and B-cell activation. The present findings imply a possible role for RFs as EBV and B-cell activators.

Arthritis, Rheumatoid↗

PubMed2004

Alternate promoter and 5'-untranslated exon usage of the mouse adrenocorticotropin receptor gene in adipose tissue.

Mouse adrenocorticotropin receptor (ACTH-R/MC2R) messenger ribonucleic acid (mRNA) is expressed predominantly in the adrenal gland and, to a lesser extent, in adipose tissue. In this study, we found a novel 135-bp exon 1 (exon 1f) of the ACTH-R gene transcribed in mouse adipose tissue by RNA ligase-mediated rapid amplification of cDNA ends, which was located 1.4 kb downstream in the genome of previously-reported exon 1 (exon 1a) transcribed in the adrenal gland. The novel promoter region, 1.4 kb upstream of exon 1f contained three CCAAT boxes. RT-PCR analysis revealed that ACTH-R mRNA from adipose tissue and differentiated 3T3-L1 adipocytes exclusively contained exon 1f. Thus, the promoter region flanking to exon 1f is thought to be essential for adipose tissue, while that flanking to exon 1a is specific for the adrenal gland. A search for a similar sequence of mouse ACTH-R exon 1f and its flanking region in the human genome sequence database of GenBank Human Genome Resources did not reveal such a sequence in the region of the human ACTH-R gene. This may explain the absence of ACTH-R expression in human adipose tissue.

5' Untranslated Regions↗

PubMed2004

A woman with infectious endocarditis caused by Abiotrophia defectiva.

A 74-year-old woman with recurrent fever and multiple joint pain was admitted to Hokkaido University Hospital. Trans-esophageal echocardiogram revealed bacterial vegetation and destruction of the aortic valve. Although few bacteria grew in regular blood agar, Gram-positive coccobacillus was specifically grown in chocolate blood agar and Brucella agar, and it was identified to be Abiotrophia defectiva. Infectious endocarditis caused by Abiotrophia defectiva was diagnosed, she was treated with diuretics, penicillin G and gentamicin, and she immediately improved. Infectious diseases caused by Abiotrophia defectiva are extremely rare, and identification of this pathogen is important, as its bacterial characteristics require proper attention.

Aged↗

PubMed2004

Adult-onset idiopathic hypogonadotropic hypogonadism due to isolated pituitary gonadotropin deficiency.

A 25-year-old Japanese man with adult-onset idiopathic hypogonadotropic hypogonadism is reported. He had been delivered normally, had normal puberty, and experienced erectile dysfunction at age 24 years. Brain MRI revealed no abnormal findings and endocrinological data supported the diagnosis of isolated gonadotropin deficiency. Although most patients with idiopathic hypogonadotropic hypogonadism have a hypothalamic dysfunction, the lesion in this case may be considered to be in the pituitary since repetitive GnRH loading failed to increase serum LH and FSH.

Adult↗

PubMed2004

Features associated with epilepsy in the antiphospholipid syndrome.

OBJECTIVE: To assess the frequency of epilepsy in primary and secondary antiphospholipid syndrome (APS); to analyze the clinical and laboratory features characterizing those with epilepsy in a cohort of 538 patients with APS; and to find associated features that would suggest risk factors for epilepsy in APS. METHODS: We analyzed the clinical features of patients with APS who had epilepsy and compared them to the clinical features of non-epileptic APS patients. RESULTS: Of 538 APS patients, 46 (8.6%) had epilepsy. Epilepsy was more prevalent among APS secondary to systemic lupus erythematosus (SLE) compared to primary APS (13.7% vs 6%; p < 0.05). The patients with epilepsy had a higher prevalence of central nervous system (CNS) manifestations including focal ischemic events (strokes or transient ischemic events, 54.3% vs 24.6%; p < 0.0001) and amaurosis fugax (15.2% vs 4.9%; p < 0.05). APS patients with epilepsy had a higher frequency of valvular pathology (30.4% vs 14.6%; p < 0.01), thrombocytopenia (43.5% vs 25%; p < 0.05), and livedo reticularis (26.1% vs 11.5%; p < 0.01). The multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio (OR) of 4.05 (95% confidence interval, CI: 2.05-8), followed by SLE (OR 1.4, 95% CI 1.2-4.7), and valvular vegetations (OR 2.87, 95% CI 1-8.27). CONCLUSION: Epilepsy is common in APS and most of the risk seems to be linked to vascular disease as manifested by extensive CNS involvement, valvulopathy, and livedo reticularis and to the presence of SLE. These factors, however, explain only part of the increased occurrence of epilepsy in APS and other causes such as direct immune interaction in the brain should be investigated.

Adult↗