Aki Nishioka

Hyogo College of Medicine, Nishinomiya, Hyōgo, Japan

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Publications (13)11.08 Total impact

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    ABSTRACT: Background Biological disease-modifying antirheumatic drugs (bDMARDs) inhibit progression of structural damage in rheumatoid arthritis (RA). These results suggest the possibility that bDMARDs improve osteoclastic bone destruction of RA. However, the detailed mechanism of bDMARDs for bone metabolism in RA is poorly understood. Objectives To clarify the mechanism of tocilizumab (TCZ) or abatacept (ABT) for bone metabolism in active RA. Methods We selected 80 female patients with active RA, 44 patients were treated with TCZ and 36 patients were treated with ABT intravenously. Next, Circulating levels of type I collagen cross-linked N-telopeptides (NTx), osteocalcin (OC), soluble receptor activator of NF-kappa B ligand (sRANKL), osteoprotegerin (OPG), Dicckopf-1 (DKK-1), and osteopontin (OPN) were examined by ELISA at baseline and after 12 weeks of each treatment. Results Matching of patients according to propensity score resulted in a cohort that consisted of 28 patients in TCZ group and 28 patients in ABT group. Patient's background between TCZ group and ABT group, including age, prednisolone or methotrexate dose, and baseline of DAS-28 was matched. In TCZ group, average of NTx, DKK-1 and OPN levels at 12 weeks decreased significantly from the baseline (24.4 vs 21.5 nmol BCE/L; p<0.05, 2743 vs 2138 pg/mL; p<0.01, 90 vs 60 pg/mL; p<0.01 respectively). Average of OC levels at 12 weeks increased significantly from the baseline (8.6 vs 10.1 ng/mL; p<0.01). Average of sRANKL and sRANKL/OPG levels at 12 weeks tended to decrease from the baseline (0.47 vs 0.41 pmol/L, 0.13 vs 0.10% respectively). Interestingly, average of OPG levels at 12 weeks tended to increase from the baseline (5.03 vs 5.23 pmol/L). In ABT group, similarly, average of NTx and OPN levels at 12 weeks decreased significantly from the baseline (16.1 vs 14.7 nmol BCE/L; p<0.05, 86 vs 71 pg/mL; p<0.05 respectively). OC levels tended to increase (6.4 vs 6.8 ng/mL). However, sRANKL, OPG and sRANKL/OPG levels were not changed. In contrast, average of DKK-1 levels at 12 weeks increased significantly from the baseline (2336 vs 2558 pg/mL; p<0.05). In comparison of the rate of change from the baseline (%change) of these biomarkers between TCZ group and ABT group, %change of OPG in TCZ group increased significantly compared with ABT group (5.56 vs -1.77%; p<0.05) and %change of DKK-1 in TCZ group decreased significantly compared with ABT group (-18.2 vs 10.4%; p<0.01). Conclusions TCZ or ABT has improved inflammatory bone destruction of RA. However, the main mechanism of TCZ and ABT is different. These results suggest that TCZ has improved bone metabolism in RA through the control of osteoclastogeneis via RANKL/OPG balance. Especially, the promotion of osteoblastogenesis via the inhibition of DKK-1 may be a specific effect in TCZ compared with ABT. On the other hands, In ABT, it is suggested that the suppression mechanism involved in osteoclastogenesis which does not pass control of RANKL/OPG balance exists. This mechanism may be a direct inhibiting effect of osteoclast precursors. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: A 39-year-old woman was diagnosed with Systemic lupus erthymatosus (SLE) in 1993, and initially received 30 mg of prednisolone (PSL) daily as treatment. In 2012, the patient was diagnosed with pregnancy-induced hypertension (PIH) complecated with proteinurea, hypertension and pretibial edema at 24 weeks of gestation. At onset, protein urea was 1.6 g/day and she was given bed rest in the hospital with a protein-restricted and low salt diet, which led to a decrease in protein urea to approximately 1 g/day. At 34 weeks of gestation epigastric pain developed, and laboratory examinations showed liver dysfunction and low platelets. We made a diagnosis of hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome and performed an emergency cesarean procedure. Thereafter blood pressure was elevated, protein urea was 3.2 g/daily, anti-ds-DNA antibody level was elevated and serum C3/C4/CH50 was reduced, thus we gave. plasma exchange therapy, along with immunoadsorption and steroid pulse therapy (methyl-prednisolone 500 mg/daily for 3 days), as well as PSL at 30 mg/day. Overtime clinical symptoms and laboratory data gradually improved. Conclusion: Some reports suggest that SLE during pregnancy is a risk factor for hypertension, nephritis, SLE relapse and HELLP syndrome. In the patient, ADAMTS13 activity did not decrease, while there was an increase in VW factor level. We assessed this case was as atypical thrombotic microangiopathy. And herein report HELLP syndrome during pregnancy associated with SLE in our patient.
    No preview · Article · May 2015 · Japanese Journal of Clinical Immunology
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    ABSTRACT: To assess changes in salivary epidermal growth factor (EGF) levels within three years and investigate the correlation between these changes and the severity of intraoral manifestations in patients with Sjögren's syndrome (SS). Twenty-three SS patients (14 primary SS, 9 secondary SS) and 14 controls were followed up for three years. Salivary EGF concentration was measured using an enzyme-linked immunosorbent assay, and intraoral manifestations were evaluated using a short version of the Oral Health Impact Profile (OHIP-14). Changes in salivary flow rate, EGF level, and severity of intraoral manifestations were analyzed, along with associations among them. The OHIP-14 score significantly increased and the total salivary EGF output significantly decreased after three years in the SS group (10.2 ± 8.8 vs. 12.6 ± 9.2, p = 0.040; 10158.4 ± 9820.9 vs. 8352.8 ± 7813.3 pg/10 min, p = 0.032), though the salivary flow rate did not change. The decrease in total EGF output was especially high in patients with long disease duration and poor oral health-related quality of life (OHRQoL). In patients with poor OHRQoL, the change in total EGF output significantly correlated with the OHIP-14 score (r = -0.847, p = 0.008). However, there was no correlation between the change in salivary flow rate and the OHIP-14 score. The rapid decrease in salivary EGF level contributes to the progression of intraoral manifestations of SS.
    No preview · Article · Apr 2015 · Modern Rheumatology
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    ABSTRACT: Background Xerostomia accompanied in patients with Sjögren's syndrome (SS) relates to reduced salivary flow rate as a result of salivary gland dysfunction. Dry mouth causes various intraoral manifestations such as refractory stomatitis, ulcer and atrophic changes in the oral mucosa and tongue, and patients' quality of life (QOL) is impaired severely. These intraoral manifestations are believed to be caused mainly by a decreased clearance in the oral cavity due to hyposalivation. Because saliva has several beneficial physiological effects on the oral environment, however, qualitative changes in sialochemistry should be considered. Salivary epidermal growth factor (EGF) is considered to be an important cytoprotective factor against injuries and it contributes to wound healing and maintenance of mucosal integrity in the oral cavity. Objectives In the present study, we examined changes in salivary EGF levels and assessed the association between salivary EGF levels and the severity of intraoral manifestations in SS patients. Methods Forty SS patients (27 primary SS, 13 secondary SS; 37 females, 3 males; mean age 55.4±13.2 years; mean disease duration 5.6±3.7 years) and 23 controls (18 females, 5 males; mean age 56.1±17.4 years) were enrolled. All SS patients fulfilled the 2002 American-European Consensus Group classification criteria for SS. SS patients and controls who had factors that affect the intraoral environment or saliva secretion and salivary EGF were excluded. All saliva samples were similarly collected by the chewing gum test before breakfast, with fasting. Salivary EGF levels were measured using an enzyme-linked immunosorbent assay. Subjective intraoral manifestations were evaluated using a short version of the Oral Health Impact Profile (OHIP-14), which is a self-administered questionnaire concerning oral health-related QOL (OHRQoL). Results The OHIP-14 score in the SS group was significantly higher than that in the non-SS group (11.3±9.4 vs 7.1±7.6, p=0.037), indicating that the OHRQoL of the SS group was poor compared with that of the non-SS group. The total salivary EGF output was decreased in the SS group compared with the non-SS group (9237.6±8447.0 vs 13296.9±7907.1 pg/10 min, p=0.033), and it was markedly reduced in the SS group with long disease duration or with severe intraoral manifestations, respectively (4087.2±4356.7 pg/10 min, 6965.8±6161.1 pg/10 min). In the SS group, total salivary EGF output and salivary flow rate showed a strong positive correlation (r s=0.824, p=0.0005), while total salivary EGF output and disease duration showed a negative correlation (r s=–0.484, p=0.008). Further, total salivary EGF output was significantly and inversely correlated with the OHIP-14 score (r s=–0.721, p=0.012). Conclusions The salivary flow rate and salivary EGF levels were decreased with the progression of the disease, indicating that not only lower intraoral clearance by hyposalivation but also deterioration of saliva quality play a role in the pathogenesis of refractory intraoral manifestations in SS. Our findings provide new specific targets for therapeutic intervention for SS. References Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1418
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: A 62-year-old-man presented to our hospital with complaints of coldness, numbness, pain, weakness and cyanosis on the fingers and toes in March 2010. Laboratory findings revealed marked eosinophilia (46.6%; WBC 20600/μl), an elevation of serum creatine kinase, proteinuria and hematuria. He was diagnosed as hypereosinophilic syndrome (HES) without evidence to support a diagnosis of underlying diseases causing eosinophilia. After the initiation of corticosteroid therapy, peripheral eosinophil count was dramatically decreased, and both serum CK value and urinary findings became normalized. However, his symptoms persisted and digital necrotic changes developed. Angiography of the bilateral upper and lower extremities showed multiple arterial occlusions with poor collaterals. The digital gangrenes were unresponsive to peripheral circulation ameliorators and gradually progressed. In July 2010, autologous transplantation of bone marrow mononuclear cells was performed for achievement of therapeutic angiogenesis. His digital skin color was ameliorated by the angiogenic therapy in two weeks, and digital gangrenes did not progress after that. After amputation of his fingers and toe, cut surfaces healed with favorable epithelization, and the symptoms were subsequently eliminated. Moreover, during three years after the therapy, as well as the effect on the skin lesion, the significant improvement in peripheral circulation was observed. Therefore, we proposed that therapeutic angiogenesis by autologous bone marrow mononuclear cells transplantation was a novel and effective treatment for intractable digital gangrene associated with HES.
    No preview · Article · May 2014 · Japanese Journal of Clinical Immunology
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    ABSTRACT: Background Abatacept (CTLA4-Ig) is a new therapeutic agent used for rheumatoid arthritis (RA). Recently, it is reported that CTLA-4 directly inhibits osteoclast formation. On the other hand, Osteopontin (OPN) is produced by activated T lymphocytes and has been recognized as one of the key molecules for osteoclastic bone-resorption in RA. However, the effect of abatacept on bone homeostasis and OPN production in RA is poorly understood. In this study, we investigated the effects of abatacept on biochemical markers of bone, serum soluble receptor activator of NF-kappa B ligand (sRANKL), osteoprotegerin (OPG), and plasma osteopontin (OPN) in patients with RA. Objectives To demonstrate the effect of abatacept on bone homeostasis in RA. Methods 24 patients with RA (19 females, 5 males; age 59.8±14.7 years; disease duration 6.1±8.0 years; stage 2.0±1.2; class 1.8±0.6; DAS28-CRP 4.6±1.4; SDAI 26.7±12.8; use of MTX 83%; average dose of MTX 5.9±3.3mg/week; use of PSL 71%; average dose of PSL 3.9±3.2mg/day) were started on treatment with abatacept for 24 weeks. All patients were biologics naïve. In addition, circulating levels of type I collagen cross-linked N-telopeptides (NTx), osteocalcin, sRANKL, OPG, and plasma OPNwere examined by ELISA at baseline and after 12 and 24 weeks. Results After 24 weeks of abatacepttreatment, DAS28-CRP and SDAI decreased significantly from the baseline (4.6±1.4 vs 2.5±0.9; p<0.01, 26.7±12.8 vs 8.6±6.0; p<0.01, respectively), so that 14 patients achieved DAS28-CRP remission. After 12 weeks, average of NTx levels decreased significantly from the baseline (16.27±5.81 vs 14.23±3.48 nmol BCE/l; p<0.01). After 24 weeks, average of osteocalcin levels increased significantly (5.80±3.02vs 6.45±2.61 ng/ml; p<0.05) and average of OPN levels decreased significantly from the baseline (101.57±57.40 vs 71.76±29.49 pg/ml; p<0.01). Average of RANKL levels tended to decrease from the baseline ((0.22±0.39 vs 0.12±0.20 pmol/l; p=0.06), whereas average of OPG levels did not change significantly from the baseline (4.67±1.96 vs 4.90±2.44 pmol/L; p=0.17). Conclusions These findings suggest that abatacept improves systemic bone metabolism in patient with RA through the increase of bone formation markers and the decrease of bone degradation markers. We consider that these mechanism result from the regulation of OPN and RANKL expression in activated T lymphocytes. Consequently, abatacept may control osteoclastic-bone destruction in RA via the suppression of RANKL induced-osteoclastogenesis and OPN induced-osteoclast attachment of bone surface. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases

  • No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Objective: To assess changes in salivary epidermal growth factor (EGF) levels and the correlation between these levels and the severity of intraoral manifestations in Sjögren's syndrome (SS). Methods: Forty SS patients and 23 controls were enrolled. Salivary EGF concentration was measured using an enzyme-linked immunosorbent assay, and intraoral manifestations were evaluated using a short version of the Oral Health Impact Profile (OHIP-14). The associations among salivary flow rate, EGF levels and the severity of intraoral manifestations were analyzed. Results: The total salivary EGF output was significantly decreased in the SS patients compared with the controls (9237.6 ± 8447.0 vs. 13296.9 ± 7907.1 pg/10 min, respectively, p = 0.033). In the SS patients, total EGF output and salivary flow rate showed a strong positive correlation (rs = 0.824, p = 0.0005), while total EGF output and disease duration showed a negative correlation (rs = -0.484, p = 0.008). Further, total EGF output was significantly correlated with the OHIP-14 score (rs = -0.721, p = 0.012). Conclusions: The salivary flow rate and EGF levels are decreased in SS, and this deterioration in saliva quality causes refractory intraoral manifestations. Our findings have provided new therapeutic targets for SS.
    No preview · Article · Nov 2013 · Modern Rheumatology
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    Naoto Azuma · Aki Nishioka · Masataka Kuwana · Hajime Sano

    Preview · Article · Sep 2012 · Rheumatology (Oxford, England)
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    ABSTRACT: In May 2009, a 57-year-old woman who had rheumatoid arthritis since 9 years was admitted to our hospital for dyspnea due to interstitial pneumonia (IP). On admission, she exhibited proximal scleroderma, finger edema, Raynaud's phenomenon, digital pitting scars, ankyloglossia, and esophageal dysmotility. The patient was diagnosed as having systemic sclerosis (SSc), according to the American College of Rheumatology criteria. After initiation of high-dose corticosteroid therapy, gradual amelioration of IP was observed. However, the patient complained of abdominal fullness. Computed tomography and intestine series findings revealed significant dilatation of the small intestine due to intra-abdominal free air and pneumatosis cystoides intestinalis but no mechanical obstruction, leading to a diagnosis of SSc with pseudo-obstruction. The patient underwent decompression with a long intestinal tube, which led to improvement in her symptoms. Although erythromycin (EM) and some prokinetic agents were administered, abdominal involvement recurred several days after resumption of oral ingestion. Therefore, we changed the antibiotic from EM to metronidazole (750 mg/day). Her manifestations were promptly ameliorated by metronidazole therapy in 4 days and did not recur. Metronidazole is an antibiotic used to treat intra-abdominal anaerobic bacterial infections and is also commonly used in preoperative treatment for colorectal surgery. In conclusion, we report a case where SSc-associated pseudo-obstruction was successfully managed by metronidazole therapy.
    No preview · Article · Jan 2011 · Japanese Journal of Clinical Immunology
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    ABSTRACT: In August 2010, a 73-year-old woman with rheumatoid arthritis receiving etanercept (ETN) therapy for two years, developed high-fever and abdominal fullness. Though she had not been exposed to tuberculosis, isoniazid prophylaxis was administrated. Antibiotics were not effective. CT images revealed the massive ascites and peritonitis, and Ga scintigraphy demonstrated notable uptake in the peritoneum. Ascites analysis showed an elevated adenosine deaminase activity value (104.9 IU/l) without malignant cells. Moreover, PCR and culture for Mycobacterium tuberculosis were positive. Finally, a diagnosis of tuberculous peritonitis was established. After initiating a standard anti-tuberculosis regimen with four drugs, her clinical condition ameliorated and ascites promptly regressed. Although the tuberculous peritonitis during ETN therapy is rare, this report emphasized the importance of initial suspicion of tuberculosis in these patients with tumor necrosis factor inhibitors such as ETN.
    No preview · Article · Jan 2011 · Japanese Journal of Clinical Immunology
  • Naoto Azuma · Naoaki Hashimoto · Aki Nishioka · Hajime Sano

    No preview · Article · Jan 2010 · Internal Medicine
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    ABSTRACT: A 56-year-old-woman presented a local otolaryngologist with a complaint of hearing loss. She was treated with antibiotics as acute otitis media, however her symptom did not improved. She admitted to our hospital because of hearing loss on both sides, fever, otorrhea and vertigo. On admission, an audiogram showed bilateral mixed conductive-sensorineural hearing loss, and CT image revealed the exudates in bilateral middle ear cavities and mastoid air cells. Moreover, serum level of myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) elevated (133EU). Although pulmonary, renal and cutaneous involvements were not noted and the histopathological examination of operated specimen taken from otitis media revealed non-specific inflammatory changes, in the absence of any other obvious causes of otitis media, these findings might be associated with positive serum MPO-ANCA value itself. After the initiation of therapy with methylprednisolone and azathioprine, her symptoms and hearing ability ameliorated and both CRP value and the titer of ANCA became normalized. But, after the improvement by the immunosuppressive treatment, MRSA in the otorrhea persisted. This case suggests that otitis media may be one of the symptoms of vasculitis, and some previous cases described otitis media or hearing loss as rare manifestations of vasculitis. It is important to make an early diagnosis for good prognosis of hearing ability, and we have to consider the differential diagnosis including of ANCA-related vasculitis.
    No preview · Article · Jan 2010 · Japanese Journal of Clinical Immunology
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    ABSTRACT: A 25-year-old-man was referred with an approximately 1-year history of recurrent fever, tonsillitis, testicular pain and testicular swelling in June 2009. He also complained of visual disturbance, some erythema nodosum (EN) like lesions on his lower extremities and oral aphthous ulcerations for 5 months. Opthalmological consultation confirmed retinochoroiditis, and ultrasonography revealed epididymitis. A biopsy of the EN like lesion showed a necrotizing vasculitis of the small and medium-sized vessels with septal panniculitis in the subcutis. The laboratory findings revealed an elevation of CRP and positive HLA-B51. He was diagnosed with incomplete Behcet's disease according to the Japanese criteria (1987). After the initiation of the therapy with 10 mg/day of prednisolone, his symptoms promptly ameliorated. In our case, although epididymitis as well as the histopathological findings suggested polyarteritis nodosa (PN), a diagnosis of BD was established on the basis of other contemporaneous findings. Necrotizing vasculitis as a cutaneous manifestation in patients with BD has been rarely reported. However, BD and PN, including cutaneous PN, have rarely described in conjunction. Therefore, we propose that PN-like necrotizing vasculitis might be the subtype of BD.
    No preview · Article · Jan 2010 · Japanese Journal of Clinical Immunology
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    ABSTRACT: A 63-year-old woman was admitted to our hospital because of auricular chondritis, conjunctivitis, polyarthralgia, productive cough and dyspnea. On admission, pulmonary function test demonstrated an obstructive pattern, and flow-volume curve (FVC) revealed a constrictive upper airway flow pattern. Chest CT showed a thickened tracheal wall and narrowing of the airway. The laboratory findings revealed an elevation of CRP and high titer of anti-type II collagen antibody. She was diagnosed as relapsing polychondritis (RP) according to Damiani's criteria. After the initiation of the therapy with 32 mg/day of methylprednisolone, her symptoms, pulmonary function, FVC and CT findings ameliorated promptly, and the titer of anti-type II collagen antibody became normalized. Moreover, we measured the airway wall thickness, percentage wall area (WA%) and percentage wall thickness (WT%), by CT and HRCT, and also evaluated the airway involvement quantitatively. Both WA% and WT% were inversely correlated with FEV1.0%. The airway inlolvement is most important prognostic factor in patients with RP, and sequential evaluation of airway manifestation are necessary. We suggest that a quantitative evaluation of bronchial structures by sequential CT is useful for the evaluation of RP as well as pulmonary function tests.
    No preview · Article · Sep 2009 · Japanese Journal of Clinical Immunology
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    ABSTRACT: We report a case of cytomegalovirus (CMV) pneumonitis that presented as a cavitary lung lesion in a patient with systemic lupus erythematosus receiving immunosuppressive treatment. The lesion was confirmed by positive polymerase chain reaction (PCR) for CMV in bronchoalveolar lavage fluid (BALF) and CMV antigenemia. PCR for CMV in BALF was demonstrated to be useful for the diagnosis of CMV pneumonitis on the basis of high sensitivity and specificity. After initiating ganciclovir, the lesion gradually regressed. A cavitary lung lesion associated with CMV is extremely rare. This presentation suggests that the differential diagnosis of cavitary lung lesion in immunocompromised individuals should include CMV.
    No preview · Article · Jan 2009 · Internal Medicine
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    ABSTRACT: We herein report a case of spontaneous rupture of Achilles tendon in a 51-year-old man with refractory Reiter's syndrome. On the diagnosis in November, 2006, physical examinations and MR images showed a remarkable inflammation at the calcaneal insertion area of Achilles tendon. He required aggressive treatments with nonsteroidal anti-inflammatory drug (NSAID), oral prednisolone 30 mg daily and methotrexate (8 mg weekly) to control the disease. Two months later, the Achilles tendon ruptured at its insertion point. This ruptured lesion of Achilles tendon was an unusual site compared to previous reports. Histological findings in the ruptured lesion of Achilles tendon revealed the existence of granulomatous lesion consisted of severe infiltration of fibroblasts and vessels proliferation beside tendon. These findings suggest a prolonged inflammation. Although it is widely accepted that Reiter's syndrome is associated with enthesis, especially at the attachment of Achilles tendon to calcaneum, there have been only two reports of Achilles tendon rupture associated with Reiter's syndrome. The possible cause of the Achilles tendon rupture in this patient might be due to the weakened strength of the Achilles tendon by the prolonged and severe enthesis of Achilles tendon near the insertion lesion.
    No preview · Article · May 2008 · Japanese Journal of Clinical Immunology