RESUMEN
Anti-neutrophil cytoplasmic antibody (ANCA) is associated with small-vessel vasculitis particularly in the kidneys and can induce the formation of neutrophil extracellular traps (NETs) from primed neutrophils. Recently we have reported that the induction of NETs correlates with ANCA affinity for myeloperoxidase (MPO) and disease activity in patients with MPO-ANCA-associated microscopic polyangiitis. To investigate whether MPO-ANCA affinity is associated with the formation of NETs in vivo, we examined the occurrence of NETs in the renal tissues of patients with MPO-ANCA-associated microscopic polyangiitis and ANCA affinity by double immunofluorescence staining for NET components of citrullinated histone, MPO and PAD4 and by ELISA competition with MPO, respectively. We divided 30 MPO-ANCA-associated microscopic polyangiitis patients into 2 groups based on their ANCA affinity levels (IC50 for the high: 0.11 ± 0.04 µg/mL (Group1) and IC50 for the low: 0.66 ± 0.24 µg/mL (Group2)). Group1 showed a higher Birmingham vasculitis activity score (15.6 ± 5.7) and 73% of the patients presented clinically with rapidly progressive glomerulonephritis and histologically with focal/crescentic glomerulonephritis (GN). Group 2 showed a lower Birmingham vasculitis activity score (9.2 ± 4.9) and 73% of the patients presented clinically with chronic renal failure and histologically with mixed/sclerotic GN. Group 1 showed a much higher occurrence of NETs than Group 2. Our findings indicate that ANCA affinity was associated with the in vivo formation of NETs, which might be involved in the pathophysiology of patients with MPO-ANCA-associated microscopic polyangiitis.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Trampas Extracelulares/inmunología , Riñón/inmunología , Poliangitis Microscópica/inmunología , Neutrófilos/inmunología , Peroxidasa/inmunología , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Biomarcadores/sangre , Biopsia , Citrulina/análisis , Ensayo de Inmunoadsorción Enzimática , Trampas Extracelulares/química , Femenino , Técnica del Anticuerpo Fluorescente , Histonas/análisis , Humanos , Hidrolasas/análisis , Riñón/química , Riñón/patología , Masculino , Poliangitis Microscópica/metabolismo , Poliangitis Microscópica/patología , Persona de Mediana Edad , Neutrófilos/química , Valor Predictivo de las Pruebas , Arginina Deiminasa Proteína-Tipo 4 , Desiminasas de la Arginina ProteicaRESUMEN
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti-aquaporin-4-positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice.
Asunto(s)
Técnicas de Inmunoadsorción , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/terapia , Enfermedad Aguda , Adulto , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/aislamiento & purificación , Enfermedad Crónica , Humanos , Masculino , Fuerza Muscular , Neuromielitis Óptica/fisiopatología , Intercambio Plasmático , Plasmaféresis , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
Microscopic polyangiitis (MPA) is an ANCA-associated vasculitis that affects small vessels, especially renal glomeruli. We recently demonstrated that the abnormal formation and impaired degradation of neutrophil extracellular traps (NETs) may be crucially involved in the generation of myeloperoxidase (MPO)-ANCA and subsequent development of MPA. This study assessed the formation and regulation of NETs in patients with MPO-ANCA-associated MPA. Peripheral blood samples were obtained from 38 patients with MPO-ANCA-associated MPA, 23 patients with systemic lupus erythematosus (SLE), and 8 healthy controls. IgG eluted from MPO-ANCA-associated MPA sera demonstrated the highest ability to induce NETs, and this ability correlated with disease activity and paralleled ANCA affinity for MPO. Moreover, addition of recombinant human MPO to these IgG samples reduced NET induction. Additionally, MPO-ANCA-associated MPA sera exhibited lower rates of NET degradation that recovered partially upon depletion of IgG. The activity of DNase I, an important regulator of NETs, was also lower in MPO-ANCA-associated MPA and SLE sera. IgG depletion from MPO-ANCA-associated MPA sera partially restored the rate of NET degradation, and addition of DNase I synergistically enhanced this restoration. Addition of anti-MPO antibodies did not inhibit DNase I activity, and some MPO-ANCA-associated MPA sera contained anti-NET antibodies at levels not correlated with MPO-ANCA titers, suggesting the involvement of unidentified autoantibodies as well. The collective evidence suggests a vicious cycle involving MPO-ANCA and the regulation of NETs could be critically involved in the pathogenesis of MPO-ANCA-associated MPA.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/biosíntesis , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/fisiología , Poliangitis Microscópica/inmunología , Neutrófilos/inmunología , Peroxidasa/metabolismo , Regulación hacia Arriba/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Afinidad de Anticuerpos , Estudios de Casos y Controles , Desoxirribonucleasa I/metabolismo , Femenino , Humanos , Masculino , Poliangitis Microscópica/enzimología , Persona de Mediana Edad , Neutrófilos/enzimologíaRESUMEN
We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Peroxidasa/inmunología , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Pueblo Asiatico , Ciclofosfamida/uso terapéutico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Japón , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: para-Cresol, which is present in the blood mainly as p-cresyl sulphate, is a protein-bound uraemic toxin that is produced in the intestine by certain intestinal bacteria, and its production is affected by various intestinal environmental factors. Patients with end-stage renal disease who are undergoing haemodialysis (HD) often have defective bowel function leading to abnormal defecation. Since treatment with synbiotics (SYN), which are a combination of probiotics and prebiotics, is reported to improve bowel habit, we examined the effects of SYN on the serum p-cresol level in HD patients. METHODS: Nine HD patients received SYN (Lactobacillus casei strain Shirota and Bifidobacterium breve strain Yakult as probiotics and galacto-oligosaccharides as prebiotics) three times a day for 2 weeks. The duration of the study was 4 weeks (2 weeks of pretreatment observation and 2 weeks of treatment). The subjects were asked to complete a questionnaire about their bowel habits (defecation frequency, stool quantity, stool form and ease of defecation) during the study period. Serum p-cresol levels before and after SYN treatment were determined. RESULTS: According to the questionnaire conducted during the pretreatment observation period, HD patients with a high serum p-cresol level tended to have hard stools with difficulty in defecation. With SYN treatment, stool quantity increased significantly and hard, muddy or soft stools tended to be replaced by normal ones. The serum p-cresol level also decreased significantly. CONCLUSIONS: It was found that uraemic toxin, p-cresol, was associated with constipation and that SYN treatment resulted in normalization of bowel habits and a decrease of serum p-cresol levels in HD patients. Therefore, SYN treatment may be anticipated to reduce the toxic effect of p-cresol in HD patients.
Asunto(s)
Cresoles/sangre , Fallo Renal Crónico/terapia , Diálisis Renal , Simbióticos/estadística & datos numéricos , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Rechazo de Injerto/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Encuestas y Cuestionarios , Tasa de SupervivenciaRESUMEN
Beta-glucan is a major component of fungal cell walls and shows various immunopharmacological activities including antitumor activity. Previously, we detected anti-beta-glucan antibody in human sera. Anti-beta-glucan antibody participates in the immune response to fungal cell wall beta-glucan. Patients on dialysis are at high risk of infection including fungal infections. We examined the plasma beta-glucan level and the titer of anti-beta-glucan antibody in dialysis patients. We measured plasma beta-1,3-glucan concentrations with the limulus G test and anti-beta-glucan antibody titers by ELISA with Candida beta-glucan-coated plates. We also examined the influence of the period of dialysis and the kind of dialysis membrane. The patients were positive for beta-1,3-glucan in their plasma. The anti-beta-glucan antibody titer was lower in the dialysis patients than in healthy volunteers. Long-term dialysis patients showed lower anti-beta-glucan antibody titers than short-term dialysis patients. No significant difference was found between the kinds of dialysis membrane. The titer of anti-beta-glucan antibody as recognition molecule of beta-glucan was low in dialysis patients compared with healthy volunteers. This is likely to be one factor explaining the sensitivity to infection of the dialysis patients. An appropriate application of culinary-medicinal mushroom such as Agaricus brasiliensis has potential for the prevention of fungal infection in dialysis patients.
Asunto(s)
Agaricus/inmunología , Anticuerpos Antifúngicos/sangre , Pared Celular/inmunología , beta-Glucanos/sangre , beta-Glucanos/inmunología , Anciano , Anticuerpos Antifúngicos/inmunología , Aspergillus niger/química , Aspergillus niger/inmunología , Candida/inmunología , Candida albicans/química , Candida albicans/inmunología , Femenino , Humanos , Fallo Renal Crónico/inmunología , Fallo Renal Crónico/microbiología , Prueba de Limulus , Masculino , Persona de Mediana Edad , Micosis/inmunología , Micosis/prevención & control , Diálisis RenalRESUMEN
BACKGROUND: Tonsillectomy and steroid pulse (TSP) therapy was proposed as a curative treatment for IgA nephropathy by Hotta et al. (Am J Kidney Dis 38:736-742, 2001) based on data that about 50% of patients achieved clinical remission (CR) of urinary abnormalities. MATERIALS AND METHODS: As a primary survey, we sent a questionnaire and letter to 848 hospitals in Japan, each of which employed a Fellow of the Japanese Society of Nephrology between October and December of 2006, in order to gather information about the prevalence and efficacy of TSP therapy for patients with IgA nephropathy. As a secondary survey, we collected data from both low- and high-CR-rate groups to determine which factors predicted resistance to TSP therapy. RESULTS: A total of 2,746 patients received TSP therapy between 2000 and 2006. The CR rates, calculated by measuring urinary criteria 6 and 12 months after TSP therapy, were 32.0% (347/1,085) and 45.6% (452/991), respectively. Analysis of the 30 hospitals in which TSP therapy had been performed on at least ten patients revealed that the CR rates varied from below 10% to 100%. A secondary survey of ten hospitals revealed that, after correction of the CR rate from each hospital, patients could be categorized into three groups: those with a low CR rate (122 patients in four hospitals), a middle CR rate (78 patients in four hospitals), and a high CR rate (103 patients in two hospitals). The CR rate of all patients (N = 303) was 54.1%. A comparison of patient data between the low- and high-CR-rate groups showed a significant difference in age at onset (years; P = 0.05), amount of proteinuria (g/day; P = 0.02), total protein (g/dl; P = 0.02), pathological grade (P = 0.009), and prognostic score as described by Wakai et al. [Nephrol Dial Transplant 21:2800-2808, 2006, (P = 0.04)]. Univariate analysis revealed that there was a significant difference between non-CR and CR subgroups in duration from diagnosis until TSP therapy (6.9 +/- 6.8 versus 5.3 +/- 5.2 years; P = 0.02), amount of proteinuria (1.5 +/- 1.6 versus 0.8 +/- 0.8 g/day; P < 0.0001), serum creatinine (0.99 +/- 0.40 versus 0.87 +/- 0.34 mg/dl; P = 0.006), pathological grade (P = 0.0006), and Wakai et al.'s prognostic score (37.4 +/- 17.8 versus 28.1 +/- 15.1; P < 0.0001). A multivariate logistic analysis demonstrated that resistance to TSP therapy depends on age at onset, amount of proteinuria, hematuria grade, and pathological grade, and a score predicting resistance to TSP therapy could be derived by the formula: [(-0.0330) x (age) + (0.4772) x log (amount of proteinuria) - (0.0273) x (hematuria grade: 0, 1, 2, and 3) + (0.7604) x (pathological grade: 1, 2, 3, and 4) - 0.1894]. A receiver operating characteristic (ROC) curve showed that patients with a resistance score of greater than -0.02 easily resist TSP therapy (sensitivity 69%, specificity 75%, positive likelihood ratio 2.76). CONCLUSION: TSP therapy shows promise as a treatment that can bring about CR of urinary abnormalities, but unfortunately the average CR rate is about 50% at 1 year after treatment. Predictive factors for resistance to TSP therapy are age at onset, amount of proteinuria, hematuria grade, and pathological grade. The present study suggests that patients with either early-stage or mild to moderate IgA nephropathy easily achieve CR following TSP therapy, whereas patients with late-stage or severe disease are prone to TSP therapy resistance.
Asunto(s)
Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/cirugía , Esteroides , Tonsilectomía , Adolescente , Adulto , Terapia Combinada , Recolección de Datos , Femenino , Glomerulonefritis por IGA/patología , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Curva ROC , Inducción de Remisión , Esteroides/administración & dosificación , Esteroides/uso terapéutico , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The optimal cutoff value of fractional flow reserve (FFR) derived from coronary computed tomography angiography (FFRCT) remains unclear. METHODS: The current study population consisted of 93 patients with 139 vessels, who had suspected coronary artery disease by computed tomography angiography and underwent invasive FFR. We evaluated diagnostic performance of FFRCT according to different FFRCT cutoff values and FFRCT ranges with invasive FFR ≤0.80 as the reference standard. RESULTS: In per-vessel analysis, median invasive FFR was 0.85 (interquartile range, 0.75-0.90), and 57 out of 139 vessels (41%) showed hemodynamically significant stenosis (≤0.80). Median FFRCT was 0.77 (interquartile range, 0.66-0.84; mean difference [invasive FFR-FFRCT], 0.06±0.11). Per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 73%, 95%, 59%, 61%, and 94% for the cutoff value of FFRCT ≤0.80, 81%, 86%, 78%, 73%, and 89% for FFRCT ≤0.75, and 83%, 74%, 89%, 82%, and 83% for FFRCT ≤0.70, respectively. Per-vessel accuracy across the different ranges of FFRCT ≤0.60, 0.61 to 0.70, 0.71 to 0.80, 0.81 to 0.90, and >0.90 with the cutoff value of FFRCT ≤0.80 were 95%, 74%, 32%, 93%, and 100%, respectively. Setting a gray zone of FFRCT 0.71 to 0.80 provided high positive predictive value (82%; n=42/51) in the range of FFRCT ≤0.70 and high negative predictive value (94%; n=48/51) in FFRCT >0.80. CONCLUSIONS: This study suggested that referral to invasive coronary angiography should be considered individually in the range of FFRCT 0.71 to 0.80, whereas dichotomous decision could be made in FFRCT ≤0.70 and >0.80. Future prospective studies evaluating clinical outcomes are needed to establish optimal FFRCT-based diagnostic algorithm.
Asunto(s)
Angiografía por Tomografía Computarizada/métodos , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Reserva del Flujo Fraccional Miocárdico , Anciano , Femenino , Humanos , Masculino , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Leptin is a small peptide hormone which centrally regulates weight. Leptin receptor (OB-R) is expressed in hematopoietic cells, the central nervous, and immune systems. OB-R bears a homology similar to members of the class Iota cytokine family, and therefore, leptin appears to modulate immune responses. The aim of this study was to examine the effect of plasma leptin, soluble OB-R (sOB-R), and the free leptin index (FLI), the ratio between leptin and sOB-R levels, on the sensitivities of peripheral blood mononuclear cells (PBMCs) to prednisolone and cyclosporine in 16 healthy subjects and seven nephrotic syndrome (NS) patients. The NS patients had significantly higher serum sOB-R and lower FLI, compared with the healthy subjects (respectively, P=0.0026, P=0.0383). Whereas, the NS patients had significantly lower PBMC sensitivity to prednisolone (P=0.0049). PBMCs sensitivity to cyclosporine was not significantly different between the healthy subjects and the NS patients. In addition, when the data from all subjects were analyzed, there was a significantly positive correlation between plasma sOB-R concentrations and the IC50 values of prednisolone (P=0.0478). In contrast, plasma leptin concentrations and FLIs did not correlate significantly with the prednisolone and cyclosporine IC50 values. From these observations it can be suggested that plasma leptin has little effect on PBMC sensitivity to immunosuppressive drugs in NS patients. Molecular background(s) for the influence of sOB-R on the PBMC sensitivity to glucocorticoids remain(s) to be elucidated.
Asunto(s)
Inmunosupresores/farmacología , Leptina/sangre , Síndrome Nefrótico/sangre , Prednisolona/farmacología , Receptores de Leptina/sangre , Adulto , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections. RESULTS: The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1-8.5). CONCLUSION: One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/mortalidad , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Administración Oral , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Japón , Fallo Renal Crónico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Estudios Prospectivos , Recurrencia , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
A simple and rapid method using refractive index high-performance liquid chromatography (RI-HPLC) was developed for the determination of polysorbates (PS) in processed foods. PS were extracted with ethyl acetate containing 5% methanol. The extract was cleaned up on a multimode cartridge (300 mg) and an Alumina-N cartridge (500 mg) to remove fats and food color. HPLC separation was performed on a C18 column (4.6 i.d. x 150 mm) with methanol as the mobile phase. The recoveries of PS80 from nine kinds of foods fortified at the levels 1-5 g/kg were 80-99%. The limit of quantitation for PS80 in foods was 0.10 g/kg. The proposed method was applied to Worcestershire sauce that was PS-positive by TLC, and PS was confirmed to be present as PS80 at the concentration of 0.13 g/kg.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Polisorbatos/análisis , Análisis de los Alimentos/métodosRESUMEN
Successful immunosuppressive therapy is critical for the treatment of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and nephrosis. However, a considerable number of patients have shown clinical resistance to therapy. Bacterial infection might influence the clinical response of patients to immunosuppressive drugs, but few studies have been carried out to investigate the effect of bacterial superantigens on the efficacy of the drugs in these patients. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the blastogenesis of PBMCs obtained from 12 ANCA-associated vasculitis patients (ANCA patients), eight patients with nephrotic syndrome, and eight healthy subjects. PBMC-stimulation index was calculated from the formula: [3H]thymidine incorporated in the presence of stimulant (dpm)/[3H]thymidine incorporated in the absence of stimulant (dpm). In vitro drug concentrations giving 50% inhibition (IC50s) of PBMC blastogenesis stimulated with concanavalin A (con A) or toxic shock syndrome toxin 1 (TSST-1) derived from Staphylococcus aureus (S. aureus) were calculated. The IC50 values for the four drugs evaluated in TSST-1-stimulated PBMCs were significantly higher than those evaluated in con A-stimulated PBMCs in both ANCA patients and nephrosis patients (p<0.012-0.044). Whereas, the IC50 values for these immunosuppressive drugs, except methylprednisolone, were not significantly different between con A- and TSST-1-stimulated PBMCs in healthy subjects. The stimulation index was not significantly different between the con A- and TSST-1-stimulated PBMCs in either of the subject groups. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in ANCA patients and nephrosis patients.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/sangre , Toxinas Bacterianas/farmacología , Enterotoxinas/farmacología , Inmunosupresores/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Superantígenos/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Calcineurina , Proliferación Celular/efectos de los fármacos , Concanavalina A/farmacología , Ciclosporina/farmacología , Femenino , Glucocorticoides/farmacología , Humanos , Concentración 50 Inhibidora , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/patología , Activación de Linfocitos/efectos de los fármacos , Masculino , Metilprednisolona/farmacología , Persona de Mediana Edad , Nefrosis/sangre , Nefrosis/patología , Prednisolona/farmacología , Tacrolimus/farmacología , Vasculitis/sangre , Vasculitis/patologíaRESUMEN
We have recently detected an anti-beta-glucan antibody in normal human and normal mouse sera. The anti-beta-glucan antibody showed reactivity to pathogenic fungal Aspergillus and Candida cell wall glucan. Anti-beta-glucan antibody could bind whole Candida cells. It also enhanced the candidacidal activity of macrophages in vitro. The anti-beta-glucan antibody titer of DBA/2 mice intravenously administered either Candida or Aspergillus solubilized cell wall beta-glucan decreased remarkably dependent on dose. Moreover, in deep mycosis patients, the anti-beta-glucan antibody titer decreased, and this change correlated with clinical symptoms and other parameters such as C-reactive protein. It was suggested that the anti-beta-glucan antibody formed an antigen-antibody complex and participated in the immune response as a molecule recognizing pathogenic fungi.
Asunto(s)
Anticuerpos Antifúngicos/sangre , Aspergillus/inmunología , Candida/inmunología , beta-Glucanos/inmunología , Animales , Especificidad de Anticuerpos , Complejo Antígeno-Anticuerpo , Antígenos Fúngicos , Aspergilosis/inmunología , Aspergilosis/microbiología , Aspergillus/patogenicidad , Candida/patogenicidad , Candidiasis/inmunología , Candidiasis/microbiología , Pared Celular/inmunología , Femenino , Humanos , Inmunidad Innata , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos DBAAsunto(s)
Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/inmunología , Inmunosupresores/administración & dosificación , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/inmunología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Ciclofosfamida/administración & dosificación , Ciclosporina/administración & dosificación , Esquema de Medicación , Humanos , Inmunosupresores/efectos adversos , Mercaptopurina/administración & dosificación , Mercaptopurina/análogos & derivados , Metilprednisolona/administración & dosificación , Prednisolona/administración & dosificación , Inducción de Remisión , Rituximab , Tacrolimus/administración & dosificaciónRESUMEN
BACKGROUND: High blood cholesterol concentrations in patients with minimal change nephrotic syndrome may affect cyclosporine (INN, ciclosporin) pharmacodynamics and its clinical efficacy, but few attempts have been carried out to disclose this problem. METHODS: We evaluated the cellular pharmacodynamics of cyclosporine in 24 patients with minimal change nephrotic syndrome. In vitro cyclosporine concentrations yielding 50% inhibition (IC(50)) of blastogenesis of peripheral blood mononuclear cells (PBMCs) stimulated with concanavalin A were calculated. The relationships between the IC(50) values and laboratory data including serum total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations were examined. Clinical cyclosporine efficacy was assessed by a decreasing rate (percentage) of urinary protein 1 week after cyclosporine therapy. Percentages of LDL receptor-positive or CD3-positive PBMCs were evaluated with flow cytometry in 7 patients and 15 healthy subjects. RESULTS: The cyclosporine IC(50) values negatively correlated with the clinical cyclosporine efficacy assessed by a decreasing rate of urinary protein (r = -0.708, P =.0006). Cyclosporine IC(50) values significantly correlated with either serum total cholesterol (r = 0.681, P =.0003) or LDL cholesterol (r = 0.751, P =.0034) concentrations. Furthermore, serum total or LDL cholesterol levels significantly correlated negatively with clinical cyclosporine efficacy (r = -0.613, P =.0057, and r = -0.773, P =.0399, respectively). In 7 patients, serum total and LDL cholesterol concentrations were significantly higher than those of 15 healthy subjects (P <.005), whereas the percentages of LDL receptor-expressing cells in CD3-enriched PBMCs were not significantly different between these patients and healthy subjects. In addition, the cyclosporine IC(50) values and the percentages of LDL receptor-expressing PBMCs did not negatively correlate in either the patients or the healthy subjects. CONCLUSIONS: The data raised the possibility that hypercholesterolemia in patients with minimal change nephrotic syndrome attenuates cellular and clinical cyclosporine pharmacodynamics. Down-regulation of LDL receptor in T cells was not observed in these patients, and individual deviation of PBMC response to cyclosporine does not appear to be related to the difference of LDL receptor-positive cell numbers.
Asunto(s)
Colesterol/sangre , Ciclosporina/farmacología , Inmunosupresores/farmacología , Nefrosis Lipoidea/metabolismo , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Ciclosporina/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , MasculinoRESUMEN
ANCA are associated with small sized vessel vasculitis; one subtype is an antibody against myeloperoxidase(MPO), which stains in a perinuclear pattern(P-ANCA) indirect immunofluorescence(IIF) using a neutrophil substrate, and the other subtype is an antibody against proteinase-3(PR-3), which stains in a diffuse granular cytoplasmic pattern ANCA by IIF. PR-3 ANCA is more specific in Wegener's granulomatosis(WG) than the other primary vasculitides. MPO-ANCA can be found in microscopic polyangiitis (MPA), Churg Strauss Syndromes(CSS), drug-induced vasculitis, and environmental factor-induced such as silicosis vasculitis more frequently than WG. The value of the IIF test for ANCA detection can be greatly increased by the addition of a standardized antigen-specific ELISA. The intra-assay and inter-assay CV of the MPO and PR-3 ELISA were 6.6 to 4.8%, respectively. Close ANCA titer correlation was shown between MPO-ANCA ELISA and the activity of ANCA associated vasculitis. Renal manifestations and pulmonary manifestations are observed in 70-90% of AAV as the initial manifestation. The changes in titers of ANCA seem to reflect disease activity in 60-70% of AAV patients. A combination of steroids and immunosuppressive drugs is effective in relieving the clinical symptoms of AAV.