Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study.

OBJECTIVE: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. METHOD: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). RESULTS: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = -0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. CONCLUSIONS: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.

Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan.

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

Complete renal response at 12 months after induction therapy is associated with renal relapse-free rate in lupus nephritis: a single-center, retrospective cohort study.

BACKGROUND: Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in systemic lupus erythematosus (SLE). METHODS: We retrospectively analyzed cases of proliferative and membranous LN patients who underwent a renal biopsy at our hospital in 1993-2016. We analyzed the association between complete renal response (CR) rates at 12 months after induction therapy and predictive factors for CR and their association with renal flares. RESULTS: Of the 95 cases analyzed, we were able to track the therapeutic responses of 81 patients at 12 months after their induction therapy. The median follow-up duration after renal biopsy was 51 months (interquartile range: 16.5-154.5 months). The Cox proportional hazards model showed that, compared to not attaining CR at 12 months, the attainment of CR at 12 months was correlated with being free from renal flares. The multivariate logistic analysis revealed that the predictive factors for CR at 12 months were the anti-La/SSB antibodies (U/ml) (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.63, p = 0.0220), blood urea nitrogen (BUN) (OR 0.68, 95% CI 0.44-0.90, p = 0.00048) and serum ß2 microglobulin (MG) (OR 0.26, 95% CI 0.06-0.74, p = 0.00098) levels. CONCLUSIONS: Among LN patients, being free from renal flares was associated with attaining CR at 12 months after induction therapy. Anti-La/SSB antibodies were a positive predictive factor, and BUN and serum ß2MG levels were negative predictive factors of CR at 12 months.

Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.

BACKGROUND: Lupus nephritis (LN) is a major determinant of mortality in systemic lupus erythematosus (SLE). Here we evaluated the association between complete renal response (CR) and mortality in LN. METHODS: We retrospectively analyzed the cases of 172 of 201 patients with LN for whom data on the therapeutic response at 6 and 12 months after induction therapy were available. The patients underwent a renal biopsy at Nagasaki University Hospital and community hospitals in Nagasaki between the years 1990 and 2016. We determined the CR rates at 6 and 12 months after induction therapy initiation and evaluated the predictive factors for CR and their relationship with mortality. We performed univariate and multivariable competing risks regression analyses to determine the factors predictive of CR. The patients' survival data were analyzed by the Kaplan-Meier method with a log-rank test. RESULTS: The median follow-up duration after renal biopsy was 120 months (interquartile range: 60.3-191.8 months). The 5-, 10-, 15- and 20-year survival rates of our cohort were 99.3, 94.6, 92.0 and 85.4%, respectively. During follow-up, nine patients (5.2%) died from cardiovascular events, infection, malignancy and other causes. The multivariate analysis revealed that the following factors were predictive of CR. At 6 months: male gender (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.08-0.65, p = 0.0028), proteinuria (g/gCr) (OR 0.83, 95% CI 0.71-0.97, p = 0.0098) and index of activity (0-24) (OR 0.84, 95% CI 0.71-0.99, p = 0.0382). At 12 months: male gender (OR 0.25, 95% CI 0.09-0.67, p = 0.0043) and index of activity (0-24) (OR 0.82, 95% CI 0.69-0.98, p = 0.0236). The Kaplan-Meier analysis showed that compared to not achieving CR at 12 months, achieving CR at 12 months was significantly correlated with the survival rate (OR 0.18, 95% CI 0.04-0.92, p = 0.0339). CONCLUSIONS: Our results suggest that the survival rate of patients with LN is associated with the achievement of CR at 12 months after induction therapy, and that male gender and a higher index of activity (0-24) are the common predictive factors for failure to achieve CR at 6 and 12 months.

Association of distinct clinical subsets with myositis-specific autoantibodies towards anti-155/140-kDa polypeptides, anti-140-kDa polypeptides, and anti-aminoacyl tRNA synthetases in Japanese patients with dermatomyositis: a single-centre, cross-sectional study.

OBJECTIVE: To determine the association of distinct clinical subsets with myositis-specific autoantibodies (MSAs) towards anti-155/140-kDa polypeptides [anti-155/140 antibodies (Abs)], anti-140-kDa polypeptides (anti-140 Abs), and anti-aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). METHODS: We compared the clinical features and short-term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. RESULTS: Anti-155/140 Abs (n = 5), anti-140 Abs (n = 8), and anti-ARS Abs (n = 7) did not overlap each other. All of the anti-155/140 Ab-positive patients (n = 5) were complicated by malignancies, as were all of the anti-140 Ab-positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti-140 Ab-positive patients than in the other patients. CONCLUSION: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti-155/140 Ab-positive group, an anti-140 Ab-positive group, or an anti-ARS Ab-positive group. Our data also confirm previous evidence that anti-155/140 Abs are involved in malignancies and that anti-140 Abs are involved in rapidly progressive ILD.

Endostatin peptide, an inhibitor of angiogenesis, prevents the progression of peritoneal sclerosis in a mouse experimental model.

Peritoneal sclerosis is a major and serious complication in patients on long-term continuous ambulatory peritoneal dialysis (PD). The involvement of angiogenesis and proangiogenic factors such as vascular endothelial growth factor (VEGF)-A in progressing peritoneal sclerosis has been reported. We previously reported the therapeutic efficacy of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in a mouse diabetic nephropathy model. Here, we examined the therapeutic effect of endostatin peptide in preventing progression in a mouse peritoneal sclerosis model. Male ICR mice received intraperitoneal injections of chlorhexidine gluconate (CG) every other day to induce peritoneal sclerosis. Endostatin peptide (1 or 4 mg/kg/day) was administered via subcutaneously implanted osmotic minipumps. Peritoneal sclerosis (day 24) was significantly suppressed by endostatin peptide in a dose-dependent manner. Peritoneal accumulation of type III collagen was significantly suppressed by endostatin peptide. Increase in the number of CD31(+) blood vessels, F4/80(+) monocyte/macrophage accumulation, and 5-bromodeoxyuridine(+) proliferating cells was significantly inhibited by endostatin peptide. Increase in peritoneal expression of VEGF-A, profibrotic transforming growth factor-beta1, and alpha-smooth muscle actin was suppressed by endostatin peptide. Immunoreactivity for endogenous endostatin (whole molecule) and endostatin receptor alpha5beta1-integrin was increased and colocalized to CD31(+) blood vessels in the thickened peritonea of CG-injected mice. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in preventing peritoneal sclerosis, a severe complication in patients undergoing long-term PD.

Resistance of CD4-positive T lymphocytes to etoposide-induced apoptosis mediated by upregulation of Bcl-xL expression in patients with HTLV-I-associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) is characterized by chronic inflammation of the spinal cord. The exact mechanisms that enhance the development of chronic myelopathy remain to be determined. One such mechanism could be an altered response of peripheral blood CD4(+) T lymphocytes to apoptotic stimuli. We examined the sensitivity of these cells to apoptosis in HAM patients and control. Apoptosis was induced by etoposide, which induces mitochondria-dependent apoptosis through the release of cytochrome c from the mitochondria. The percentage of apoptotic cells that expressed hypodiploid DNA among etoposide-treated CD4(+) T lymphocytes was significantly lower in HAM patients than in the control. Western blot analysis of cell lysates derived from CD4(+) T lymphocytes demonstrated that the expression level of Bcl-xL protein was significantly higher in HAM patients than in the control. Our results indicate that peripheral blood CD4(+) T lymphocytes of HAM patients are resistant to apoptosis triggered through mitochondrial death pathway through upregulation of expression of anti-apoptotic protein, Bcl-xL. This phenomenon might contribute to the prolongation and perpetuation of the chronic inflammatory process in the spinal cord of HAM patients.

The NDP-sugar co-substrate concentration and the enzyme expression level influence the substrate specificity of glycosyltransferases: cloning and characterization of deoxysugar biosynthetic genes of the urdamycin biosynthetic gene cluster.

BACKGROUND: Streptomyces fradiae is the principal producer of urdamycin A. The antibiotic consists of a polyketide-derived aglycone, which is glycosylated with four sugar components, 2x D-olivose (first and last sugar of a C-glycosidically bound trisaccharide chain at the 9-position), and 2x L-rhodinose (in the middle of the trisaccharide chain and at the 12b-position). Limited information is available about both the biosynthesis of D-olivose and L-rhodinose and the influence of the concentration of both sugars on urdamycin biosynthesis. RESULTS: To further investigate urdamycin biosynthesis, a 5.4 kb section of the urdamycin biosynthetic gene cluster was sequenced. Five new open reading frames (ORFs) (urdZ3, urdQ, urdR, urdS, urdT) could be identified each one showing significant homology to deoxysugar biosynthetic genes. We inactivated four of these newly allocated ORFs (urdZ3, urdQ, urdR, urdS) as well as urdZ1, a previously found putative deoxysugar biosynthetic gene. Inactivation of urdZ3, urdQ and urdZ1 prevented the mutant strains from producing L-rhodinose resulting in the accumulation of mainly urdamycinone B. Inactivation of urdR led to the formation of the novel urdamycin M, which carries a C-glycosidically attached D-rhodinose at the 9-position. The novel urdamycins N and O were detected after overexpression of urdGT1c in two different chromosomal urdGT1c deletion mutants. The mutants lacking urdS and urdQ accumulated various known diketopiperazines. CONCLUSIONS: Analysis of deoxysugar biosynthetic genes of the urdamycin biosynthetic gene cluster revealed a widely common biosynthetic pathway leading to D-olivose and L-rhodinose. Several enzymes responsible for specific steps of this pathway could be assigned. The pathway had to be modified compared to earlier suggestions. Two glycosyltransferases normally involved in the C-glycosyltransfer of D-olivose at the 9-position (UrdGT2) and in conversion of 100-2 to urdamycin G (UrdGT1c) show relaxed substrate specificity for their activated deoxysugar co-substrate and their alcohol substrate, respectively. They can transfer activated D-rhodinose (instead of D-olivose) to the 9-position, and attach L-rhodinose to the 4A-position normally occupied by a D-olivose unit, respectively.

Selective uptake by cancer cells of liposomes coated with polysaccharides bearing 1-aminolactose.

We investigated the selective uptake of liposomes chemically modified by polysaccharides-cholesterol derivatives with 1-aminolactose (lactose) in two human hepatoma cell lines (HUH7 and Alexander), a human colon cancer cell line (FCC) and a human lung cancer cell line (KNS). The uptakes of the labeled liposomes alone (conventional liposomes), those with cholesterol pullulan (CHP) and with lactose (lactose CHP) were compared in four cancer cells and normal rat hepatocytes after 3 hours of incubation. The radioactivities of the lactose CHP were 4.4, 4, 3.4 and 4.4 times greater than those of CHP in HuH7, Alexander, FCC and KNS cells, respectively, after 3 hours of incubation. All the above differences were statistically significant (p < 0.01). No statistically significant differences were seen in the case of hepatocytes. Thus, cancer cells have a common affinity with lactose CHP liposomes, however, these mechanisms appear to have no connection with the galactose-specific asialoglycoprotein receptors of hepatocytes.

Antitumor activity of dextran derivatives immobilizing platinum complex (II).

The in vivo antitumor activity and toxicity of a newly synthesized polymeric prodrug of cisplatin was investigated and also compared with plain cisplatin. The prodrug included a dicarboxymethyl-dextran conjugate of cisplatin (DCM-Dex/CDDP). DCM-Dex/CDDP was i.v. injected in mice bearing s.c. Colon 26 mouse colon cancer cells. The tissue distribution of platinum was thereafter determined by flameless atomic absorption spectrophotometry. The platinic concentration of the organs showed a high rate of retention at 24 h after injection in the DCM-Dex/CDDP-treated mice. No biochemical or hematologically adverse effects were observed. In addition, DCM-Dex/CDDP showed a significantly higher antitumor activity than cisplatin alone. These results indicate that DCM-Dex/CDDP may therefore be a potentially effective cancer chemotherapy.

[Localized right atrial tamponade after aortic valve replacement].

A 78-year-old man developed isolated right atrial tamponade 15 hours following aortic valve replacement. There were excessive postsurgical bleeding, low blood pressure, and low cardiac output. Volume expansion and inotropic therapy did not increase blood pressure. There were no cardiomegaly and echo-free space. Diagnosis was made by appearance of pulsus paradoxus and transthoracic echocardiography and confirmed by surgery. The clinical picture was improved dramatically after surgical removal of the hematoma. Right atrial tamponade leads to a unique clinical conglomeration of hemodynamic and echocardiographic features. Constant attention to this entity is necessary to make a timely diagnosis.

Utility of liposomes coated with polysaccharide bearing 1-amino-lactose as targeting chemotherapy for AH66 hepatoma cells.

The cell recognition element is very important for drug delivery systems. We synthesized cholesteryl pullulan (CHP) bearing 1-aminolactose (1-AL) and introduced a saccharide, cholesteryl pullulan bearing 1-aminolactose (1-AL/CHP), to an outer layer of the conventional liposome as a cell recognition element. Lectin recognized the beta-galactose by aggregation of 1-AL/CHP coated liposome (1-AL/CHP liposome). The uptake of this liposome to AH66 rat hepatoma cells was greater than in liposomes without 1-aminolactose in vitro. Furthermore, 1-AL/CHP liposomal adriamycin showed a stronger antitumor effect in comparison with other types of liposomal adriamycin in vitro. When in vivo tumor-targeting efficacy was investigated in AH66 tumor transplanted mice using 3H-liposome, the tumor/serum radioactivity ratio in mice injected with 1-AL/CHP liposome was higher than that of mice injected with other liposomes. These observations suggest that 1-AL is effective as a cell recognition element. As a result, 1-AL/CHP liposome is considered to be a good carrier of anticancer drugs for the active targeting of tumor cells.

Immunohistochemical demonstration of cytokeratin is useful for detecting micrometastatic foci from gallbladder carcinoma in regional lymph nodes.

BACKGROUND: The histological detection of lymph node metastasis in patients with gallbladder carcinoma is of major prognostic significance. However, it may be difficult to identify nodal involvement by conventional pathological examination of hematoxylin-eosin (HE)-stained sections when metastases are of microscopic size. In the present study, an attempt was made to detect lymph node metastasis precisely from gallbladder carcinoma, even by low-power microscopic examination, using immunohistochemistry with an anti-cytokeratin antibody. METHODS: A total of 431 lymph node specimens dissected during surgery from 33 patients with carcinoma of the gallbladder were investigated. A pair of mirror-image sections were obtained from each of the dissected lymph nodes and then stained using standard HE and immunohistochemical methods utilizing a monoclonal antibody against cytokeratin 7. The HE- and immunohistochemically stained sections were examined for the presence of tumor cells using light microscopy. RESULTS: All 78 lymph nodes from 12 patients with early gallbladder carcinoma were negative for both HE- and cytokeratin-positive cancer cells. Of 353 lymph nodes from 21 patients with advanced gallbladder carcinoma, HE staining showed that 98 were metastasis-positive. Among these 98 lymph nodes, 95 (97%) proved to be positive for metastasis based on cytokeratin immunostaining. On the other hand, the remaining 255 lymph nodes were cancer-free on the basis of HE staining results. Of the 255 HE-negative lymph nodes, seven (2.7%) were found to be positive for micrometastasis on the basis of cytokeratin staining. CONCLUSIONS: Cytokeratin staining of dissected lymph nodes is a useful new diagnostic tool for detecting micrometastatic foci in regional lymph nodes of patients with gallbladder carcinoma.

Detection of the pancreas-specific gene in the peripheral blood of patients with pancreatic carcinoma.

The prognosis of patients with pancreatic carcinoma remains very poor. To improve the therapeutic results, the early detection of this cancer is needed. The present study was performed to detect the pancreas-specific gene, chymotrypsinogen, in the peripheral blood from patients with pancreatic carcinoma by using reverse transcription polymerase chain reaction (RT-PCR) in order to evaluate the clinical significance of this gene. Ten patients with pancreatic carcinoma, two with acute pancreatitis, three with chronic pancreatitis and ten control subjects were examined for the presence of chymotrypsinogen using RT-PCR techniques in the peripheral blood. To confirm that the chymotrypsinogen gene was expressed in a pancreas-specific manner, the expression of chymotrypsinogen in various types of human adult tissue was evaluated by RT-PCR. The specific band of the chymotrypsinogen gene was detected in the pancreas. Serial dilution studies demonstrated the chymotrypsinogen gene to be detected at a concentration of one pancreatic cell per 10(6) peripheral blood cells. Seven out of the ten (70%) patients with pancreatic carcinoma were found to be positive based on the RT-PCR findings. In contrast, no pancreas-specific gene was detected in the peripheral blood of any patients with acute pancreatitis, chronic pancreatitis or the control subjects. Our observations show that the detection of the pancreatic specific gene, chymotrypsinogen, is therefore useful as a genetic diagnostic marker in pancreatic carcinoma.

In vitro characteristics and in vivo plasma disposition of cisplatin conjugated with oxidized and dicarboxymethylated dextrans.

In vitro release behavior and cytotoxic activity, and in vivo plasma disposition of newly synthesized macromolecular derivatives of cisplatin (CDDP) were investigated and compared with CDDP. The derivatives included oxidized dextran conjugate of CDDP (OX-Dex/CDDP) and dicarboxymethylated dextran conjugate of CDDP (DCM-Dex/CDDP). In vitro release of platinum complex from dextran conjugated CDDP was determined by an equilibrium dialysis method. These dextran conjugates showed sustained release of the platinum complex. In vitro release half-life for DCM-Dex/CDDP was significantly longer (4.5 times) than that for OX-Dex/CDDP. In vitro cytotoxic activity of CDDP and dextran conjugated CDDP against colon 26, mouse colon cancer cell line, was measured using the MTT assay method. OX-Dex/CDDP showed a similar cytotoxic activity to CDDP. However, both cytotoxic activities were markedly decreased when preincubated with the medium containing serum. On the other hand, DCM-Dex/CDDP retained residual cytotoxic activity at a significantly higher level than OX-Dex/CDDP after preincubation with the medium containing serum, although it showed the lowest cytotoxic activity. This indicated longer maintenance of the in vitro antitumor activity of DCM-Dex/CDDP in serum compared with OX-Dex/CDDP. Plasma disposition of CDDP and dextran conjugated CDDP was determined by intravenous administration to rats. Although the total platinum plasma concentration-time profile for OX-Dex/CDDP was similar to that for CDDP, its markedly higher profile was achieved when DCM-Dex/CDDP was administered. The values of the total platinum AUC and MRT, where AUC is the area under the platinum concentration-time curve and MRT is the mean residence time, for DCM-Dex/CDDP were 11.2 times and 4.8 times significantly higher than with OX-Dex/CDDP in plasma, respectively. DCM-Dex/CDDP also showed a significantly lower total clearance compared with OX-Dex/CDDP. These results from the in vivo experiments revealed that retention of DCM-Dex/CDDP in blood circulation was much greater than that for OX-Dex/CDDP. DCM-Dex/CDDP thus has potential as a macromolecular derivative of CDDP for passive tumor targeting.

[Recurrent transient increases in liver enzymes specifically after isoflurane anesthesia].

A 69 y-old female underwent orthopedic surgery 12 times in our hospital. A variety of agents were used for anesthesia. She developed episodes of transient increase in liver enzymes only after each of three isoflurane anesthesia (GOT : 311, 292, 328 IU.l-1, GPT: 341, 264, 274 IU.l-1). We suspected drug-induced liver dysfunction, but results of a lymphocyte stimulation test were negative. We conclude that her liver dysfunction was not severe enough to cause clinical symptoms. In such susceptible patients we should be careful of our choice of anesthetic drugs.

Antitumor effect of polysaccharide coated liposomal adriamycin on AH66 hepatoma in nude mice.

Drug delivery systems play a crucial role in cancer chemotherapy, not only in the achievement of sufficient tumoricidal effect but also in minimizing systemic side effects. We investigated the effect of liposomal adriamycin with tumor recognition molecule, 1-aminolactose (1-AL), on AH66 hepatoma transplanted into nude mice. Adriamycin (ADM) was encapsulated in liposome coating with cholesterol pullulan (CHP) to increase the stability in the blood stream. 1-AL was assembled to the outer layer of CHP-coated liposomal ADM as a tumor recognition molecule. In an in vivo therapeutic study. 1-AL/CHP-coated liposomal ADM restrained tumor growth more when compared with CHP-coated liposomal ADM. Thus, 1-AL/CHP-coated liposome seems to be a carrier of ADM to tumor cells.

Increased production of inflammatory cytokines in cultured CD4+ cells from patients with HTLV-I-associated myelopathy.

We investigated the production of inflammatory cytokines derived from cultured T cells of peripheral blood lymphocytes (PBL) in 14 patients with HTLV-I-associated myelopathy (HAM). The production of inflammatory cytokines, such as tumor necrosis factor-alpha, interferon-gamma, and granulocyte-macrophage colony stimulating factor, was significantly increased in patients with HAM, compared to HTLV-I seronegative controls. On the contrary, interleukin-4 production in cultured T cells was detected in only two patients with HAM, and not detected in HTLV-I seronegative controls. These results suggest that the production of inflammatory cytokines derived from TH1 cell population was simultaneously exaggerated in HAM patients. Interestingly, accelerated production of these cytokines was derived from CD4+ cells, which are main target cells in HTLV-I infection. These findings suggest that an inflammatory state in the central nervous system might be related to the pathogenesis of HAM.

Spontaneous proliferation of and cytokine production by T cells adherent to human endothelial cells in patients with human T-lymphotropic virus type I-associated myelopathy.

We previously reported increased adherence of T cells to human endothelial cells (EC) in patients with HTLV-I-associated myelopathy (HAM). To define the immunological function of EC-adherent T cells from HAM patients, we investigated the degree of spontaneous proliferation and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF). Both the degree of spontaneous proliferation and the production of TNF-alpha, IFN-gamma, and GM-CSF by EC-adherent T cells of HAM patients were significantly increased, compared to anti-HTLV-I seronegative controls. Furthermore, in HAM patients, spontaneous proliferation and production of inflammatory cytokines by EC-adherent T cells were significantly higher than that of EC-non-adherent T cells. Conversely, those functions of EC-non-adherent T cells were significantly lower than that of unseparated cells, which were T cells before application to EC. We demonstrated that EC-adherent T cells were qualitatively and quantitatively more hyperactive than those of anti-HTLV-I seronegative controls and the population of activated T cells of HAM patients was concentrated in EC-adherent T cells rather than in EC-non-adherent T cells. Our results suggest that EC-adherent T cells in the peripheral blood of HAM are intimately involved in the immunopathogenesis of HAM.