Incidence of CD4+ IL-2R alpha+ and CD4+ CD45RA+ T-cells in progressive multiple sclerosis and the influence of short-term (3 months) FK 506 therapy.
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Adult↗
Biomedical subjects
J Woo
Publications and source records attributed to J Woo.
Inhibitory effect of FK 506 on autoimmune thyroid disease in the PVG rat.
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Animals↗
FK 506: a novel immunosuppressant for treatment of autoimmune disease. Rationale and preliminary clinical experience at the University of Pittsburgh.
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Adult↗
Low bone mineral density, grip strength and skinfold thickness are important risk factors for hip fracture in Hong Kong Chinese.
The purpose of the study was to compare the bone mineral density (BMD) at the hip and spine, the grip strength and the skinfold thickness in Chinese hip fracture patients and controls, and to document the relative risk of hip fracture associated with different levels of these risk factors. The study was conducted on 163 elderly patients with hip fracture (32 men and 131 women) and 317 controls (104 men and 213 women). BMD at the hip and spine was measured by dual-energy X-ray densitometry (Norland NR26). The mean grip strength was measured in both hands by a hand dynamometer; and bicep, tricep and iliac skinfold thicknesses were measured by a caliper (Holstain). Student's t-test was used to compare the mean bone densities, recalled body weight, grip strength and skinfold thickness; and multiple logistic regression was used to calculate the relative risk and 95% confidence intervals in quartiles of bone density, grip strength and skinfold thickness. In women, the mean BMD and anthropometric measurements were significantly lower in patients than controls. However, in men the mean recalled body weight and measured skinfold thickness were not significantly different between patients and controls. In both men and women the relative risk of hip fracture increased significantly with diminishing bone density at the spine, femoral neck and intertrochanteric area, but not at the Ward's triangle. In women the relative risk of hip fracture also increased significantly with a low recalled body weight, grip strength and skinfold thickness.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Blood lymphocytes of autoimmune disease patients receiving FK506 exhibit normal ex vivo cytokine gene expression and proliferative responses.
It is well recognized that FK506 (Tacrolimus) is a powerful inhibitor of CD4+ T-cell activation and proliferation in vitro. In this study, immunophenotypic and functional analyses were performed on peripheral blood mononuclear cells from a total of 30 patients with various autoimmune disorders before and whilst the patients were receiving systemic FK506 therapy. The expression of cell surface IL-2R alpha and -beta on CD4+ and CD8+ cells, cytokine message (IL-2, IFN-gamma, IL-4, IL-10) and the proliferative activity of lymphocytes in response to rIL-2 were examined. Despite plasma levels of FK506 compatible with the blockade of IL-2 production by stimulated T cells in vitro, cells from patients on FK506 treatment cultured ex vivo with either ConA or IL-2 did not differ from normal cells in their expression of cytokine mRNA or their proliferative responses. These data indicate that the presumed in vivo suppression of T-cell function by FK506 is rapidly reversible ex vivo. Alternatively/additionally, they suggest that FK506 may mediate its in vivo action primarily by mechanisms other than blockade of T-cell function.
Adolescent↗
Lipids, lipoproteins and other coronary risk factors in Chinese male survivors of myocardial infarction.
OBJECTIVE: To assess the importance of an abnormal lipid profile as a risk factor in relation to non-biochemical risk factors, and to define the risk levels for lipid, lipoprotein and apolipoprotein in a Chinese population. PATIENTS AND METHODS: Serum lipids, lipoproteins, apolipoproteins and other cardiovascular risk factors were studied in 89 Chinese men 3 months after acute myocardial infarction and 56 controls. RESULTS: Cases had higher mean total cholesterol (TC), LDL- and VLDL-cholesterol, triglycerides and apolipoprotein B (Apo B), and lower mean HDL-cholesterol and apolipoprotein AI (Apo AI). Mean BMI was also higher, as was the prevalence of smokers and subjects with a history of hypertension. In univariate analysis, the odds ratios for TG > or = 1.6 mmol/l, LDL-cholesterol > or = 4.1 mmol/l, VLDL-cholesterol > or = 0.73 mmol/l, Apo B > or = 104 mg/dl were of the same order of magnitude as being a current smoker, having a BMI > or = 24.3 kg/m2, and a history of hypertension. High HDL-cholesterol (> or = 1.39 mmol/l) and Apo AI (> or = 139 mg/dl) were protective factors. The odds ratios for successively higher quartile values of cholesterol were not statistically significant. Multiple logistic regression identified smoking habit, history of hypertension, obesity, high Apo B and low Apo AI concentrations as independent risk factors for myocardial infarction. CONCLUSIONS: In a Chinese population, low serum Apo AI and high Apo B are risk factors for myocardial infarction of a comparable magnitude to smoking, hypertension and obesity.
Apolipoprotein A-I↗
The prevalence of diabetes mellitus and impaired glucose tolerance among Hong Kong Chinese adults of working age.
We studied 1513 employees (910 men and 603 women) from a public utility company and a regional hospital to document the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) in the Chinese working population of Hong Kong using a 75-g oral glucose tolerance test and World Health Organisation (1985) criteria. The overall prevalence of DM was 4.5 (95% confidence interval: 3.5-5.7%) and that of IGT 7.3 (6.0-8.6%). The prevalence of DM was 5.1 (3.7-6.5%) in men and 3.6 (2.1-5.1%) in women, while that of IGT was 7.4 (5.7-6.5%) in men and 7.1 (5.1-9.1%) in women. The truncated age-adjusted rate of DM for age 30-64 is 7.7% which is comparable to the age-adjusted prevalence rates among Chinese living in Singapore and Mauritius but in marked contrast to the low prevalence rate in Chinese living in Mainland China. Among the diabetic subjects, 38.2% had been previously diagnosed and 32% gave a family history affecting at least one first degree relative. Using polychotomous logistic regression analysis, the independent predictive factors for the development of DM include age (t = 7.31, P < 0.001), family history (t = 5.1, P < 0.001), waist hip ratio (t = 4.05, P < 0.001) and body mass index (t = 4.62, P < 0.001). Our data further confirm that Hong Kong Chinese have a moderate to high susceptibility to non-insulin-dependent diabetes (NIDDM) when exposed to sufficient environmental and lifestyle factors. The high prevalence of IGT indicates a potential for the prevalence of DM to continue to rise unless effective preventive measures are implemented.
Adolescent↗
Effects of combined administration of FK 506 and the purine biosynthesis inhibitors mizoribine or mycophenolic acid on lymphocyte DNA synthesis and T cell activation molecule expression in human mixed lymphocyte cultures.
Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the purine biosynthesis inhibitors mycophenolic acid (MPA; the active moiety of RS61443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six-day human mixed lymphocyte cultures (MLC), FK 506, MPA or MZB exhibited dose-dependent inhibition of T-lymphocyte DNA synthesis. FK 506, however, was 100-fold more potent than MPA, and 10,000-fold more potent than MZB. Combination of FK 506 with either MPA or MZB, each at suboptional concentrations, produced no more than additive inhibitory effects on 3H thymidine incorporation. Two-colour flow cytometric analysis of lymphocytes revealed that none of the drugs affected cell surface activation molecule expression (CD25 = IL-2R 55 kD alpha-chain, HLA-DR or CD71 = transferrin receptor [TR]) on allostimulated CD4+ or CD8+ cells harvested at three days of culture. By day six, however, all three agents, at levels which markedly inhibited proliferation, suppressed the expression of activation markers on both CD4+ and CD8+ cells. Also at day six, inhibition of activation molecule expression on CD4+ cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which, on their own, were ineffective. These data provide new, additional information on the in vitro antilymphocytic action of FK 506, MPA and MZB when used alone and in combination.
Cells, Cultured↗
The evaluation of a portable clinical analyzer in the emergency department.
A recently available portable clinical analyzer (PCA), which examines sodium, potassium, chloride, glucose, urea nitrogen, and hematocrit levels on 60 microL of blood and calculates hemoglobin and osmolality levels within 2 minutes, was evaluated. Blood from 574 patients was drawn by emergency department staff, who immediately tested the samples with the PCA and transported them for plasma analysis on a reference analyzer in the clinical laboratory. Correlations between the PCA and the reference analyzer were as follows: R2 = 0.987 for urea nitrogen; R2 = 0.97, glucose; R2 = 0.937, K;R2 = 0.79, hematocrit; R2 = 0.751, sodium; and R2 = 0.689 for chloride. With its rapid turnaround, small sample requirement, and ease of operation, the PCA is most useful in an emergency department setting, where immediate access to clinically relevant laboratory testing is required in support of urgent clinical decision-making.
Blood Chemical Analysis↗
Graft-versus-host disease after brown Norway-to-Lewis and Lewis-to-Brown Norway rat intestinal transplantation under FK506.
In LEW rats treated daily with variable doses of FK506 for 14 days and weekly thereafter, successful intestinal transplantation from fully allogeneic BN donors never was complicated by fatal GVHD. In contrast, with LEW-to-BN transplantation, rejection was difficult to control and GVHD developed after the end of the daily treatment. However, FK506 in high daily doses continued after the initial 14-day course could prevent this GVHD or even reverse it after allowing its onset. Further experiments did not clarify why the BN rat was an "easy" donor and "difficult" recipient. In unaltered animals the lymphocyte population of normal LEW rats had a higher proportion of T cells, fewer B cells, and a lower CD4:CD8 ratio than normal BN rats. However, one-way MLR reactions of the BN and LEW combinations were generally similar in either direction and not affected differently by the addition of FK506 to the medium. The two-way lymphocyte traffic from graft to host lymphoid organs and vice versa also was similar with BN-to-LEW and LEW-to-BN models. The BN rat may be a useful tool to investigate inadequately explained mechanisms of GVHD.
Animals↗
The antilymphocytic activity of brequinar sodium and its potentiation by cytidine. Effects on lymphocyte proliferation and cytokine production.
Based on its capacity to inhibit de novo pyrimidine biosynthesis by blocking dihydroorotate dehydrogenase activity, the antitumor agent brequinar sodium (BQR) has emerged as a new immunosuppressive agent. Since BQR is known to prevent the synthesis of nucleotides during cell proliferation, we hypothesized that it would be highly effective in controlling strong lymphocyte proliferative responses but might be less effective in controlling comparatively weak responses that do not necessarily involve new nucleotide synthesis. We addressed this question by culturing murine spleen cells with different types of stimuli, including Con A, phorbol myristate acetate +/- ionomycin, anti-CD3, and anti-Igs. Addition of BQR (0.001 microgram/ml to 10 micrograms/ml) at the start of a 72-hr culture period caused dose-dependent inhibition of strong proliferative responses, induced either by Con A (5 micrograms/ml) or PMA+ionomycin. A residual degree of proliferation persisted, however, even at the highest BQR concentrations. In contrast, no impairment of low-concentration Con A (0.5 or 0.1 microgram/ml), anti-CD3, or anti-Igs responses was observed. In order to ascertain its role in arresting nucleotide synthesis, we attempted to reverse the inhibitory effect of BQR by adding exogenous uridine or cytidine to lymphocyte cultures. BQR's inhibitory activity was reversed completely by adding uridine at 0.1 mM. In contrast, combination of BQR and cytidine (0.1 mM) potentiated BQR's activity and abrogated anti-CD3 or anti-Igs-induced lymphocyte proliferation in a dose-dependent manner. A synergistic inhibitory action between BQR and cytidine was observed when the BQR concentration was higher than 0.1 microgram/ml and with cytidine at 0.1 mM. Production of interleukin-2 and IL-4 was only slightly affected by BQR, but was significantly suppressed by coadministration of BQR and cytidine. Neither BQR (5 micrograms/ml) on its own, however, nor combination of BQR with cytidine affected production of mRNA for IL-2, IL-4, or interferon-gamma, as determined by reverse-transcription polymerase chain reaction. Our observations suggest that BQR may not only affect dihydroorotate dehydrogenase activity, but may also inhibit the enzyme cytidine deaminase, which converts cytidine to uridine. These antimetabolic effects of BQR complement the well-known cytokine synthesis inhibitory actions of FK506 or CsA. The combination of BQR and cytidine, however, offers a further possibility for inhibition of both cytokine production and T and B cell proliferation, and may have potential for the control of graft rejection.
Animals↗
Suppression of autoimmune thyroid disease by FK 506: influence on thyroid-infiltrating cells, adhesion molecule expression and anti-thyroglobulin antibody production.
Autoimmune thyroid disease was induced in female PVG/c rats by neonatal thymectomy, followed by sublethal, whole body x-irradiation. Disease development, assessed by histological evidence of lymphocytic thyroiditis and circulating levels of anti-thyroglobulin antibodies, was reduced significantly by a 3-week course of FK 506 (0.5 or 1.5 mg/kg per day) commencing after the detection of autoantibody production. Thyroid-infiltrating mononuclear cells (MNC) in untreated rats stained predominantly for CD4+ and MHC class II antigen which was expressed widely on dendritic cells. Fewer infiltrating cells expressed TCR alpha/beta, CD5, CD8 or LFA-1 beta. Intercellular adhesion molecule-1 (ICAM-1) was observed on MNC, vascular endothelial cells and a minority of residual thyroid epithelial cells. FK 506 administration reduced markedly the incidence of infiltrating TCR alpha/beta +, CD5+, CD4+, CD8+, and LFA-1 beta + cells and the expression both of MHC class II antigens and ICAM-1 on MNC, endothelial cells and thyrocytes. Compared with normal PVG/c rats, there were reduced incidences of CD4+ CD8- and CD4- CD8+ lymphocytes and an elevation in the CD4+/CD8+ cell ratio in the spleens of animals with autoimmune thyroiditis. These changes were partially reversed by FK 506. Systemic drug levels estimated by enzyme immunosorbent assay were in excess of those known to blockade cytokine production by CD4+ T lymphocytes in vitro and some evidence of minor renal dysfunction was observed. The results are consistent with a therapeutic effect of FK 506 mediated via interference with CD4+ T lymphocyte function and adhesion molecule-dependent cytotoxic effector mechanisms.
Animals↗
Lipid profile in the Chinese old-old: comparison with younger age groups and relationship with some cardiovascular risk factors and presence of diseases.
In a health survey of 2,032 elderly Hong Kong Chinese aged 70 years and over selected by stratified random sampling, a subset of 199 subjects (96 M, 103 F) were selected for a study of their lipid profile. No age and sex differences were observed in mean total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride concentrations in this subgroup. Compared with values from younger Chinese subjects from a previous survey, TC and LDL-C showed an age-related rise up till about 60 years, followed by a gradual decline. HDL-C concentrations showed little variation with age. Nonagenarians had a LDL/HDL ratio similar to subjects in the < 24 age group and lower than male subjects in the age 35-64 age group. HDL-C was lower in those with heart disease or hypertension. Other lipid parameters were not influenced by the presence of other chronic diseases, self-perceived health status, or cognitive impairment. TC was positively associated with the Barthel Index, a measure of functional ability. Positive associations between obesity indices and diastolic blood pressure, and TC, LDL-C, and triglycerides were present.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Serum lipid profile and its association with some cardiovascular risk factors in an urban Chinese population.
The lipid profile of a Chinese population, which has a lower prevalence of coronary heart disease compared with Caucasians, is studied to determine whether lipid-modifying disease prevention programs are necessary. The study population consisted of 910 men (mean age 36.7 +/- 9.2 yrs) and 603 women (mean age 38.6 +/- 9.1 yrs), who were employees of a public utility company and non-medical staff of a district hospital. Indices of obesity, fasting cholesterol (TC), and its various subfraction, triglycerides (TG), apolipoprotein A-I (Apo A-I), and apolipoprotein B (Apo B) concentrations were measured. Glucose tolerance was also estimated by measuring fasting and 2 h glucose after a 75 g oral glucose load. The lipid profile was similar to that of the North American population, with an overall prevalence of low density lipoprotein cholesterol (LDL-C) > or = 4.1 mmol/L of 21% and 11% in men and women respectively. Similar variations with age, sex, smoking and glucose tolerance compared with Caucasian populations were observed. The high prevalence of subjects with "undesirable" lipid values in this Chinese population, which at present has a coronary artery disease prevalence of one-eighth to one-quarter compared with that in Caucasians, suggests that the incidence of the disease may well rise in the future to pose a similar problem to that in Caucasian populations. Cut off values of lipids conferring increased cardiovascular risks need to be determined in this population, so that public health strategies may be formulated.
Adult↗
ICAM-1 and E-selectin expression in lesional biopsies of psoriasis patients responding to systemic FK 506 therapy.
FK 506 is a new immunosuppressive agent with a similar molecular action to cyclosporin A. We have investigated immunohistochemical changes in lesional biopsies of seven patients with severe recalcitrant chronic plaque psoriasis receiving systemic FK 506 therapy. Within 4 weeks of start of treatment, there was a striking reduction in psoriasis area and severity index (mean reduction 87.4%), accompanied by marked reductions in dermal and epidermal CD4+ and CD8+ cells. Investigation of biopsies obtained 4-8 weeks after start of treatment revealed a significant fall in the numbers of activated mononuclear cells expressing CD25 (IL-2 receptor alpha-chain), HLA-DR, or CD11a (lymphocyte function-associated antigen-1, LFA-1 alpha chain). In contrast, the number of epidermal CD1+ (Langerhans) cells increased in response to FK 506 therapy. Study of leukocyte adhesion-related epitopes in active disease revealed strong expression of CD54 (intercellular adhesion molecule-1, ICAM-1) and E-selectin (previously known as endothelial leukocyte adhesion molecule-1) both on microvascular endothelial cells and of ICAM-1 on infiltrating mononuclear cells; ICAM-1 was also expressed weakly on epidermal keratinocytes. Vascular cell adhesion molecule-1 (VCAM-1) was either absent or expressed rarely on vascular endothelium. In response to FK 506 treatment, both ICAM-1 and E-selectin expression on blood vessels was reduced consistently but nevertheless persisted, even in individuals exhibiting total clearance of psoriatic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Comparative effects of rapamycin, FK 506 and cyclosporine on antibody production, lymphocyte populations and immunoglobulin isotype switching in the rat.
The immunosuppressive activity and comparative efficacy of rapamycin (RAPA), FK 506 and cyclosporine A (CsA) were investigated in rats following immunization with either xenogeneic sheep red blood cells (SRBC) or allogeneic blood transfusion. RAPA formulated in a polyethylene glycol vehicle, and at a dose of 1.5 mg.kg-1 i.p., was relatively ineffective when compared with FK 506 (1 mg.kg-1) or CsA (15 mg.kg-1) in suppressing antibody production to SRBC. Like FK 506 and CsA however, RAPA proved highly effective in suppressing both the B lymphocytosis and the increase in circulating major histocompatibility complex class II+ cells observed following immunization. All three immunosuppressants caused thymic medullary atrophy, with evidence of epithelial cell damage and increased macrophage phagocytic activity. Administered i.m. (3 mg.kg-1 in olive oil), RAPA was also highly effective in suppressing 1 degree alloantibody responses to MHC class I antigens following blood transfusion. Unlike FK 506 and CsA however, a short (14-day) course of RAPA following 1 degree immunization (transfusion) did no suppress 2 degree alloantibody responses elicited 6 weeks later. Moreover, RAPA did not prevent immunoglobulin isotype switching as observed with FK 506 and CsA. This may reflect the distinct mechanisms of action of RAPA and the latter two agents on T-cell activation/proliferation. Further comparative and combination studies of RAPA with in particular, CsA, are required to further explore to potential of RAPA as an immunotherapeutic agent.
Animals↗
Effects of the immunosuppressive macrolides rapamycin and FK 506 in high responder rats presensitized to major histocompatibility complex antigens.
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Analysis of Variance↗
Humoral and cellular immunopathology of hepatic and cardiac hamster-into-rat xenograft rejection. Marked stimulation of IgM++bright/IgD+dull splenic B cells.
Normal Lewis rat serum contains antibodies (IgM > IgG) that bind to hamster leukocytes and endothelial cells. Transplantation of either the heart or liver from hamster rat results in release of hamster hematolymphoid cells from the graft, which lodge in the recipient spleen (cell migration), where recipient T- and B-cell populations initiate DNA synthesis within one day. There is marked stimulation of splenic IgM++(bright)/IgD+(dull) B cells in the marginal zone and red pulp, which account for 48% of the total splenic blast cell population by 4 days after liver transplantation. CD4+ predominant T-cell proliferation in the splenic periarterial lymphatic sheath and paracortex of peripheral lymph nodes occurs almost simultaneously. The effector phase of rejection in cardiac recipients is dominated by complement-fixing IgM antibodies, which increase daily and result in graft destruction in 3 to 4 days, even in animals treated with FK506. In liver recipients, combined antibody and cellular rejection, associated with graft infiltration by OX8+ natural killer, and fewer W3/25+ (CD4) lymphocytes, are responsible for graft failure in untreated recipients at 6 to 7 days. FK506 inhibits the T-cell response in liver recipients and significantly prolongs graft survival, but does not prevent the rise or deposition of IgM antibodies in the graft. However, a single injection of cyclophosphamide 10 days before transplantation effectively depletes the splenic IgM++(bright)/Ig+(dull) cells and in combination with FK506, results in 100% survival of both cardiac and hepatic xenografts for more than 60 days. Although extrapolation of morphological findings to functional significance is fraught with potential problems, we propose the following mechanisms of xenografts rejection. The reaction initially appears to involve primitive host defense mechanisms, including an IgM-producing subpopulation of splenic B cells and natural killer cells. Based on the reaction and distribution of OX8+ and W3/25+ cells, antibody-dependent cell cytotoxicity and delayed-type hypersensitivity responses seem worthy of further investigation as possible effector mechanisms. Effective control of xenograft rejection is likely to require a dual pharmaceutical approach, one to contain T-cell immunity and another to blunt the primitive B-cell response.
Animals↗