Additive immunosuppressive effects of 1,25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses

BACKGROUND: The biologic role of the vitamin D analogue 1, 25-dihydroxyvitamin D(3), such as antiinflammatory functions, reduction of cytokine production by T cells, and immunoglobulin production by B cells, has been reported. Such immunomodulatory effects may be potentially useful in dealing with autoimmunity and transplantation. However, whether this hormone has an additive immunosuppressive effect when it is used with corticosteroids has not been investigated, although these agents are commonly used together. OBJECTIVE: Our purpose was to investigate the additive immunomodulatory effects of 1,25-dihydroxyvitamin D(3) on lymphocyte proliferation and cytokine production when used with corticosteroids. METHODS: To investigate the additive effects of 1, 25-dihydroxyvitamin D(3) and dexamethasone on suppression of lymphocyte proliferation, normal PBMCs were cultured in anti-CD3 with or without different concentrations of dexamethasone (0-10(-7) mol/L) plus or minus different concentrations of 1, 25-dihydroxyvitamin D(3) (0-10(-6) mol/L). After 3 days, lymphocyte proliferation was assessed by [(3)H]-thymidine incorporation. To investigate the additive effects of 1,25-dihydroxyvitamin D(3) and dexamethasone on cytokine production, PBMCs were cultured for 3 days in the presence of anti-CD3 with or without 10(-6) mol/L dexamethasone plus or minus 10(-6) mol/L 1,25-dihydroxyvitamin D(3). IFN-gamma, IL-5, and IL-13 production in supernatants were measured by ELISA. RESULTS: Our study demonstrated that, at concentrations of 10(-8), 10(-7), and 10(-6) mol/L, 1,25-dihydroxyvitamin D(3) significantly decreased lymphocyte proliferation compared with an ethanol control (P <.05). The IC(50) for dexamethasone was 4 x 10(-9) mol/L in culture without 1,25-dihydroxyvitamin D(3.) When 10(-9) mol/L of 1,25-dihydroxyvitamin D(3) was added to cultures with dexamethasone, IC(50) became 2 x 10(-9) mol/L. Moreover, when 10(-6), 10(-7), and 10(-8) mol/L of 1,25-dihydroxyvitamin D(3) were added in culture with dexamethasone, IC(50) became less than 1 x 10(-9) mol/L. IFN-gamma production in culture with either dexamethasone or 1,25-dihydroxyvitamin D(3) was significantly decreased compared with media or ethanol control (P <.0001). Moreover, when both agents were added in the same culture, IFN-gamma production was further decreased compared with either agent alone (P <.05). In contrast, 1,25-dihydroxyvitamin D(3) significantly (P <. 0001) increased IL-5 and IL-13, whereas dexamethasone significantly decreased these 2 cytokines (P <.0005). When 1,25-dihydroxyvitamin D(3) was combined with dexamethasone, IL-5 and IL-13 production was increased compared with dexamethasone alone (P <.001). CONCLUSIONS: Our results demonstrate that 1,25-dihydroxyvitamin D(3) has significant additive effects on dexamethasone-mediated inhibition of lymphocyte proliferation. This hormone also has additive effects on inhibition of T(H)1 cytokine production when combined with dexamethasone. However, this hormone upregulates T(H)2 cytokines and inhibits steroid-mediated suppression of cytokines. These findings demonstrate the potential use of 1,25-dihydroxyvitamin D(3) as an immunosuppressive agent when combined with corticosteroids in T(H)1, but not T(H)2, immune responses.     

Improvement of pulmonary function with arm swing exercise in patients with type 2 diabetes

[Purpose] Obesity and hyperglycemia play roles in the impairment of pulmonary function in type 2 diabetes mellitus (T2DM) patients. Low-intensity exercise is known to reduce body fat and improve hyperglycemia. The arm swing exercise (ASE), a low-intensity exercise, is easy and convenient to perform without any equipment and is suitable for daily practice. Therefore, we aimed to investigate the effects of ASE on lung function and obesity in overweight T2DM patients. [Subjects and Methods] Twenty-four subjects continued their daily life routines for 8 weeks (control period), and then performed ASE for 8 weeks (30 minutes per day, 3 days per week) (ASE period). Pulmonary function tests were performed, and fasting blood glucose, haemoglobin A1c (HbA1c), lipid profiles, high-sensitive C-reactive protein (HSCRP), insulin concentration, and anthropometric parameters were measured before and after each period. [Results] After the ASE period, the forced vital capacity, forced expiratory volume in the first second of expiration, and maximal voluntary ventilation were increased when compared with after the control period. HbA1c, a low-density lipoprotein, malondialdehyde, oxidized glutathione, and the percent body fat were significantly decreased when compared with after the control period. However, other parameters, such as lung volume, anthropometric parameters, and fasting blood glucose, insulin, high-density lipoprotein, triglycerides, total cholesterol and glutathione concentrations, showed no differences between the two periods. [Conclusion] These data suggest that there is improvement of pulmonary functions in T2DM patients after ASE training.Key words: Physical activity, Pulmonary functions, Fatness     

Prospective Comparison of Infective Endocarditis in Khon Kaen,Thailand and Rennes,France

Prospectively collected, contemporary data are lacking on how the features of infective endocarditis (IE) vary according to region. We, therefore, compared IE in Rennes, France and Khon Kaen, Thailand. Fifty-eight patients with confirmed IE were enrolled at each site during 2011 and 2012 using a common protocol. Compared with French patients, Thais had a lower median age (47 versus 70 years old; P < 0.001) and reported more animal contact (86% versus 21%; P < 0.001). There were more zoonotic infections among Thai than France patients (6 and 1 cases; P = 0.017) and fewer staphylococcal infections (4 versus 15 cases; P = 0.011). Underlying rheumatic heart disease was more prevalent in Thai than in French patients (31% and 4%; P = 0.001), whereas prosthetic heart valves were less prevalent (9% and 35%; P = 0.001). Our data strengthen previous observations that IE in the tropics has distinctive demographic characteristics, risk factors, and etiologies and underscore the need for improved prevention and control strategies.     

Defining Biomarkers to Predict Natural Resolution in Shrimp Allergy

PurposeTolerance to shrimp has been reported in some patients with a history of shrimp allergy. The predictors of the natural resolution of shrimp allergy have not been widely explored. This study aimed to investigate the role of specific IgE (sIgE) and specific IgG4 (sIgG4) to shrimp extracts and the cross-reactive shrimp allergens tropomyosin (TM), arginine kinase (AK) and myosin light-chain (MLC), as markers of persistent or resolved shrimp allergy (PSA or RSA).MethodsSeventeen patients with a 10-year history of allergy to Penaeus monodon (Pm) and/or Macrobachium rosenbergii (Mr) were recruited. Oral shrimp challenges identified 10 patients with PSA and 7 patients with RSA. Sera from these patients were evaluated for sIgE and sIgG4 to Mr and Pm extracts as well as to TM, AK and MLC.ResultsThe levels of sIgE to Mr and Pm extracts were lower in the RSA than in the PSA groups (P = 0.05 and P = 0.008, respectively), but sIgG4 or sIgG4:sIgE ratio did not show statistical significance. The sIgE to AK and MLC, but not TM, were lower in the RSA group than in the PSA group (P = 0.009 and P = 0.0008, respectively). There was no difference in sIgG4 to TM, AK and MLC between both groups. The ratio of sIgG4:sIgE to MLC, but not TM or AK, was higher in the RSA than in the PSA group (P = 0.02). A higher diversity of sIgE to shrimp components was found in the PSA group than in the RSA group (P = 0.006).ConclusionsSpecific bioassays can be used to identify patients with RSA. Oral shrimp challenges in these patients may provide a higher rate of passing the challenges and finally reintroducing shrimp in their diet.     

The modulation of cytokine and IgE production by tumor necrosis factor-beta in atopic dermatitis

Atopic dermatitis (AD) is associated with increased IL-4, IL-5, and IL-13 but decreased IFN-gamma production. This cytokine profile may account for the atopic features of this illness, including IgE upregulation. Recent studies have demonstrated that tumor necrosis factor (TNF)-beta is produced by Th1-like cells, but the cytokine modulation by TNF-beta and the clinical significance of this cytokine in AD is not known. Therefore, this study was carried out to determine the potential role of TNF-beta in AD. In this study, we cultured peripheral blood mononuclear cells from patients with AD and normal subjects with anti-CD3 monoclonal antibodies and investigated the production of TNF-beta by ELISA. The mean +/- SEM of TNF-beta production in AD was significantly lower than normal subjects (p = 0.03). The effect of TNF-beta on cytokine production was investigated by culturing peripheral blood mononuclear cells with anti-CD3 monoclonal antibodies in the presence or absence of TNF-beta. Compared with medium control, TNF-beta significantly decreased IL-5 (p = 0.0004) and IL-13 (p = 0.008) but increased IFN-gamma (p = 0.001) production. The effect of TNF-beta on IgE production was determined by culturing peripheral blood mononuclear cells in the IL-4- and anti-CD40-induced IgE production system. Interestingly, TNF-beta significantly decreased IgE (p = 0.02), but not IgG production compared with medium control. Our study demonstrates that TNF-beta production is downregulated in AD. This cytokine increases IFN-gamma production but decreases IL-5, IL-13, as well as IgE production. These findings suggest a potential role for TNF-beta in the pathogenesis of AD.     

Immunophenotypic profile of adult acute myeloid leukemia (AML): analysis of 267 cases in Thailand

Little data exists in Thailand and other Southeast Asian countries regarding the biological characteristics of adult acute myeloid leukemia (AML). In this study, we performed a flow cytometric analysis of 267 Thai adult AML cases to delineate the pattern of leukemic cell surface antigens. Forty-eight cases (18%) were identified as acute promyelocytic leukemia (M3) and 219 cases as non-M3. The most frequent subtype of AML in Thailand was M1/M2 and the least frequent was M7. M3 immunophenotypes were characterized by their unique lack of expression of CD34 and HLA-DR as contrast to the high mean expression of 50% and 70%, respectively, in non-M3. Overall, 60% of cases expressed CD34. Aberrant lymphoid antigens were uniquely seen in specific subtypes of Thai AML, including CD19 (33% of non-M3 vs 23% of M3) and CD2 (12% of M3 vs 2% of non-M3). CD56 was frequently expressed in both M3 and non-M3 while CD16 appeared to be associated with M4/M5 (24% of cases) and CD7 with M1/M2 (21% of cases). Eighty-one percent of non-M3 expressed CD38 while only 53% of M3 did. We found that most Thai adult AML patients were on average 15-20 years younger than those of the West or Japan with only 25% of Thai cases over 60 years of age, although the immunophenotypes were not markedly different. Biological studies of acute leukemia in various countries should help to provide epidemiological clues that play a role in the pathogenesis of leukemia in different geographic regions of the world. Our study represents the largest series of AML ever investigated in the Southeast Asian region.     

Maternal complications after Caesarean section in HIV-infected pregnant women

A study of maternal complications after elective Caesarean section in HIV-infected women was carried out from January 1999 to April 2001. The control group consisted of all the seronegative pregnant women who underwent the elective Caesarean section during the study period. The study group was divided into two subgroups. Subgroup 1 patients were given 600 mg zidovudine (ZDV) orally and 300 mg lamivudine (3TC) daily from 34 to 38 weeks' gestation. Subgroup 2 patients were given 600 mg ZDV orally daily from 34 to 38 weeks' gestation and 150 mg nevirapine orally on the morning of the Caesarean section day. In both groups, the elective Caesarean section was carried out at 38 weeks' gestation and ZDV syrup (2 mg/kg) was given orally to the newborn immediately in the operating theatre and then every 6 h for 4 weeks. No statistically significant differences in maternal complications were found between the HIV-infected and non HIV-infected women.     

Interaction among smoking status,single nucleotide polymorphisms and markers of systemic inflammation in healthy individuals

Cigarette smoke contains toxic and carcinogenic substances that contribute to the development of cancer and various diseases. Genetic variation might be important, because not all smokers develop smoking‐related disease. The current study addressed the possible interactions among selected single nucleotide polymorphisms (SNPs) in genes related to systemic inflammation, smoking status, the levels of circulating immune response cells and plasma biomarkers of systemic inflammation. Sixty‐four healthy blood donors were recruited, 31 of whom were current smokers and 33 were never‐users of tobacco products, references. Compared to references, the smokers showed significantly increased levels of circulating total white blood cells, lymphocytes, monocytes, neutrophils, basophils and C‐reactive protein (CRP). Smokers also more frequently exhibited circulating cell phenotypes that are associated with an immunocompromised state: CD8^dim cells in the lymphocyte group, CD13⁺ CD11⁺, CD13⁺ CD14⁺, CD13⁺ CD56⁺ cells in the monocyte group and CD13⁺ CD11⁺, CD13⁺ CD56⁺ cells in the neutrophil group. We observed an interaction among SNPs, smoking status and some of the studied biomarkers. The average plasma CRP level was significantly higher among the smokers, with the highest level found among those with the CRP rs1800947 CC genotype. Additionally, an increased CD8⁺ GZB⁺ cells in the CD8^dim group were found among smokers with the GZB rs8192917 AA genotype. Thus, smoking appears to be associated with systemic inflammation and increased levels of circulating immunosuppressive cells. The extent of these effects was associated with SNPs among the smokers. This observation may contribute to a better understanding of the genetic susceptibility of smoking‐related disease and the variations observed in clinical outcomes.     

Development of flow cytometry for detection and quantitation of red cell bound immunoglobulin G in autoimmune hemolytic anemia with negative direct Coombs test

About 2-10% of patients with warm-antibody autoimmune hemolytic anemia (WAIHA) exhibit a negative direct Coombs test (DAT), requiring more sensitive tests, including detection of RBC-bound immunoglobulins by flow cytometry, for diagnosis. In this study, the optimal conditions for detection and quantitation of RBC-bound IgG by flow cytometry were studied using blood samples from six patients with AIHA and two healthy individuals. Quantitation of RBC-bound IgG was performed using quantum simply cellular (QSC) beads coated with goat anti-mouse IgG antibodies. For detection of RBC bound IgG, a 60-minute incubation of all blood samples with 40 microl of 1:10 dilution of FITC-conjugated mouse anti-human IgG gave mean fluorescent intensity (MFI) values comparable to experiments using larger amounts or higher concentrations of the anti-human IgG. The acquired antibody binding capacity (ABC) values (or IgG molecules) for each QSC bead level, at 40 microl of 1:5 and 1:10 dilution of anti-human IgG for 60 minutes were close to the manufacturer-assigned ABC values. The IgG molecules per RBC in all six patients with positive DAT of 4+, 3+, 2+, 1+, trace and negative DAT were 31,725, 3,823, 1,753, 524, 260 and 88 respectively and in two healthy individuals with negative DAT they were 104 and 78.