Immunomodulatory action of Copaifera spp oleoresins on cytokine production by human monocytes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Paracoccidioides brasiliensis interferes on dendritic cells maturation by inhibiting PGE(2) production

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Antiulcerogenic activity and toxicity of bauhinia holophylla hydroalcoholic extract

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Hydrophobicity and antioxidant activity acting together for the beneficial health properties of nordihydroguaiaretic acid

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Association of a Large Panel of Cytokine Gene Polymorphisms with Complications and Comorbidities in Type 2 Diabetes Patients

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Activation of monocytes and cytokine production in patients with peripheral atherosclerosis obliterans

Background: Arterial peripheral disease is a condition caused by the blocked blood flow resulting from arterial cholesterol deposits within the arms, legs and aorta. Studies have shown that macrophages in atherosclerotic plaque are highly activated, which makes these cells important antigen-presenting cells that develop a specific immune response, in which LDLox is the inducing antigen. As functional changes of cells which participate in the atherogenesis process may occur in the peripheral blood, the objectives of the present study were to evaluate plasma levels of anti-inflammatory and inflammatory cytokines including TNF-alpha, IFN-gamma, interleukin-6 (IL-6), IL-10 and TGF-beta in patients with peripheral arteriosclerosis obliterans, to assess the monocyte activation level in peripheral blood through the ability of these cells to release hydrogen peroxide (H(2)O(2)) and to develop fungicidal activity against Candida albicans (C. albicans) in vitro.Methods: TNF-alpha, IFN-gamma, IL-6, IL-10 and TGF-beta from plasma of patients were detected by ELISA. Monocyte cultures activated in vitro with TNF-alpha and IFN-gamma were evaluated by fungicidal activity against C. albicans by culture plating and Colony Forming Unit (CFU) recovery, and by H(2)O(2) production.Results: Plasma levels of all cytokines were significantly higher in patients compared to those detected in control subjects. Control group monocytes did not release substantial levels of H(2)O(2) in vitro, but these levels were significantly increased after activation with IFN-gamma and TNF-alpha. Monocytes of patients, before and after activation, responded less than those of control subjects. Similar results were found when fungicidal activity was evaluated. The results seen in patients were always significantly smaller than among control subjects. Conclusions: The results revealed an unresponsiveness of patient monocytes in vitro probably due to the high activation process occurring in vivo as corroborated by high plasma cytokine levels.

Adalimumab for maintenance therapy for one year in Crohn's disease: results of a Latin American single-center observational study

Adalimumab is a fully-human antibody that inhibits TNF alpha, with a significant efficacy for long-term maintenance of remission. Studies with this agent in Latin American Crohn's disease patients are scarce. The objective of this study was to outline clinical remission rates after 12 months of adalimumab therapy for Crohn's disease patients. Retrospective, single-center, observational study of a Brazilian case series of Crohn's disease patients under adalimumab therapy. Variables analyzed: demographic data, Montreal classification, concomitant medication, remission rates after 1, 4, 6 and 12 months. Remission was defined as Harvey-Bradshaw Index ≤ 4, and non-responder-imputation and last-observation-carried-forward analysis were used. The influence of infliximab on remission rates was analyzed by Fischer and Chi-square tests (P<0.05). Fifty patients, with median age of 35 years at therapy initiation, were included. Remission rates after 12 months of therapy were 54% under non-responder-imputation and 88% under last-observation-carried-forward analysis. After 12 months, remission on patients with previous infliximab occurred in 69.23% as compared to 94.59% in infliximab-naïve patients (P = 0.033). Adalimumab was effective in maintaining clinical remission after 12 months of therapy, with an adequate safety profile, and was also more effective in infliximab naïve patients.

Direct retrospective comparison of adalimumab and infliximab in preventing early postoperative endoscopic recurrence after ileocaecal resection for crohn's disease: results from the MULTIPER database

Both adalimumab [ADA] and infliximab [IFX] seem to be effective in the prevention of early postoperative endoscopic recurrence [EPER] after ileocaecal resection in Crohn's disease [CD] patients. There is lack of data with direct comparison between the two agents in the postoperative scenario. The aim of this study was to compare the rates of EPER in patients treated with ADA and IFX after ileocaecal resection for CD. This was a multicentre retrospective analysis of EPER rates in CD patients after ileocaecal resections, from seven referral centres in three countries. Endoscopic recurrence was defined as Rutgeerts' score ≥ i2. The patients were allocated according to treatment to two groups: ADA or IFX. The EPER rates were compared between the two treatment groups. Among the 168 patients included in the database, 96 received anti-tumour necrosis factor [TNF] agents after resection [37 in the ADA and 59 in the IFX groups] and were included in this comparative study. The groups were comparable in all baseline characteristics, mainly age, gender, previous resections, perianal CD, and mono or combination therapy. EPER was identified in 9/37 [24.32%] in the ADA group vs 16/59 [27.12%] in the IFX group [p = 0.815]. In this retrospective direct comparison between ADA and IFX therapy after ileocaecal resection, there was no significant difference between the two anti-TNF agents in terms of EPER rates. However, prospective randomised studies are needed to confirm these data and better define the role of each agent in the prevention of EPER.

TNF blockers show distinct patterns of immune response to the pandemic influenza A H1N1 vaccine in inflammatory arthritis patients

Methods. One hundred and twenty patients (RA, n = 41; AS, n = 57; PsA, n = 22) on anti-TNF agents (monoclonal, n = 94; soluble receptor, n = 26) were compared with 116 inflammatory arthritis patients under DMARDs and 117 healthy controls. Seroprotection, seroconversion (SC), geometric mean titre, factor increase in geometric mean titre and adverse events were evaluated 21 days after vaccination. Results. After immunization, SC rates (58.2% vs 74.3%, P = 0.017) were significantly lower in SpA patients receiving anti-TNF therapy, whereas no difference was observed in RA patients receiving this therapy compared with healthy controls (P = 0.067). SpA patients receiving mAbs (infliximab/adalimumab) had a significantly lower SC rate compared with healthy controls (51.6% vs 74.3%, P = 0.002) or those on DMARDs (51.6% vs 74.7%, P = 0.005), whereas no difference was observed for patients on etanercept (86.7% vs 74.3%, P = 0.091). Further analysis of non-seroconverting and seroconverting SpA patients revealed that the former group had a higher mean age (P = 0.003), a higher frequency of anti-TNF (P = 0.031) and mAbs (P = 0.001) and a lower frequency of MTX (P = 0.028). In multivariate logistic regression, only older age (P = 0.015) and mAb treatment (P = 0.023) remained significant factors for non-SC in SpA patients. Conclusion. This study revealed a distinct disease pattern of immune response to the pandemic influenza vaccine in inflammatory arthritis patients receiving anti-TNF agents, illustrated by a reduced immunogenicity solely in SpA patients using mAbs. Trial Registration: ClinicalTrials.gov, ext-link-type="uri" xlink:href="www.clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">www.clinicaltrials.gov, NCT01151644.

Naturally acquired antibodies to Plasmodium vivax blood-stage vaccine candidates (PvMSP-1(19) and PvMSP-3 alpha(359-798)) and their relationship with hematological features in malaria patients from the Brazilian Amazon

An important step when designing a vaccine is identifying the antigens that function as targets of naturally acquired antibodies. We investigated specific antibody responses against two Plasmodium vivax vaccine candidates, PvMSP-1(19) and PvMSP-3 alpha(359-798). Moreover, we assessed the relationship between these antibodies and morbidity parameters. PvMSP-1(19) was the most immunogenic antigen and the frequency of responders to this protein tended to increase in P. vivax patients with higher parasitemia. For both antigens, IgG antibody responses tended to be lower in patients who had experienced their first bout of malaria. Furthermore, anemic patients presented higher IgG antibody responses to PvMSP-3 alpha(359-798). Since the humoral response involves a number of antibodies acting simultaneously on different targets, we performed a Principal Component Analysis (PCA). Anemic patients had, on average, higher first principal component scores (IgG1/IgG2/IgG3/IgG4 anti-MSP3 alpha), which were negatively correlated with hemoglobin levels. Since antibodies against PfMSP-3 have been strongly associated with clinical protection, we cannot exclude the possibility of a dual role of PvMSP-3 specific antibodies in both immunity and pathogenesis of vivax malaria. Our results confirm the high immunogenicity of the conserved C terminus of PvMSP-1 and points to the considerable immunogenicity of polymorphic PvMSP-3 alpha(359-798) during natural infection. (C) 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Cytokine Balance in Human Malaria: Does Plasmodium vivax Elicit More Inflammatory Responses than Plasmodium falciparum?

Background: The mechanisms by which humans regulate pro-and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. Methodology/Principal Findings: We measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF)-alpha receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85), P. falciparum (n = 30), or both species (n = 12), and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL)-10, which correlated positively with parasite density, and elevated IL-10/TNF-alpha, IL-10/interferon (IFN)-gamma, IL-10/IL-6 and sTNFRII/TNF-alpha ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-alpha receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species. Conclusions: Controlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction of regulatory cytokines may be a critical mechanism protecting vivax malaria patients from severe clinical complications.

Experimental arthritis exacerbates Aggregatibacter actinomycetemcomitans-induced periodontitis in mice

Aim This study aimed to investigate whether chronic antigen-induced arthritis (AIA) influences infection-induced periodontitis (PD) in mice and whether PD modifies the clinical course of AIA. The contribution of anti-TNF-a therapy was also evaluated. Materials and methods The PD was induced in C57BL/6 mice by oral infection with Aggregatibacter actinomycetemcomitans. AIA was induced after infection. Anti-TNF-a and chlorhexidine therapies were used to investigate the role of TNF-a and oral infection on PD and AIA interaction. Maxillae, knee joints, lymph nodes and serum samples were used for histomorphometric, immunoenzymatic and/or real time-PCR analyses. Results Antigen-induced arthritis exacerbated alveolar bone loss triggered by PD infection. In contrast, PD did not influence AIA in the evaluated time-points. PD exacerbation was associated with enhanced production of IFN-? in maxillae and expression of the Th1 transcription factor tBET in submandibular lymph nodes. Increased serum levels of IL-6 and C-reactive protein were also detected. Anti-TNF-a and antiseptic therapies prevented the development and exacerbation of infectious-PD. Anti-TNF-a therapy also resulted in reduced expression of IFN-?, TNF-a and IL-17 in maxillae. Conclusions Altogether, the current results indicate that the exacerbation of infection-induced PD by arthritis is associated with an alteration in lymphocyte polarization pattern and increased systemic immunoreactivity. This process was ameliorated by anti-TNF-a and antiseptic therapies.

Induction of TNF-alfa and CXCL-2 mRNAs in different organs of mice infected with pathogenic Leptospira

The role of innate immune response in protection against leptospirosis is poorly understood. We examined the expression of the chemokine CXCL2/MIP-2 and the cytokine TNF-alpha. in experimental resistant and susceptible mice models, C3H/HeJ, C3H/HePas and BALB/c strains, using a virulent strain of Leptospira interrogans serovar Copenhageni. Animals were infected intraperitoneally with 107 cells and the development of the disease was followed. Mortality of C3H/HeJ mice was observed whereas C3H/HePas presented jaundice and BALB/c mice remained asymptomatic. The infection was confirmed by the presence of leptospiral DNA in the organs of the animals, demonstrated by PCR. Sections of the organs were analyzed, after H&E stain. The relative expression of mRNA of chemokine CXCL2/MIP-2 and cytokine TNF-alpha was measured in lung, kidney and liver of the mice by qPCR. The concentrations of these proteins were measured in extracts of tissues and in serum of the animals, by ELISA. Increasing levels of transcripts and protein CXCL2/MIP-2 were detected since the first day of infection. The highest expression was observed at third day of infection in kidney, liver and lung of BALB/c mice. In C3H/HeJ the expression of CXCL2/MIP-2 was delayed, showing highest protein concentration in lung and kidney at the 5th day. Increasing in TNF-alpha transcripts were detected after infection, in kidney and liver of animals from the three mice strains. The expression of TNF-alpha protein in C3H/HeJ was also delayed, being detected in kidney and lung. Our data demonstrated that Leptospira infection stimulates early expression of CXCL2/MIP-2 and TNF-alpha in the resistant strain of mice. Histological analysis suggests that the expression of those molecules may be related to the influx of distinct immune cells and plays a role in the naturally acquired protective immunity. (C) 2012 Elsevier Ltd. All rights reserved.

Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E-2 and cytokines

The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E-2 (PGE(2)), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE(2) after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1 beta, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE(2) in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE(2) amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-alpha peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1 beta, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE(2), suggesting that these last are the central mediators of this response.

Lipid Transfer to HDL is Higher in Marathon Runners than in Sedentary Subjects, but is Acutely Inhibited During the Run

Although exercise increases HDL-cholesterol, exercise-induced changes in HDL metabolism have been little explored. Lipid transfer to HDL is essential for HDL's role in reverse cholesterol transport. We investigated the effects of acute exhaustive exercise on lipid transfer to HDL. We compared plasma lipid, apolipoprotein and cytokine levels and in vitro transfer of four lipids from a radioactively labeled lipid donor nanoemulsion to HDL in sedentary individuals (n = 28) and in marathon runners (n = 14) at baseline, immediately after and 72 h after a marathon. While HDL-cholesterol concentrations and apo A1 levels were higher in marathon runners, LDL-cholesterol, apo B and triacylglycerol levels were similar in both groups. Transfers of non-esterified cholesterol [6.8 (5.7-7.2) vs. 5.2 (4.5-6), p = 0.001], phospholipids [21.7 (20.4-22.2) vs. 8.2 (7.7-8.9), p = 0.0001] and triacylglycerol [3.7 (3.1-4) vs. 1.3 (0.8-1.7), p = 0.0001] were higher in marathon runners, but esterified-cholesterol transfer was similar. Immediately after the marathon, LDL- and HDL-cholesterol concentrations and apo A1 levels were unchanged, but apo B and triacylglycerol levels increased. Lipid transfer of non-esterified cholesterol [6.8 (5.7-7.2) vs. 5.8 (4.9-6.6), p = 0.0001], phospholipids [21.7 (20.4-22.2) vs. 19.1 (18.6-19.3), p = 0.0001], esterified-cholesterol [3.2 (2.2-3.8) vs. 2.3 (2-2.9), p = 0.02] and triacylglycerol [3.7 (3.1-4) vs. 2.6 (2.1-2.8), p = 0.0001] to HDL were all reduced immediately after the marathon but returned to baseline 72 h later. Running a marathon increased IL-6 and TNF-alpha levels, but after 72 h these values returned to baseline. Lipid transfer, except esterified-cholesterol transfer, was higher in marathon runners than in sedentary individuals, but the marathon itself acutely inhibited lipid transfer. In light of these novel observations, further study is required to clarify how these metabolic changes can influence HDL composition and anti-atherogenic function.