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Biomedical subjects

Melchor Alvarez-Mon

Publications and source records attributed to Melchor Alvarez-Mon.

At least 19 recordsLinked to original sources
PubMed2006

Increased spontaneous ex vivo apoptosis and subset alterations in peripheral blood T cells from patients with multiple sclerosis.

In order to characterize the immunophenotype and the lymphocyte apoptosis in multiple sclerosis (MS) patients, the peripheral blood lymphocytes of 46 MS patients and 12 healthy volunteers were studied by flow cytometry. Immunophenotypic alterations included significant increases in T CD4+ lymphocytes and reductions in the percentages of CD3+ and CD8+ T cells. After 24 h of culture spontaneous apoptosis was increased in almost T lymphocyte subsets from MS patients and it was significantly higher in those patients who had suffered more than two relapses in the two previous years. The incidence of spontaneous apoptosis was not dependent on FasL-Fas interactions and correlated with the percentages of cells positive for active caspases but not with percentages of Fas+ cells. The increased susceptibility to apoptosis of peripheral blood T lymphocytes from MS patients is difficult to reconcile with the previously proposed role of a defective lymphocyte apoptosis in the pathophysiology of MS.

Adult↗
PubMed2006

Distinctive pattern of cytokine production and adhesion molecule expression in peripheral blood memory CD4+ T cells from patients with active Crohn's disease.

An expansion of both circulating and intestinal lamina propria CD4+ CD45RO+ T cells has been described in patients with Crohn's disease. We studied both the cytokine profile and the expression of adhesion molecules on this T-cell subset. Peripheral blood CD4+ CD45RO+ T cells from patients with Crohn's disease (n=45) were assessed by flow cytometry and RT-PCR methods. The cytokine profile was also measured in intestinal lamina propria from seven patients. They were classified according to the CDAI and the results were compared with those of patients with ulcerative colitis (n=21) and noninflammatory intestinal conditions (n=15), and healthy controls (n=39). The mean percentage of circulating CD4+ CD45RO+ T cells producing intracellular TNF was higher in active than in inactive Crohn's disease patients (p < 0.001), active (p = 0.49) and inactive ulcerative colitis (p = 0.019), and healthy controls (p =0. 017). TNF expression correlated with CDAI (p < 0.001). An increased expression of intracellular IL-2, IL-6, and IL-10 in active Crohn's disease patients was also found. CD62L was downregulated in active Crohn's disease patients while no differences were observed in CD49d and CD11a expression. Lamina propria CD4+ CD45RO+ T cells from active Crohn's disease lesions showed an increased intracellular staining of TNF, IFN-gamma, and IL-10. Both peripheral and intestinal mucosa CD4+ CD45RO+ T cells from active Crohn's disease patients show an increased production of TNF. In addition, the circulating CD4+ CD45RO+ T-cell subset expresses a pattern of adhesion molecules that promotes homing to extranodal lymphoid tissues. This T-cell subset may play a relevant role in the immunopathogenesis of Crohn's disease.

Adolescent↗
PubMed2006

Accurate apoptosis measurement requires quantification of loss of expression of surface antigens and cell fragmentation.

BACKGROUND: The use of ratiometric cell enumeration methods emerges as a more accurate method of measurement of the occurrence of apoptosis in cell cultures. These new flow cytometry methods were used to quantify the impact of cell fragmentation and loss of lineage antigen (LAg) expression on measurement of apoptosis. METHODS: Highly purified human lymphocyte populations were negatively sorted and cultured for 24 h. Apoptotic cells were identified using annexin V, 7-amino-actinomycin D and their LAgs were stained with antibodies. A new indicator, the apoptotic rate, was used to determine apoptosis occurrence and its validity compared with the widely accepted percentage of apoptotic cells (apoptotic index, AI). RESULTS: Loss of LAg expression and cell fragmentation were observed under all conditions assayed and for all cell populations studied. CONCLUSIONS: Current methods for quantifying of apoptosis involving AI systematically underestimate apoptosis occurrence in all populations and conditions, especially among cells undergoing spontaneous apoptosis.

Antigens, Surface↗
PubMed2006

Treatment with AM3 restores defective T-cell function in COPD patients.

BACKGROUND: Lymphocyte alterations have been associated with an increased prevalence of acute respiratory infections in COPD patients. AM3 is an oral immunomodulator that normalizes the defective functions of peripheral blood natural killer and phagocytic cells in COPD patients and improves their health-related quality of life. OBJECTIVES: To characterize putative systemic abnormalities of the T-cell compartment in COPD patients, and to investigate whether AM3 can restore such abnormalities. DESIGN: The study was a randomized, prospective, double-blind, placebo-controlled trial in a cohort of COPD patients. The results were also compared to those of nonsmoker and ex-smoker healthy control subjects. SETTING: Outpatient departments of four hospitals. PATIENTS: Seventy COPD patients were randomized to receive either AM3 or a placebo orally for 90 consecutive days. Populations of 36 healthy nonsmokers and 36 healthy ex-smokers were used as control subjects. MEASUREMENTS: Peripheral blood mononuclear cell (PBMC) proliferation and production of interleukin (IL)-2, IL-4, IL-12p40, tumor necrosis factor-alpha, and interferon (IFN)-gamma proteins in response to the T-cell polyclonal mitogens were assessed at baseline and at the end of treatment. RESULTS: The proliferative response was significantly decreased in COPD patients. Decreased production of IFN-gamma was the only defect in the profiles of the cytokine measures, and was selectively observed in COPD patients, but not in nonsmoker and ex-smoker healthy control subjects. Treatment with AM3 significantly restored the PBMC proliferative response to polyclonal mitogens and significantly promoted stimulated IFN-gamma production in these patients. The normalization of these proliferative responses was not related to significant variations in the numbers of peripheral blood monocytes, CD3+, CD4+, CD8+ cells or of any major naïve/memory/activated T-cell subset. The increased IFN-gamma production in the AM3 study arm was associated with an increase in the mean of number of IFN-gamma molecules produced per CD8+ T cells. CONCLUSIONS: PBMCs of COPD patients showed clear functional T-lymphocyte abnormalities that are rescued by AM3 treatment.

Adjuvants, Immunologic↗
PubMed2005

Mesenteric Th1 polarization and monocyte TNF-alpha production: first steps to systemic inflammation in rats with cirrhosis.

A systemic inflammatory state with increased circulating tumor necrosis factor alpha (TNF-alpha) has been related to the bacterial infection susceptibility and hemodynamic derangement of patients with cirrhosis. We compared the activation status of immune cell subpopulations defined by 4-color cytometry in mesenteric and peripheral lymph nodes and blood of rats with CCl(4)-cirrhosis to define the immune response initiation site, the T-cell and monocyte contribution to pro-inflammatory cytokine production, as well as the pathogenic role of enteric bacteria in the cirrhosis immune response. Th1 cells and monocytes were expanded in the mesenteric nodes (P < .001) and blood (P < .001) of rats with cirrhosis, and activated to produce interferon gamma (P < .0001) and TNF-alpha (P < .0001), respectively. The greater numbers of recently activated CD134(+) Th cells in mesenteric nodes compared with blood, the correlation between their numbers in mesenteric nodes and blood (r = 0.66, P < .001), and the expansion of activated CD45RC(-) Th cells, which are unable to re-enter lymph nodes, in mesenteric nodes but not in blood or axillary nodes points to mesenteric nodes as the origin site of activated Th cells. Abrogation of bacterial translocation by bowel decontamination reduced the number of activated Th cells and monocytes, and normalized interferon gamma production by Th cells and TNF-alpha production by monocytes in mesenteric nodes and blood, respectively. In conclusion, in cirrhosis, enteric bacteria start off an orchestrated immune response cascade in mesenteric nodes involving Th1 polarization and monocyte activation to TNF-alpha production. Later, the recirculation of these activated effector immune cells into blood promotes systemic inflammation.

Animals↗
PubMed2005

Treatment with the immunomodulator AM3 improves the health-related quality of life of patients with COPD.

BACKGROUND: COPD has a severe impact on patient quality of life. AM3 is an orally effective immunomodulator that can normalize the defective antimicrobial functions of the immune system effector cells of COPD patients. OBJECTIVES: We analyzed the effect of AM3 on exacerbation frequency and health-related quality of life (HRQL) of COPD patients with moderate disease. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Outpatient departments of 21 hospitals. METHODS: A total of 253 COPD patients with a mean age of 67.7 years (SD, 8.1 years) and mean FEV(1) percentage of predicted of 49.6% (SD, 10.2%) were evaluated. Patients received (orally) either 3 g/d AM3 or a matched placebo for 180 consecutive days. Patient quality of life was measured using the St. George's Respiratory Questionnaire (SGRQ). RESULTS: There were no differences in the exacerbation frequency of the two groups (0.82 episodes per patient in the AM3 arm vs 0.84 in the placebo arm), and 55.3% of patients were exacerbation free in the AM3 arm compared to 48.8% in the placebo arm (p = 0.11). At the end of treatment, quality of life was significantly better in the AM3 arm than in the placebo arm (SGRQ total score, 32.9; SD, 16.4, compared to 37.5; SD, 17.5 [p < 0.05]: activity score, 47.5; SD, 22.4, compared to 54.6; SD, 20.5 [p < 0.05]). The improvements in total SGRQ scores were 8.9 U (SD, 13.4 U) in the AM3 arm and 5.6 U (SD, 15.9 U) in the placebo arm (p = 0.076). Improvements on the symptoms subscale were 15.9 U (SD, 20.7 U) for the AM3 arm and 10.2 U (SD, 21.3 U) for the placebo arm (p < 0.05). Both AM3 and the placebo were clinically, biochemically, and hematologically well tolerated. CONCLUSIONS: AM3 is a safe, easily tolerated, effective treatment that improves the quality of life of COPD patients as measured by SGRQ scores. This effect was observed with no significant reduction in the frequency of exacerbations.

Adjuvants, Immunologic↗
PubMed2004

Statins inhibit HIV-1 infection by down-regulating Rho activity.

Human immunodeficiency virus (HIV)-1 infectivity requires actin-dependent clustering of host lipid raft-associated receptors, a process that might be linked to Rho guanosine triphosphatase (GTPase) activation. Rho GTPase activity can be negatively regulated by statins, a family of drugs used to treat hypercholesterolemia in man. Statins mediate inhibition of Rho GTPases by impeding prenylation of small G proteins through blockade of 3-hydroxy-3-methylglutaryl coenzyme A reductase. We show that statins decreased viral load and increased CD4+ cell counts in acute infection models and in chronically HIV-1-infected patients. Viral entry and exit was reduced in statin-treated cells, and inhibition was blocked by the addition of l-mevalonate or of geranylgeranylpyrophosphate, but not by cholesterol. Cell treatment with a geranylgeranyl transferase inhibitor, but not a farnesyl transferase inhibitor, specifically inhibited entry of HIV-1-pseudotyped viruses. Statins blocked Rho-A activation induced by HIV-1 binding to target cells, and expression of the dominant negative mutant RhoN19 inhibited HIV-1 envelope fusion with target cell membranes, reducing cell infection rates. We suggest that statins have direct anti-HIV-1 effects by targeting Rho.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites.

Serum lipopolysaccharide-binding protein is increased in a subset of non-infected ascitic cirrhotic patients, a finding previously related to bacterial passage from the gut to the circulation without overt infection. We prospectively analysed the risk factors associated with a first episode of severe bacterial infection in 84 ascitic cirrhotics, followed up for a median of 46 weeks. The cumulative probability of such infection in patients with raised and normal lipopolysaccharide-binding protein was 32.4% and 8.0% (p=0.004), respectively. Increased lipopolysaccharide-binding protein was the only factor independently associated with severe bacterial infection in a multivariate analysis (relative risk 4.49, 95% CI 1.42-14.1). Monitoring of serum lipopolysaccharide-binding protein could, therefore, help to target cirrhotic patients with ascites for antibiotic prophylaxis.

Acute-Phase Proteins↗
PubMed2004

APRIL promotes B-1 cell-associated neoplasm.

A tumor-supporting role for the TNF-like ligand APRIL has been suggested. Here we describe that 9- to 12-month-old APRIL transgenic mice develop lymphoid tumors that originate from expansion of the peritoneal B-1 B cell population. Aging APRIL transgenic mice develop progressive hyperplasia in mesenteric lymph nodes and Peyer's patches, disorganization of affected lymphoid tissues, mucosal and capsular infiltration, and eventual tumor cell infiltration into nonlymphoid tissues such as kidney and liver. We detected significantly increased APRIL levels in sera of B cell chronic lymphoid leukemia (B-CLL) patients, indicating that APRIL promotes onset of B-1-associated neoplasms and that APRIL antagonism may provide a therapeutic strategy to treat B-CLL patients.

Aging↗
PubMed2004

Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin.

BACKGROUND/AIMS: To investigate the distribution and activation state of circulating monocytes and T-cell subsets, their contribution to tumour necrosis factor-alpha (TNFalpha) production, and their potential relationship with bacterial products of enteric origin in alcoholic cirrhosis. METHODS: Peripheral blood monocytes and T-lymphocytes from 60 cirrhotic patients and 24 controls were characterized by four-color flow-cytometry after labelling of differentiation antigens and cytokines, before and after a 4-week course of norfloxacin or placebo. RESULTS: Monocytes from ascitic patients showed increased number, enhanced CD80 and HLA-DR surface levels, and spontaneous intracytoplasmic TNFalpha expression, when compared to non-ascitic patients and controls. Blood TNFalpha levels directly correlated with the amount of TNFalpha expressed by monocytes. In ascitic patients, there was a collapse of virgin CD4(+) and CD8(+) T-cell subsets; and, an expansion of activated CD4(+) T-cells. The above abnormalities were mainly restricted to ascitic patients with high serum levels of lypolysaccharide-binding-protein. Norfloxacin normalized the number of monocytes, reduced their activated phenotype and ability to produce TNFalpha and improved the abnormal T-cell homeostasis. CONCLUSIONS: In ascitic cirrhosis with high lipolysaccharide-binding-protein, monocytes are spontaneously activated to produce TNFalpha and are major contributors to the elevated serum TNFalpha. The T-cell compartment is profoundly depleted. Enteric bacterial products play a relevant role in these immune cellular abnormalities.

Acute-Phase Proteins↗
PubMed2004

Active Crohn's disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells.

In a previous study we found an expansion of circulating memory (CD45RO(+)) CD4(+) T cells in patients with Crohn's disease (CD). The aim of this work was to investigate the phenotypic and functional characteristics of this T-cell subset in CD. We analyzed in peripheral blood CD4(+)CD45RO(+) T cells from CD patients the expression of surface markers associated to immune activation, costimulation, and apoptosis. In sorted CD4(+)CD45RO(+) T cells apoptosis was quantified by fluorescent annexin V binding. Healthy subjects and patients with ulcerative colitis and acute bacterial enterocolitis served as control groups. An increased percentage of memory CD4(+)CD45RO(+) T cells lacking the expression of costimulatory receptor CD28 was detected in patients with active CD when compared to the other groups evaluated. This expanded CD4(+)CD45RO(+)CD28(null) T-cell subset expressed mostly the effector-cell marker CD57(+). Both CD28 downregulation and CD57 expression correlated to CDAI and surrogate markers of disease activity. These phenotypic changes observed on CD4(+)CD45RO(+) T cells from active CD returned to values similar to healthy controls after clinical remission. Moreover, this memory CD28(null) T-cell subset might express more intracytoplasmic TNF and IFN-gamma than their CD28(+) counterpart. Significantly lower frequencies of memory CD4(+)CD45RO(+) T cells expressing CD95 apoptosis receptor were found in patients with active CD. Moreover, sorted CD4(+)CD45RO(+)and CD4(+)CD45RO(+) CD28(null) T cells from patients with active CD exhibited a lower apoptotic rate than that found in healthy controls and inactive CD patients. According to our data, circulating T lymphocytes from active CD patients show distinctive phenotypic and functional changes, characterized by an expansion of memory CD4(+)CD45RO(+)CD28(null) T cells expressing effector-associated cell surface molecules and displaying enhanced resistance to apoptosis.

Adult↗
PubMed2004

Protection against muscle damage in competitive sports players: the effect of the immunomodulator AM3.

Strenuous physical exercise of the limb muscles commonly results in damage, especially when that exercise is intense, prolonged and includes eccentric contractions. Many factors contribute to exercise-induced muscle injury and the mechanism is likely to differ with the type of exercise. Competitive sports players are highly susceptible to this type of injury. AM3 is an orally administered immunomodulator that reduces the synthesis of proinflammatory cytokines and normalizes defective cellular immune fractions. The ability of AM3 to prevent chronic muscle injury following strenuous exercise characterized by eccentric muscle contraction was evaluated in a double-blind and randomized pilot study. Fourteen professional male volleyball players from the First Division of the Spanish Volleyball League volunteered to take part. The participants were randomized to receive either placebo (n=7) or AM3 (n=7). The physical characteristics (mean+/-s) of the placebo group were as follows: age 25.7+/-2.1 years, body mass 87.2+/-4.1 kg, height 1.89+/-0.07 m, maximal oxygen uptake 65.3+/-4.2 ml.kg(-1).min(-1). Those of the AM3 group were as follows: age 26.1+/-1.9 years, body mass 85.8+/-6.1 kg, height 1.91+/-0.07 m, maximal oxygen uptake 64.6+/-4.5 ml.kg(-1).min(-1). All participants were evaluated for biochemical indices of muscle damage, including concentrations of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatine kinase (CK) and its MB fraction (CK-MB), myoglobin, lactate dehydrogenase, urea, creatinine and gamma-glutamyltranspeptidase, both before and 30 days after treatment (over the peak of the competitive season). In the placebo group, competitive exercise (i.e. volleyball) was accompanied by significant increases in creatine kinase (494+/-51 to 560+/-53 IU.l(-1), P < 0.05) and myoglobin (76.8+/-2.9 to 83.9+/-3.1 microg.l(-1), P < 0.05); aspartate aminotransferase (30.8+/-3.0 to 31.1+/-2.9 IU.l(-1)) and lactate dehydrogenase (380+/-31 to 376+/-29 IU.l(-1)) were relatively unchanged after the 30 days maximum effort. AM3 not only inhibited these changes, it led to a decrease from baseline serum concentrations of creatine kinase (503+/-49 to 316+/-37 IU.l(-1), P < 0.05) and myoglobin (80.1+/-3.2 to 44.1+/-2.6 IU.l(-1), P < 0.05), as well as aspartate aminotransferase (31.1+/-3.3 to 26.1+/-2.7 IU.l(-1), P < 0.05) and lactate dehydrogenase (368+/-34 to 310+/-3 IU.l(-1), P < 0.05). The concentration of CK-MB was also significantly decreased from baseline with AM3 treatment (11.6+/-1.2 to 5.0+/-0.7 IU.l(-1), P < 0.05), but not with placebo (11.4+/-1.1 to 10.8+/-1.4 IU.l(-1)). In conclusion, the use of immunomodulators, such as AM3, by elite sportspersons during competition significantly reduces serum concentrations of proteins associated with muscle damage.

Adjuvants, Immunologic↗
PubMed2003

Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.

Intestinal bacterial overgrowth and translocation, both common in cirrhosis with ascites, may lead to the activation of monocytes and lymphocytes, increased levels of proinflammatory cytokines, and enhanced synthesis of nitric oxide present in cirrhosis. Bacterial endotoxin promotes the synthesis of lipopolysaccharide (LPS)-binding protein (LBP), and forms a LPS-LBP complex that binds to CD14. This study was designed to evaluate LBP levels and their correlation to the immune response and the hemodynamic status in cirrhotic patients. Plasma LBP, endotoxin, soluble CD14 (sCD14), cytokines, renin, nitrites, and systemic vascular resistance were determined before and 4 weeks after norfloxacin or placebo in 102 cirrhotic patients and 30 controls. LBP was elevated in 42% of ascitic cirrhotic patients (15.7 +/- 0.7 versus 6.06 +/- 0.5 microg/mL, P <.01). In 60% of high LBP patients, endotoxin was within normal range. Among ascitic patients, those with high LBP showed greater (P <.05) levels of sCD14, tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), nitrites + nitrates (NOx)/creatinine, and renin, and lower vascular resistance. In the cirrhotic patients with high LBP, norfloxacin normalized (P <.01) LBP (from 16.6 +/- 0.5 to 5.82 +/- 0.8 microg/mL) and sCD14; reduced the level of cytokines, NOx/creatinine, and renin; and increased vascular resistance; but lacked effect in patients with normal LBP. Portal pressure was unchanged after norfloxacin in another group of 18 cirrhotic patients with high and 19 with normal LBP. In conclusion, the subset of ascitic cirrhotic patients with marked immune and hemodynamic derangement is identified by increased LBP levels. Amelioration of these abnormalities by norfloxacin suggests the involvement of enteric bacteria or their products in the triggering of the process.

Acute-Phase Proteins↗