Neopterin production in SCID mice injected with human peripheral blood mononuclear cells.

Intraperitoneal transfer of peripheral blood mononuclear cells (PBMC) from human EBV+ donors into severe combined immunodeficiency (SCID) mice is a suitable model for studying some aspects of lymphomagenesis and immune activation. Neopterin is a soluble immune marker which was found to be a useful indicator for immune activation processes in humans, e.g. to monitor immunological complications in allograft recipients or to predict prognosis in HIV-infected individuals. In contrast, this pteridine compound is normally synthesized in murine organism in only very low amounts. The measurement of neopterin concentrations in serum and urine should be feasible in SCID mice reconstituted with human PBMC. In this study, we examined the usability of this experimental model for monitoring human T cell activation by neopterin measurements. The production of neopterin by SCID mice after injection of freshly isolated human PBMC, purified B or T cells and cultured Epstein-Barr virus (EBV)+ lymphoblastoid cells (LCL) was determined. It was found that neopterin can be detected early after injecting SCID mice with PBMC, whereas injection of purified human T or B cells did not result in neopterin production. Highest neopterin levels were detected in mice treated with LCL cells when developing lymphoma. We discuss the possible sources of neopterin along this process and its usefulness in this model.

Miastenia gravis tras tratamiento con tetrazepan / Myasthenia gravis after tetrazepam treatment

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Increased peripheral mononuclear cells expression of adhesion molecules in alcoholic cirrhosis: its relation to immune activation.

BACKGROUND/AIMS: Cell adhesion phenomena are relevant in the immune mechanisms leading to organ damage in various diseases. Patients with alcoholic cirrhosis present with immune alterations that include findings of immunodeficiency and indications of an activated immune response. METHODS: In 37 patients with alcoholic cirrhosis we have determined the expression of surface antigens and adhesion molecules on peripheral lymphocytes and monocytes, serum levels of immunoglobulins, circulating cytokines, namely tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta, serum soluble intercellular adhesion molecule and neopterin. RESULTS: In patients, we found an increased expression of several adhesion molecules ICAM-1, LFA-3 and MAC-1 in lymphocytes, LFA-3 in monocytes and surface activation markers CD71 and DR in lymphocytes, as well as increased concentrations of the serum parameters measured: IgA, IgG, IgM, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, soluble ICAM-1 and neopterin, in comparison with controls. CONCLUSIONS: The enhancement of the adhesion phenomena in circulating mononuclear cells of patients with cirrhosis correlates to the severity of the disease and is related to other parameters of immune activation.

[Lymphoblastic stimulation in cirrhotic and non-cirrhotic chronic alcoholics]. / Estimulación linfoblástica en alcohólicos crónicos con o sin cirrosis hepática.

OBJECTIVE: To study whether there exists a functional change in lymphocytes in chronic alcoholic patients compared with chronic alcoholic cirrhotic patients. An open, prospective study was performed of the in vitro proliferative response (lymphoblastic transformation) of lymphocytes to phytohemagglutinin, mitogen pokeweed, and concanavalin A. PATIENTS: 73 males (51.4 +/- 12 years) divided on the basis of alcoholic intake and/or chronic liver disease in: social drinkers (< 80 g ethanol/day), 23; excessive drinkers (80-160 g ethanol/day), 14; chronic alcoholics (> 160 g ethanol/day), 21; and cirrhotic patients with no current alcohol consume, 15 cases. RESULTS: In social drinkers, excessive drinkers and cirrhotic patients similar proliferative responses to mitogens were observed, with no significant differences between groups. CONCLUSIONS: Our findings support the concept that chronic alcoholism has immunosuppressive effects which precede the emergence of liver cirrhosis.

T-cell activation, expression of adhesion molecules and response to ethanol in alcoholic cirrhosis.

Abnormal immune function is a well-recognized feature in patients with alcoholic cirrhosis. It may contribute to the pathogenesis of the disease and to the clinical consequences. Nevertheless, a potential role of ethanol to elicit immune disturbances in patients is still unclear. To further examine the immune mechanisms which potentially are involved in alcoholic cirrhosis and the relationship to ethanol, we have determined the expression of surface antigens CD4, CD8, and of adhesion molecules CD25, LFA-1, ICAM-1 and LFA-3 in patients and in response to stimulation with OKT-3, IL-2 and with ethanol in vitro. In addition, we quantified the production of IL-2, TNF-alpha and IFN-gamma by lymphocytes of alcoholic cirrhosis patients compared to controls. Lymphocytes from patients showed increased basal and stimulated expression of CD4, CD25, LFA-1, ICAM-1 and LFA-3 molecules and increased TNF-alpha production in comparison to controls. When lymphocytes from patients were co-cultured with ethanol, the overexpression of activation markers and TNF-alpha production was similar to that obtained with mitogens. In contrast, a predominant suppressive effect of ethanol was observed in lymphocytes from controls. Our study underlines the importance of a chronic state of immune activation in alcoholic cirrhosis. The data further suggest a role of ethanol to stimulate immune response and to be directly involved in the development of disease.

Activated Cellular Immunity in Chronic Hepatitis C.

The importance of local immune mechanisms in the development of chronic hepatitis C and its relation with systemic immune disorders is becoming clear and suggests a more generalized involvement of the immune response in this disease. For this reason, we have investigated the serum concentrations of the soluble immune activation markers neopterin, ß2-microglobulin and interferon-γ in 28 patients with hepatitis C virus related chronic active hepatitis (n=20) or chronic persistent hepatitis (n=8). Increased levels of neopterin, ß2-microglobulin and interferon-γ were found in a subgroup of the patients. Serum ß2-microglobulin and neopterin concentrations were strongly related. Patients with chronic active hepatitis had higher ß2-microglobulin levels than those with chronic persistent hepatitis. There were no significant differences in neopterin and interferon-γ levels between chronic active hepatitis and chronic persistent hepatitis. A strong association was found between older age and higher ß2-microglobulin levels. Because patients with chronic active hepatitis were older than patients with chronic persistent hepatitis, older age may have at least partly contributed to the difference in ß2-microglobulin. Because of the known association between cell-mediated immune activation and the production of interferon-γ, neopterin and ß32-microglobulin, our results imply that a Th1-type immune response is stimulated in chronic hepatitis C.

Soluble Receptors for Tumor Necrosis Factor and Neopterin as Parameters of Cell-Mediated Immune Activation.

Tumor necrosis factor-α is a pleiotropic cytokine which is capable of inducing numerous immunological and biochemical changes in target cells and tissues, Soluble tumor necrosis factor-α receptors function to modulate the biological properties of tumor necrosis factor-α by enhancing or counteracting its action. In various pathologic states the production and release of soluble tumor necrosis factor receptors may mediate host response and determine the course and outcome of disease by the interaction with tumor necrosis factor-α and competing with cell surface receptors. The actual and forthcoming research of soluble tumor necrosis factor receptors in body fluids such as plasma or serum is a new tool to gain information about immune processes and is providing valuable insight into a variety of pathological conditions. In various diseases concentrations of sTNF-Rs correlate strongly with levels of neopterin, large amounts of which being released from human monocytes/macrophages upon stimulation with interferon-γ. Like neopterin, sTNF-Rs levels show high accuracy in the follow-up and prognosis of various diseases and correlate with the clinical stage and the progression of human immunodeficiency virus infection and sepsis. In cancer and autoimmune diseases, measurement of sTNF-Rs and neopterin provides useful information for monitoring. The quantification of sTNF-Rs and neopterin concentrations often provide even superior information than that obtained with classical disease markers, probably due to the direct involvement of the "interferon-γ/tumor necrosis factor-α system" in the pathogenetic mechanisms of the diseases. Data imply that measurement of sTNF-Rs, especially of the 75kD-type, is a useful adjunct for quantification of the Th-1 type immune response, sharing many characteristics with neopterin.

Effect of acute alcohol ingestion on mineral metabolism and osteoblastic function.

Alcohol abuse can induce osteopenia in some subjects. In order to study the effect of a single dose of alcohol on mineral metabolism and osteoblastic function, we have measured calcium, phosphate, parathyroid hormone midmolecule (PTHm), parathyroid hormone intact molecule (PTHi) and bone-gla-protein (BGP) in serum of 8 healthy men after the ingestion of a single dose of alcohol (0.6 g/kg body weight). Urinary calcium and magnesium were also measured. After alcohol intake, both serum PTHm and PTHi were decreased, as well as serum BGP. Serum phosphate and urinary calcium and magnesium were increased. An inverse significant correlation was found between PTHi and serum phosphate (r = 0.42; p < 0.02). Our data show that acute alcohol ingestion lowers serum PTH and BGP in humans, suggesting an inhibitory effect on parathyroid and osteoblastic function. These changes and the alcohol-induced transient hypercalciuria could contribute to the development of bone disease associated with chronic alcohol abuse.

[Pleuropericarditis as the only manifestation of Legionella pneumophila infection]. / Pleuropericarditis como manifestación única de infección por Legionella pneumophila.

Pleural effusion caused by Legionella is seen fairly frequently but is hardly ever of great clinical significance. Pericardial involvement has been described only rarely. We present a case of pleuropericarditis as the only sign of infection by Legionella pneumophila in a 66-years-old man with no prior history of disease. The patient came to the hospital with chest pain suggestive of pleurisy, low-grade fever, dry cough and dyspnea. The etiology was not suspected and the diagnosis was made retrospectively based on indirect immunofluorescence. After 3 weeks of treatment with high dose of erythromycin the patient recovered and remains asymptomatic to date. We conclude that infection by Legionella pneumophila should be suspected in patients with pleurisy or pericarditis of unknown cause.

Neopterin and soluble tumor necrosis factor receptor type I in alcohol-induced cirrhosis.

Alcohol-induced cirrhosis (AC) is accompanied by disturbances of immune function and cytokine production. To better define the pattern of cytokine synthesis in this disease and to relate it to the immune activation state, we measured circulating levels of soluble tumor necrosis factor receptor p55 (sTNFR-55) and neopterin in a group of 85 patients with AC (classified according to the Child-Pugh score of severity of liver disease) and 43 healthy volunteers. Serum concentrations of sTNFR-55 and neopterin were significantly raised in patients with AC. Moreover, concentrations of sTNFR-55 were significantly higher in patients with more severe disease compared with the group with lower severity. There were significant correlations between sTNFR-55 and neopterin levels in patients and controls. The results contribute to affirm the existence of an immune activation state in AC that could be responsible for the development of the disease and clinical complications.

Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis.

Soluble tumour necrosis factor receptors (sTNF-Rs) play a role as modulators of the biological function of tumour necrosis factor-alpha (TNF-alpha) in an agonist/antagonist pattern. In various pathologic states the production and release of sTNF-Rs may mediate host response and determine the course and outcome of disease by interacting with TNF-alpha and competing with cell surface receptors. The determination of sTNF-Rs in body fluids such as plasma or serum is a new tool to gain information about immune processes and provides valuable insight into a variety of pathological conditions. Regarding its immediate clinical use, sTNF-Rs levels show high accuracy in the follow-up and prognosis of various diseases. In HIV infection and sepsis, sTNF-Rs concentrations strongly correlate with the clinical stage and the progression of disease and can be of predictive value. Determination of sTNF-Rs also gives useful information for monitoring cancer and autoimmune diseases. The information provided is often even superior to that obtained with classical disease markers, probably due to the direct involvement of the "TNF system" in the pathogenetic mechanisms in these patients. The available data imply that the measurement of sTNF-Rs, especially of the sTNF-R 75kD type, is a useful adjunct for quantification of the Th1-type immune response, similar to other immune activation markers such as neopterin and beta 2-microglobulin. Endogenous sTNF-Rs concentrations appear to reflect the activation state of the TNF-alpha/TNF receptor system.

Increased immune activation during and after physical exercise.

The present study has been performed to examine the pattern of immune response during and following a long-duration of physical exercise. We have measured plasma concentrations of serum soluble immune activation markers namely soluble interleukin-2 receptor (sIL-2R), soluble CD8 (sCD8), soluble intercellular adhesion molecule 1 (sICAM-1), soluble CD23 (sCD23), soluble tumor necrosis factor receptor (sTNF-R) and neopterin in 18 individuals before, during (ascent: 3 h, descent: 2 h) and after an alpine tour. Compared to baseline levels, all the parameters were significantly increased on top of the mountain and/or after descent. Within 36 hours after the tour sIL-2R, sCD8 and sICAM-1 decreased. In contrast, sTNF-R and neopterin levels remained higher than baseline throughout the study, only partially decreasing 24 and 36 hours from start. These data show immune system activation induced by physical exercise. The increase of parameters sTNF-R and neopterin, reflecting activation of macrophages, was sustained. The data suggest that immune activation phenomena may be involved in the pathogenesis of impaired immune function after exercise and the exercise-induced asthma.

Tumour necrosis factor, interleukin-1 and interleukin-6 in alcoholic cirrhosis.

The existence of a cellular immune deficit in alcoholic cirrhosis, and the alterations described in cytokine synthesis in this disease, led us to compare serum concentrations of tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6 in a group of 33 patients with alcoholic cirrhosis (classified according to the Child-Pugh grade of severity of liver disease) and 43 healthy volunteers. Serum concentrations of tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6 were significantly raised in alcoholic cirrhosis patients, with no significant differences between patients with liver disease of different grades of severity. The results suggest that cirrhosis involves the activation of the monocyte-macrophage system, which may contribute to the progression of the disease and its clinical manifestations.