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Biomedical subjects

H M Lorenz

Publications and source records attributed to H M Lorenz.

At least 19 recordsLinked to original sources
PubMed2006

Rapid progressive eosinophilic cardiomyopathy in a patient with Churg-Strauss syndrome (CSS).

Churg-Strauss syndrome (CSS) is a rare necrotizing, systemic vasculitis that is almost invariably associated with bronchial asthma. Although overall prognosis is good and treatment with corticosteroids alone or in combination with other immunosuppressive agents is typically successful, there are reports of patients that do not show signs of clinical improvement under the usual pharmacotherapy. Small clinical studies suggested that cardiac or gastrointestinal involvement is associated with an adverse prognosis. We here report the case of a 38 year old male patient with a history of bronchial asthma who was admitted to our hospital for further evaluation of progressive dyspnea. Blood eosinophilia, infiltrates of both lungs, signs of necrosis and eosinophil deposits on myocardial biopsy combined with a history of bronchial asthma established the diagnosis of CSS with cardiac involvement. We initiated an immunosuppressive therapy with prednisone and methotrexate. Upon tapering of the dosage of prednisone, we noticed worsening of symptoms and further deterioration of cardiac function. Despite the addition of cyclophosphamide and adjustment of heart failure medication, we were not able to stabilize the cardiac situation. Due to rapid progressive eosinophilic cardiomyopathy associated with CSS refractory to medical therapy, our patient was placed on the urgent heart transplantation waiting list and, in the meantime, has undergone successful cardiac transplantation.

Adult↗
PubMed2005

Autologous haematopoietic stem cell transplantation for Behcet's disease with pulmonary involvement: analysis after 5 years of follow up.

BACKGROUND: Myeloablative chemotherapy and autologous haematopoietic stem cell transplantation (HSCT) may provide a therapeutic option in severe Behçet's disease (BD) with pulmonary involvement. CASE REPORTS: Two patients with BD with pulmonary involvement refractory to conventional immunosuppressive treatment underwent HSCT 1999. Stem cells were mobilised with cyclophosphamide (2 and 4 g/m(2)) and subsequently enriched ex vivo for CD34+ cells. The conditioning regimen used was melphalan (200 mg/m(2)). Outcome was measured by improvement of clinical features, function of affected organs, serological markers, need for immunosuppressive chemotherapy after transplant, and relapse. In both cases HSCT was successful, with good response and without serious complications. After 5 years of follow up one patient is in complete remission without immunosuppressive drugs and one has partial remission, needing low dose corticosteroids (8 mg/day). CONCLUSION: In these two patients myeloablative chemotherapy, followed by HSCT could be performed safely with marked improvement. In comparison with other observational studies the duration of more than 5 years of remission is remarkable, and its full duration is still unknown.

Adult↗
PubMed2005

Induction of apoptosis by spermine-metabolites in primary human blood cells and various tumor cell lines.

Polyamines are involved in the regulation of cellular growth and survival by interacting with processes like translation, transcription or ion transport. The aim of our study was to analyze whether polyamines induce apoptosis in hematopoetic cells and to investigate the molecular mechanisms involved. We found an induction of apoptosis by spermine in primary human cells and malignant tumor cell lines. Spermine-treatment resulted in an intracellular increase of reactive oxygen species. Apoptosis was mediated by a collapse of mitochondrial membrane potential, a decrease in Bcl-2 expression and a release of apoptosis mediating molecules from mitochondrial intermembrane space (cytochrome C, Smac/DIABLO). Spermine-mediated apoptosis was caspase-dependent. To test whether spermine mediates apoptosis through metabolites we analyzed the effects of several molecules that interfere with its catabolism. Aminoguanidine, an inhibitor of serum amine oxidase, aldehyde-dehydrogenase, which degrades aldehydes to less reactive molecules or N-acetyl-cysteine, a glutathion precursor, significantly inhibited spermine-mediated apoptosis. From these data we conclude that spermine-derived aldehydes and intracellular accumulation of reactive oxygen species result in mitochondria mediated apoptosis.

Acetylcysteine↗
PubMed2001

CD45 tyrosine phosphatase controls common gamma-chain cytokine-mediated STAT and extracellular signal-related kinase phosphorylation in activated human lymphoblasts: inhibition of proliferation without induction of apoptosis.

The objective of this study was to test whether CD45 signals can influence signaling processes in activated human lymphoblasts. To this end, we generated lymphoblasts which proliferate in response to common gamma-chain cytokines, but readily undergo apoptosis after cytokine withdrawal. In experiments with the CD45R0 mAb UCHL-1, but not control CD45 mAbs, we found significant inhibition of proliferation. Interestingly, the pan-CD45 mAb GAP8.3, which is most effective in inhibition of OKT-3-mediated proliferation in quiescent lymphocytes, was ineffective in lymphoblasts. Addition of CD3 mAb OKT-3 had no influence on IL-2-mediated proliferation (with or without UCHL-1). In contrast, after addition of OKT-3 to IL-4- and IL-7-stimulated proliferation assays, UCHL-1 signals could not significantly alter cellular proliferation. We did not find induction of apoptosis following CD45R0 signaling. In Western blots using mAbs detecting phosphorylated STAT-3, STAT-5, STAT-6, or extracellular signal-related kinase 1/2, we found that CD45R0 signaling could effectively diminish phosphorylation of these intracellular signaling components. Using RT-PCR, we found that CD45R0 signaling inhibited IL-2 mRNA production without major influence on IL-13, IL-5, or IFN-gamma mRNA levels. Costimulation with OKT-3 and IL-2 optimally induced secretion of IFN-gamma, TNF-alpha, and IL-5, which was not decreased by CD45 signals. In conclusion, we illustrate that CD45R0 signals control early cytokine receptor-associated signaling processes and mRNA and DNA synthesis in activated human lymphoblasts. Furthermore, we show the existence of CD45 epitopes (GAP8.3), which are active and critical for signaling in quiescent lymphocytes, but are nonfunctional in activated human lymphoblasts.

Apoptosis↗
PubMed2001

[New therapy developments in rheumatoid arthritis].

Despite the anti-TNF alpha based progress in the treatment of RA, it is necessary to further optimize study designs and reports (Etanercept/MTX combination with results of radiological progression; publication of D2E7 trials; combination of D2E7 with MTX). Moreover, innovative immunobiologicals (PEG-TNFRI, PEG-TNF alpha antibody fragments, soluble TNFRI, CTLA4-Ig, CD40 ligand antibody, antibodies against IFN-gamma, IL-6, IL-12, IL-15, IL-18, complements), inhibitors of TNF alpha translation (peptides, anti-sense constructs) or TNF alpha synthesis (targeting NF kappa B, p38 MAP-kinase, phosphodiesterase IV, TNF alpha converting enzyme) are forthcoming. Principally different are inhibitors of complement convertases or collagenase as well as vaccination studies or trials trying to induce T cell anergy. Furthermore, for patients with MTX side effects, alternative DMARDs need to be tested along with TNF alpha blockers. Combination studies of TNF alpha constructs with other immunobiologicals (anti-CD4, IL-4, IL-10, IL-1RA) should be evaluated. To date, TNF alpha blockers have been evaluated in very early RA. Finally, a step-down trial will test whether--after induction of remission with a TNF alpha blocker plus MTX--replacement of the TNF alpha blocker with MTX alone or in combination with leflunomide will be able to keep disease activity suppressed for a longer duration.

Antirheumatic Agents↗
PubMed2001

The pathogenesis of autoimmune diseases.

Autoimmunopathies are chronic inflammatory diseases which can be subdivided into several specificities on the ground of the clinical picture as well as serological findings and involvement of organ systems like the kidney, central nervous system or the hematopoietic system. The pathogenesis of these diseases is incompletely understood. With the exception of rare diseases in which the autoantigens are known, in the most frequent autoimmunopathies like rheumatoid arthritis or Systemic Lupus Erythematosus (SLE) only some partial aspects of the pathogenetic scenario are understood and rather well substantiated by experimental data. In RA, there are controversies concerning the central involvement of T-lymphocytes and/or synovial fibroblasts in the initiation of the diseases. It is meanwhile well known that TNF-alpha and possibly other related cytokines are involved at least in the perpetuation of the inflammatory cascades. Specific blockade of TNF-alpha leads to rapid improvement of RA disease activity and can prevent tissue destruction. An intriguing hypothesis postulates a central role for a dysregulated apoptosis in the development of SLE. In this review we will concentrate on pathogenetic concepts of autoimmune diseases as exemplified by RA and SLE.

Animals↗
PubMed2000

[Hypereosinophilia with myocardial involvement due to toxocariasis. Diagnosis of regional myocardial perfusion abnormalities by pulsed tissue Doppler echocardiography].

CASE REPORT: The case of a 57-year-old woman is reported who was admitted for peripheral hypereosinophilia. DIAGNOSIS: Detailed investigations revealed first of all a hypereosinophilic syndrome with infiltration of bone marrow and lung. The patient suffered more and more from angina pectoris with signs of heart failure. Coronary angiography was therefore carried out which showed normal coronary arteries. With suspicion of myocardial involvement endomyocardial biopsies were performed which revealed the presence of Löfflers endocarditis parietalis fibroplastica. Finally, serological studies for parasites disclosed a positive ELISA test for Toxocara, confirmed later to be rising. CONCLUSION: Myocardial involvement of hypereosinophilia, caused by Toxocara is not described until now. Further diagnostic by means of pulsed wave tissue Doppler echocardiography provided regional differentiation of a restrictive filling pattern which documented the importance of this new diagnostic tool in myocardial illness.

Animals↗
PubMed2000

Chlorpromazine induces apoptosis in activated human lymphoblasts: a mechanism supporting the induction of drug-induced lupus erythematosus?

OBJECTIVE: Drug-induced lupus erythematosus is a serious side effect of certain medications, such as procainamide, quinidine, hydralazine, chlorpromazine, and isoniazid, the underlying pathogenesis of which is unresolved. In this study, we examined the influence of these drugs on the regulation of apoptosis, or programmed cell death, in quiescent and activated human lymphocytes. We also discuss the dysregulation of apoptosis as a pathogenetic factor in systemic lupus erythematosus. METHODS: Peripheral blood mononuclear cells or activated lymphoblasts from normal donors were incubated with different concentrations of each of the above-mentioned drugs. RESULTS: We did not find induction of apoptosis in quiescent cells over a broad concentration range. In contrast, lymphoblasts readily underwent apoptosis when cultured with chlorpromazine, but not any of the other drugs, after stimulation with interleukin-2 (IL-2) in a dose-, time- and cell cycle-dependent manner. By several lines of evidence, toxicity was ruled out. Characteristic features of apoptosis-like incorporation of propidium iodide (PI), such as increased annexin V binding, changes in mitochondrial membrane potential, and induction of DNA breaks (as evidenced by TUNEL techniques), could be induced in lymphoblasts after chlorpromazine treatment. Chlorpromazine did not cause apoptosis by inhibition of cytokine binding or blockade of early intracellular signaling. The protease inhibitor Z-VAD and the ceramide inhibitor sphingosine 1-phosphate effectively blocked chlorpromazine-induced apoptosis (by PI staining and by externalization of phosphatidylserine), in contrast to the caspase 3/CPP32 inhibitor DEVD, which had only minor effects. Western blot analysis revealed IL-2-mediated phosphorylation of extracellular signal-regulated kinase, which was sensitive to chlorpromazine. Using lymphoblasts from a patient with Canale-Smith syndrome, we found that chlorpromazine-mediated apoptosis is Fas/ APO-1 independent. CONCLUSION: These data suggest that chlorpromazine mediates apoptosis in human lymphoblasts through specific activation of intracellular proapoptotic signaling cascades. This mechanism might lead to an unsynchronized inflow of apoptotic break-down products and thereby to the induction of (auto)immunity against nuclear components.

Apoptosis↗
PubMed2000

Role of apoptosis in autoimmunity.

Apoptosis is a physiological form of cell death required to ensure that the rate of cell division is balanced by the rate of cell death in multicellular organisms. Dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases: cancer, neurodegeneration, autoimmunity, heart disease and others. In this review we collect arguments supporting a hypothesis of a dysregulated apoptosis leading to development of autoimmunity like systemic lupus erythematosus (SLE). This notion is supported by occurence of known autoantigens in apoptotic blebs, in vitro findings of an increased rate of apoptotic lymphoblasts despite optimal cytokine stimulation combined with a defective in vitro clearance of apoptotic bodies by SLE phagocytes. Moreover, we and others could generate histone-specific lymphocytic cell lines from cells after activation with autologous apoptotic material. These lymphocytes could stimulate autologous B-lymphocytes to produce of anti-dsDNA antibodies, a diagnostic hallmark for SLE. Finally, antibodies against phospholipids like phosphatidylserine are often associated with systemic autoimmunopathies like SLE and others. Phosphatidylserine is exposed on apoptotic cells as early sign of programmed cell death and serves as phagocyte recognition molecule for apoptotic cells. Formation of immune complexes and deposition in tissues might lead to organ damage and disease. This scenario will be discussed in this review in detail.

Animals↗
PubMed2000

CD 95-independent mechanisms of IL-2 deprivation-induced apoptosis in activated human lymphocytes.

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from patients with CD 95 (Fas/APO-1)-deficiency revealed that functional CD95 was not required to induce apoptosis after IL-2 withdrawal. Moreover, apoptosis induction in response to various cytotoxic stimuli was found to be mediated in the absence of functional CD95 but was affirmatorily influenced by IL-2 signaling. Immunoblots showed no downregulation of Bcl-2 or Bcl-xL and no upregulation of Bax, whereas decreased mitochondrial membrane potential was readily measurable 24 h after cytokine deprivation. Tetrapeptide inhibitors showed limited efficacy in preventing apoptosis whereas the caspase inhibitor zVAD-FMK potently blocked induction of apoptosis. Cleavage of different fluorogenic substrates revealed multiple caspase enzyme activities in lymphoblasts, which were not negatively affected by the fas mutation. Starting at 8 h after IL-2 withdrawal, upregulation of active caspase-3 but not of caspase-8 could be detected. Taken together, our data argue for molecular mechanisms of cytokine deprivation-induced apoptosis in activated human lymphocytes independent of CD95.

Apoptosis↗
PubMed2000

Biological agents: a novel approach to the therapy of rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most common chronic autoimmunopathy, clinically leading to joint destruction as a consequence of the chronic inflammatory processes. The pathogenesis of this disabling disease is not well understood, but molecular events leading to tissue inflammation with cartilage and bone destruction are now defined in more detail. Established therapy, slow acting disease-modifying antirheumatic drugs (DMARDs) as with low-dose methotrexate (MTX) are the accepted 'golden standard' therapies and both lead to a significant improvement of disease symptoms, however are unable to stop joint destruction. Due to these disappointing treatment options and the identification of some inflammatory mediators as therapeutic targets, novel therapeutic agents such as monoclonal antibodies (mAbs), cytokine receptor-human immunoglobulin constructs or recombinant human proteins have been tested in RA with some success. In particular, clinical trials testing anti-TNF-alpha agents either alone or in combination with MTX have convincingly demonstrated the feasibility and efficacy of these novel approaches to the therapy of RA. Importantly, a clinical trial testing combination therapy with chimeric (mouse-human) anti-TNF-alpha mAb cA2 (Remicadetrade mark) and MTX could, for the first time in any RA trial, show that average radiological progression in the cA2/MTX groups could be completely prevented over a 12 month observation period. Similar encouraging results might evoke from trials employing other TNF-alpha-directed agents like the fully human mAb D(2)E7 or the p75 TNF-alpha-receptor-Ig construct, etanercept.

Animals↗
PubMed2000

In vivo blockade of tumor necrosis factor-alpha in patients with rheumatoid arthritis: longterm effects after repeated infusion of chimeric monoclonal antibody cA2.

OBJECTIVE: To investigate the longterm consequences of tumor necrosis factor-alpha (TNF-alpha) blockade in patients with rheumatoid arthritis (RA), to compare changes after repeated infusion of cA2 monoclonal antibody with those occurring after the initial treatment, and to investigate significant correlations of cellular or serological changes to the duration of clinical benefit for each patient. METHODS: A clinical trial testing TNF-alpha monoclonal antibody cA2 in treatment of RA showed this therapeutic agent is highly effective. A dosage of 1 mg/kg or 10 mg/kg cA2, given in a single infusion, was compared to placebo. After clinical relapse all patients were (re)treated with 3 or 10 mg/kg cA2. In parallel to this clinical study, we investigated cellular and molecular changes induced by in vivo blockade of TNF-alpha. RESULTS: After an initial transient increase, T lymphocyte counts were not significantly different from starting values throughout the observation period. Monocyte counts as well as serum interleukin 6 (IL-6) and soluble intercellular adhesion molecule 1 (sICAM-1) concentrations remained decreased for several weeks after infusion. After a repeated infusion, increases in numbers of T cells and decreases in monocytes and IL-6 and sICAM-1 concentrations were evident again. Changes in cell counts, however, were smaller, especially in the group initially treated with the low dose (1 mg/kg), despite a higher retreatment dosage of 3 or 10 mg/kg cA2. Similarly, in this group decrease of IL-6 and sICAM-1 concentrations was less pronounced, was delayed to Day 7 after infusion, and lasted for a shorter period than seen after initial treatment. CONCLUSION: We conclude that in vivo TNF-alpha blockade leads to prolonged cellular and serological changes. This effect appears to be less pronounced after repeated infusion of cA2 compared to the initial treatment, mainly in the low dose group.

Adult↗
PubMed2000

TNF inhibitors in the treatment of arthritis.

Rheumatoid arthritis (RA) is a chronic destructive arthritis leading to joint destruction as a consequence of chronic inflammatory processes. Established therapy with slow-acting disease-modifying anti-rheumatic drugs (DMARDs), as with low-dose methotrexate (MTX), leads to a significant improvement of disease symptoms, but are unable to stop joint destruction. Novel therapeutic agents like monoclonal antibodies (mAb), cytokine receptor-human immunoglobulin constructs or recombinant human proteins have been tested in RA and in other chronic arthritides like ankylosing spondylitis or psoriatic arthritis with convincing success. In particular, clinical trials testing anti-TNF alpha agents either alone or in combination with MTX have proven the feasibility and efficacy of these novel approaches.

Animals↗