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M Feldmann

Publications and source records attributed to M Feldmann.

At least 127 records · Page 7Linked to original sources
PubMed1996

[Intravascular lymphomatosis of the nervous system--case report and review of the literature].

We report on a typical case of intravascular lymphomatosis, a rarely diagnosed, generalised intravascular lymphoma usually of the B-cell type. In most cases there is a lack of clear haematological findings but in more than 50% intravascular lymphomatosis presents with symptoms of the central nervous system. Every rapidly progressive neurological deficit, especially the association of a subacute dementia with a spinal syndrome may suggest IVL-NS. However, careful examination may detect minor features for a systemic process in 25-80% i.e. B-symptoms elevation of ESR and LDH. Neurological imaging demonstrates multifocal lesions in the CNS with affinity to the deep white matter consistent with a microvascular or demyelinating disease. Angiographically IVL-NS may mimic cerebral vasculitis. CSF findings are nonspecific. Because diagnosis can only be made histologically, a cerebral biopsy should be undertaken in suspected cases. Usually the course of the disease is fatal. Therapy involving steroids, combination polychemotherapy or radiation met with only minor success.

Aged↗
PubMed1996

Effect of soluble P55 tumour-necrosis factor binding fusion protein on the local Shwartzman and Arthus reactions.

1. In this study, the effects of a protein synthesis inhibitor, cycloheximide, and a soluble tumour necrosis factor (TNF) binding/IgG fusion protein, p55-sf2, on the priming and challenge stages of the local Shwartzman reaction (LSR) were assessed and compared with their effects on the acute inflammatory response induced by recombinant human tumour necrosis factor-alpha (rhTNF), lipopolysaccharide (LPS) and a reversed passive Arthus (RPA) reaction in rabbit skin. 2. The LSR was induced in skin by giving an intradermal (i.d.) priming injection of LPS followed by two i.v. challenge injections 20 h and 22 h later. Accumulation of 51-Cr-labelled red blood cells and [125I]-albumin were measured at 24 h as markers of haemorrhage and oedema formation, respectively. 3. The RPA reaction was induced in the rabbit by giving i.d. injections of Arthus anti-serum (anti-bovine-gamma-globulin, BGG) followed 5 min later by an i.v. injection of the antigen (BGG). Oedema formation and the accumulation of 111In-labelled neutrophils produced in the RPA reaction and in response to i.d. injection of rhTNF and LPS were measured over the 4 h period after inducing the responses. 4. A single local injection of cycloheximide (10 micrograms/site) did not inhibit neutrophil accumulation or oedema formation produced by 100% Arthus anti-sera. Although LPS injected i.d. induced a marked dose-dependent neutrophil accumulation, there was little associated plasma leakage. Cycloheximide (10 micrograms/site) did not significantly inhibit the neutrophil accumulation induced by LPS (0.1 microgram/site). In the LSR, priming i.d. injections of LPS caused a dose-dependent increase in haemorrhage and plasma leakage at skin sites after challenge with LPS (two injections of 100 micrograms, i.v.). Co-injection of a single dose of cycloheximide (10 micrograms/site) with LPS (30 micrograms/site) caused a marked reduction in the amount of haemorrhage. Local cycloheximide (10 micrograms/site) administered immediately before LSR challenge did not affect the responses produced in the LSR. 5. Neutrophil accumulation induced by TNF (0.17 micrograms/site) was abolished by co-administration of p55-sf2 (3 micrograms/site) whereas neutrophil accumulation induced by i.d. LPS and produced in the RPA reaction was not affected. In the LSR, haemorrhage and oedema formation were inhibited by p55-sf2 (3 micrograms/site) when it was administered i.d. with the LPS priming injection, but not when given i.d. immediately before LSR challenge. 6. These data suggest that the acute neutrophil accumulation produced in the RPA reaction and in response to i.d. LPS may not be dependent on local protein synthesis or TNF production. On the other hand, haemorrhage appears to be dependent on local protein synthesis during the priming phase but not during the challenge stage of the LSR. Importantly, haemorrhage and plasma leakage appear to be dependent on local TNF generation during the priming phase but not during the challenge stage of the LSR. Thus TNF appears to play a key role in the LSR in rabbit skin.

Animals↗
PubMed1996

Soluble E-selectin in multiple sclerosis: raised concentrations in patients with primary progressive disease.

OBJECTIVE: To determine whether concentrations of soluble E-selectin (sE-selectin), an immunological marker of endothelial activation, were correlated with gadolinium-DPTA enhancement on MRI in patients with multiple sclerosis. METHODS: Serial sE-selectin concentrations were measured in 28 patients with multiple sclerosis undergoing monthly gadolinium (Gd) enhanced MRI of the brain and spinal cord, and in 10 control subjects. C reactive protein (CRP), von Willebrand factor (vWF), and tumour necrosis factor-alpha (TNF alpha) were also determined. RESULTS: Primary progressive patients had significantly increased sE-selectin concentrations compared with the relapsing remitting and secondary progressive patients who had normal sE-selectin concentrations (22.2 (SD1 6.1) ng/ml v 9.8 (SD2.1) ng/ml and 7.7 (SD2.7) ng/ml, respectively, P = 0.03). This difference was attributable to five of the 10 primary progressive patients who had persistently raised sE-selectin concentrations, with relatively inactive MRI studies. No correlation could be found between sE-selectin concentrations and Gd enhancement on MRI, but a close correlation existed between mean concentrations of sE-selectin and TNF alpha (r = 0.71, P < 0.001). Despite raised sE-selectin and TNF alpha concentrations, primary progressive patients had normal CRP concentrations (1.03 (SD1.14) mg/l), which were significantly lower than the relapsing remitting (3.16 (SD2.54) mg/l) and secondary progressive patients (2.28 (SD2.1) mg/l, P = 0.03). Raised CRP concentrations did correlate with infectious episodes, clinical relapse, and Gd enhancement, and were significantly raised when no MRI activity was found. Concentrations of vWF were normal in all patient groups. CONCLUSIONS: The results further high-light the differences between patients with primary progressive and those with relapsing remitting/secondary progressive multiple sclerosis.

Adult↗
PubMed1996

Role of cytokines in rheumatoid arthritis.

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

Animals↗
PubMed1996

What is the mechanism of action of anti-tumour necrosis factor-alpha antibody in rheumatoid arthritis?

The rationale for anti-tumour necrosis factor-alpha (anti-TNFalpha) therapy in rheumatoid arthritis (RA) is based on experiments on cultures of human rheumatoidjoint tissue, supported by experiments in animal models, all of which demonstrated that anti-TNFalpha antibody had profound effects on the disease activity. Clinical trials have substantiated this concept, and we have used the serum samples from the clinical trials, as well as biopsies to study the changes occurring during anti-TNFalpha therapy as clues to the pathogenesis of RA. The major effects of anti-TNFalpha therapy are in downregulating cytokine activity, and in reducing leucocyte trafficking to the joints.

Animals↗
PubMed1996

[Early neurologic-neurosurgical rehabilitation--on the epidemiology of the need for early rehabilitation beds by adult patients exemplified by the Bremen federal district].

Early neurological rehabilitation means starting rehabilitation of brain damaged patients already during the acute phase of the trauma or illness. It meanwhile is commonly accepted that early onset of specific neurological rehabilitation interventions will enhance medical improvement and social reintegration potential. On the other hand, the number of treatment places required for adequate early neurological rehabilitation remains a controversial, and as yet unresolved, issue in Germany. In the present study, an evaluation was undertaken for the first time to determine the local demand for early rehabilitation beds in the well-defined region of the federal state of Bremen, based on retrospective analysis of all adults treated for severe brain disease in the major Bremen clinics over a period of 22 months, i.e., between January 1992 and October 1993. A total of 146 early rehabilitation treatments was found, which is equivalent to 80 treatments a year. These results are compared with the figures and recommendations given by Kuratorium ZNS. Also, our findings document the apparent deficits in neurological rehabilitation at the time in the Land Bremen, which undoubtedly jeopardize our daily objectives, the progress and successes achieved in early intensive care.

Adolescent↗
PubMed1995

Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells.

CD28 is a major costimulatory signal receptor for T cells. We have used human naive CD4+ cells from cord blood to analyze the effect of the CD28/B7 costimulatory pathway on development of T helper (Th) subsets. We show that CD28 costimulation is critical for development of the Th2 cytokine-producing cells and that in the absence of CD28 costimulation, cells are not primed to produce Th2 cytokines and consequently "default" to the Th1 subset, independent of the presence of exogenous cytokines. After CD28 costimulation, cells differentiate into a subset that produces Th2 cytokines. However, further CD28 costimulation is not required to maintain Th2 cytokine production. We conclude that D28 costimulation is critical for the development of Th0 and Th2 subsets, but not for the maintenance of cytokine production.

Animals↗
PubMed1995

TNF alpha is an effective therapeutic target for rheumatoid arthritis.

Rheumatoid arthritis is the most common of a number of diseases in which inflammation and tissue destruction is driven by an autoimmune process. Current therapy is inadequate, and this has prompted major research efforts, both in academia and industry, to understand more about the pathogenesis, and hence provide the rationale for new therapeutic strategies. Here we review our studies of cytokine expression and regulation in rheumatoid joints, which has culminated in demonstrating that TNF alpha blockade, using a chimeric (human IgG1/K, mouse Fv) anti-TNF alpha antibody, cA2, markedly ameliorates arthritis. This defines a therapeutic target for rheumatoid arthritis.

Animals↗
PubMed1995

High level of interleukin-10 production by the activated T cell population within the rheumatoid synovial membrane.

OBJECTIVE: To characterize the cytokine profile of the activated T cell population derived from the synovial membrane of rheumatoid arthritis (RA) patients. METHODS: Interleukin-2 (IL-2) was used to select for in vivo-activated T cells from the synovial membrane of 2 patients with RA, and the cells were cloned nonspecifically. The cytokine production profile of these clones was compared with that of clones derived from peripheral blood monocytes (PBM) by stimulating all clones for 24 hours with immobilized anti-CD3 (coated at 10 micrograms/ml) or phorbol-12-myristate-13-acetate (10 ng/ml) plus soluble anti-CD3 (1 microgram/ml). Interferon-gamma (IFN gamma), IL-4, and IL-10, the cytokines that discriminate between Th1 and Th2 cells and are involved in immunoregulation, were assayed by enzyme-linked immunosorbent assay. RESULTS: There was a difference in the cytokines produced by the clones derived from the rheumatoid membranes compared with clones derived from the periphery. Clones derived from both membranes and PBM were mostly IFN gamma-producers, i.e., either a Th0 or a Th1 profile. There was a high proportion of IFN gamma/high IL-10-producing cells derived from the joint, but not from the periphery. Of clones derived from the synovial membrane of each of 2 RA patients, 100% and 50% produced both 1-10 ng/ml IFN gamma and > 7 ng/ml IL-10, compared with < 7% of clones derived from normal or RA peripheral blood. In addition, when autologous membrane and PBM were compared, the mean concentration of IL-10 produced by the clones derived from the synovial membrane sample was significantly different from those produced by clones derived from peripheral blood (P < 0.02). CONCLUSION: The cytokine profile of the T cell clones that were obtained from the RA joint after expansion with IL-2 is distinct from that of the T cells that are predominant in PBM. This supports the concept that the T cells subsets that accumulate in the joint are not a random sample. The high level of IL-10 production by clones derived from the synovium suggests that this cytokine may be a major contributor to the endogenous immunosuppression that occurs in RA.

Adult↗
PubMed1995

Interleukin-4 inhibits kappa light chain expression and NF kappa B activation but not I kappa B alpha degradation in 70Z/3 murine pre-B cells.

The murine pre-B cell line 70Z/3 responds to lipopolysaccharide by up-regulating the surface expression of kappa (kappa) light chain through activation of the transcription factor NF kappa B. Interleukin-4 (IL-4), a T cell cytokine, is a known inhibitor of some LPS-mediated events. We investigated whether IL-4 could inhibit the up-regulation of kappa light chain and activation of NF kappa B by LPS in 70Z/3. IL-4 partially inhibited both the LPS-induced expression of kappa light chain and also the activation of NF kappa B as judged by an NF kappa B reporter gene assay. Additionally, electrophoretic mobility shift assays confirmed this effect on LPS-induced NF kappa B DNA binding activity in the nucleus. Surprisingly, proteolytic degradation of I kappa B alpha (MAD3), a prerequisite for NF kappa B activation, was unaffected by IL-4, implying that this cytokine inhibits some subsequent undefined event in the activation of NF kappa B. IL-4 was also found partially to inhibit NF kappa B activity induced by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta). These results indicate that there may be a common mechanism for the well-documented anti-inflammatory effects of IL-4 and that this mechanism involves the transcription factor NF kappa B.

Animals↗
PubMed1995

Functional comparisons of different tumour necrosis factor receptor/IgG fusion proteins.

Nine different IgG fusion proteins and one non-fusion protein, all containing sequences from the extracellular domain of either of two human TNF receptors, were compared for their ability to bind and inhibit human TNF-alpha or TNF-beta. The fusion proteins differed with respect to TNF receptor type (p55 or p75 TNF receptor), receptor valency (one, two or four receptor domains per molecule), the presence or absence of a CH1 domain in the IgG constant region, and the proportion of the extracellular domain included in the construct. In vitro TNF binding assays and cytotoxicity assays indicated that, of the constructs that bound TNF, the greatest difference in affinity and neutralizing capability was between monovalent and bivalent receptor constructs. Differences were also noted between tetravalent and bivalent versions of p55 fusion proteins, as well as between a p75 fusion protein comprising the complete extracellular domain and one lacking the C-terminal 53 amino acids of the extracellular domain. p55 constructs that included only the second cysteine-rich domain (CRD) or only the second and third CRDs showed no TNF binding activity. The presence or absence of an IgG CH1 domain made no difference in the ability of fusion proteins to neutralize TNF-alpha or TNF-beta. Animal experiments comparing the tetravalent and bivalent p55 fusions and the effects of the CH1 domain did not show significant differences in their ability to protect mice from endotoxin-induced lethality, although the p55 fusion proteins appeared to be more protective than the p75 fusion proteins. Thus, this study has identified structural modifications to TNF receptor/IgG fusion proteins which have differing effects on their neutralizing ability towards TNF-alpha or TNF-beta.

Animals↗
PubMed1995

TNF alpha blockade in rheumatoid arthritis: rationale, clinical outcomes and mechanisms of action.

Tumor necrosis factor alpha (TNF alpha) is a cytokine with many biological functions of relevance to inflammatory disease. Although only one of several inflammatory mediators produced in abundance in rheumatoid arthritis (RA), experimental data suggest that it is in a dominant position within a cytokine hierarchy and is therefore a prime target for directed immunotherapy in this disease. We have targeted TNF alpha in vivo using a chimerised monoclonal anti-TNF alpha antibody and have now demonstrated beneficial responses to treatment in three different clinical trials. The results confirm that TNF alpha is of central importance in the inflammatory process in RA and define a new treatment strategy in this disease.

Acute-Phase Proteins↗
PubMed1995

Comparison of peptide and superantigen-induced anergy in a peptide-specific polyclonal human T cell line.

T cells recognizing tetanus toxin peptide 'p2' (sequence 830-844) raised in HLA DR6 individuals preferentially express V beta 2 in the TCR. A p2-specific T cell line (60% V beta 2+) was used to compare peptide and superantigen [toxic shock syndrome toxin-1 (TSST-1)]-induced clonal anergy. Many experiments consistently revealed that the degree of 'tolerance' or 'clonal anergy' induced by peptide was greater than with the superantigen TSST-1. These results are of interest in a number of contexts. First they suggest that using superantigens or anti-V beta to delete the majority population of T cells may not be sufficient to diminish an autoimmune response. Secondly, the results indicate that induction of anergy of a large proportion of peptide-specific T cells does not lead to a suppressive bystander effect on the remaining responsive T cells. These results emphasize the need to define the dominant autoantigenic epitopes in human autoimmune diseases, since peptide based therapy such as the use of peptide analogues to induce anergy or a change in cytokine profile, is possibly more effective in controlling undesired immune responses than the use of non-antigen, TCR-directed approaches such as superantigens.

Amino Acid Sequence↗
PubMed1995

Are CD4+ Th1 cells pro-inflammatory or anti-inflammatory? The ratio of IL-10 to IFN-gamma or IL-2 determines their function.

Human CD4+ T cells have, like their murine counterparts, been classified on the basis of their cytokine profile. Th1 cells produce IL-2 and IFN-gamma, but little or no IL-4. Th2 cells produce IL-4 but not IFN-gamma or IL-2, and Th0 produce IL-2, IL-4 and IFN-gamma. As IL-2 is the most potent T cell growth factor and IFN-gamma is the strongest activator of macrophages it is not surprising that CD4+ Th1 cells are considered to be pro-inflammatory. However, unlike results in the mouse, where IL-10 is only produced by Th2 cells, human IL-10 is produced by Th0, Th1 and Th2 cells. Hence some human Th1 cells are capable of producing both pro-inflammatory (IL-2, IFN-gamma) and anti-inflammatory (IL-10) cytokines, therefore the function of these cells may not be accurately encapsulated by the 'Th1' terminology. We thus investigated the correlation of cytokine production and function in human CD4+ Th1 clones. Cytokine production (IL-2, IFN-gamma, IL-10) was measured in supernatants by ELISA after stimulation with solid-phase anti-CD3. The capacity of these supernatants to activate or inhibit T cell proliferation or LPS induced TNF-alpha production by monocytes was assessed. The ratio of IL-2/IL-10 or IFN-gamma/IL-10 was of critical importance in determining the function of the supernatants. The inhibitory effects were verified to be due to IL-10, as they were neutralized by anti-IL-10 mAb.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1995

Cytokine expression in chronic inflammatory disease.

In chronic inflammatory diseases, typified by rheumatoid arthritis, we speculated that upregulation and/or disregulation of cytokine production in inflamed tissue might contribute both directly and/or indirectly to the pathology in the synovial joint tissue. This chapter summarises studies performed principally by our own group over the last 9 years or so, but also by others in the field who have investigated the expression of cytokines in RA. From our studies we identified one particular cytokine, tumour necrosis factor alpha (TNF alpha) as an important, 'pivotal', molecule in the disease process. This concept has led to the initiation and completion of the first successful clinical trials in RA patients to verify this hypothesis, using a neutralising antibody to TNF alpha.

Arthritis, Rheumatoid↗
PubMed1995

Gene therapy of rheumatoid arthritis via cytokine regulation: future perspectives.

Following many years of research using isolated human tissues and animal models, sufficient knowledge concerning rheumatoid arthritis has accumulated so that novel immunotherapies have been proposed. Biological agents are being tested in clinical trials and include antibodies to T cells and cytokines. Currently the most promising of these is intravenously administered neutralizing anti-TNF antibody. In order to establish disease modification, however, therapy needs to be delivered continuously over the long term. The prospect of delivering cytokine inhibitors as genetic material (naked DNA), viruses or in engineered autologous cells is considered as one option for achieving this goal. We compare two strategies, firstly, using immobile cells such as fibroblasts, myoblasts or keratinocytes, and secondly, the migratory cells of the immune system. The former provides a reservoir of systemic delivery of the therapeutic protein whereas the latter provides targeted delivery determined by the antigen specificity of the immune cells. Early validation has begun in animal models of rheumatoid arthritis.

Animals↗
PubMed1995

Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1 alpha and IL-1 receptor antagonist.

The IL-1 cytokine network in epidermal cells was studied in vitro, using the spontaneously transformed HaCAT human keratinocyte line. Intracellular (ic) IL-1 alpha and IL-1 receptor antagonist protein (IL-1Ra) following cell lysis were readily identified assayed using a capture ELISA; whereas in culture supernatants IL-1Ra was not detected, and IL-1 alpha was present at only very low levels. Confluent cultures of HaCAT cells were shown to provide optimal conditions for the study, since confluence increased the icIL-1Ra:IL-1 alpha ratio to a level as seen in vivo, which was independent of Ca2+ concentration in the culture medium. The IL-1Ra extracted from HaCAT cell lysates was functionally active, as demonstrated in the mouse thymocyte co-proliferation assay which could be blocked using a rabbit anti-IL-1Ra antibody. Transforming growth factor-beta (TGF-beta 1) stimulated a dose-dependent increase in HaCAT cell IL-1 alpha without changing IL-1Ra concentration, with a resultant reduction in the icIL-1Ra: IL-1 alpha ratio from 320:1 to 100:1. Similarly, TGF-alpha, interferon-gamma (IFN-gamma), IL-6, and tumour necrosis factor-alpha (TNF-alpha) substantially increased HaCAT cell IL-1 alpha, but had no effect on the IL-1Ra, with a concomitant reduction in the icIL-1Ra:IL-1 alpha ratio. In contrast to their effects on monocytes, IL-4 and IL-10 at biologically active levels had no effect on IL-1 alpha, IL-1Ra or the icIL-1Ra: IL-1 alpha ratio in confluent HaCAT cells. Hydrocortisone reduced IL-1 alpha to below the limit of sensitivity of the ELISA, and induced a small increase in IL-1Ra of questionable biological significance. Thus, regulation of the IL-1 cytokine network in keratinocytes involves modulation of icIL-1 alpha rather than of icIL-1Ra levels, and is markedly different from that noted in monocytes.

Calcium↗