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G R Burmester

Publications and source records attributed to G R Burmester.

At least 73 records · Page 4Linked to original sources
PubMed2000

Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells.

Autoimmune diseases that are resistant to conventional treatment cause severe morbidity and even mortality. In the present study we demonstrate that complete remissions can be achieved in refractory polychondritis and systemic lupus erythematosus (SLE), even at advanced stage, with the use of autologous stem-cell transplantation (SCT). Remissions persisted after reconstitution of the immune system. In the treatment of advanced systemic sclerosis (SSc), stable disease may be achieved with autologous SCT.

Adult↗
PubMed2000

Macrophages in rheumatoid arthritis.

The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains an efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage.

Arthritis, Rheumatoid↗
PubMed2000

Therapeutically targeting lymphocyte energy metabolism by high-dose glucocorticoids.

Lymphocytes use a considerable amount of energy, mainly in the form of ATP, especially when they become stimulated following activation by antibodies or mitogens. Cellular respiration is the major energy source, and in quiescent cells the ATP produced is used to drive protein synthesis and sodium transport. In stimulated cells there is significantly higher ATP production to balance the higher ATP demand of specific processes resulting from activation. The major ATP-consuming processes under these conditions are protein synthesis and Na(+),K(+)-ATPase (about 20% each), while Ca(2+)-ATPase and RNA/DNA syntheses contribute about 10% each. There is a wealth of available information about glucocorticoid effects on lymphocytes, but here we focus on the extent to which this lymphocyte bioenergetic machinery is targeted by glucocorticoids when they are used therapeutically at high doses. High-dose glucocorticoids have been shown recently to interfere with processes that are essential for the activation and maintenance of lymphocytes, such as sodium and potassium transport. Therefore, in this article we describe the bioenergetics of lymphocytes in resting, activated, and glucocorticoid-treated states and present a concept for discussion to describe the relationship among these states in fundamental and clinical terms.

Adenosine Triphosphate↗
PubMed2000

Identification of known and novel genes in activated monocytes from patients with rheumatoid arthritis.

OBJECTIVE: To define gene activation patterns of monocytes (MO) in patients with rheumatoid arthritis (RA). METHODS: A complementary DNA (cDNA) library was constructed from first-leukapheresis MO obtained from an RA patient with active disease; 32P-labeled cDNA from first-leukapheresis MO (activated pool) and third-leukapheresis MO (nonactivated pool) were used as probes for differential hybridization. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assess gene activation in MO from an additional 26 RA patients and 6 normal controls. RESULTS: Subtraction of genes from first- and third-leukapheresis MO resulted in 482 differentially expressed clones. In first-leukapheresis MO, these clones included the following: 1) interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, tumor necrosis factor alpha, growth-related oncogene alpha (GROalpha)/melanoma growth-stimulatory activity, macrophage inflammatory protein 2/GRObeta, ferritin, alpha1-antitrypsin, lysozyme, transaldolase, Epstein-Barr virus-encoded RNA 1 (EBER-1)/EBER-2-associated-protein, thrombospondin 1, an angiotensin receptor II (ATRII) C-terminal homolog, and RNA polymerase II elongation factor (elongin); 2) two clones homologous to functionally undefined genes (BSK-67 and BSK-83); and 3) three unknown cDNA sequences (BSK-66, 80, 89). In third-leukapheresis MO, the clones included differentiation genes (HOX-B3, thymosin-beta4, PU.1, glucocerebrosidase, MEL-18, and glucose-6-phosphate dehydrogenase) and 3 unknown/functionally undefined sequences. Differential expression of most genes from the activated pool was confirmed in leukapheresis samples from 2 additional RA patients. In MO from RA patients, not only were IL-1beta and the ATRII homolog significantly overexpressed (maximum 36-fold), but also 4 of the unknown/functionally undefined genes (maximum 102-fold). Notably, messenger RNA levels of BSK-89 correlated positively with the erythrocyte sedimentation rate (ESR), whereas those of BSK-83 correlated negatively with the ESR and C-reactive protein level. CONCLUSION: The combined strategy of gene subtraction and semiquantitative RT-PCR may allow the definition of MO activation patterns during different disease phases (including therapy-induced remission) and the identification of novel MO genes with pathogenetic relevance in RA.

Adult↗
PubMed2000

Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus.

OBJECTIVE: Double-stranded DNA (dsDNA) is a well-known target of autoantibodies in systemic lupus erythematosus (SLE). The majority of these autoantibodies are of the IgG isotype and show affinity maturation, both of which are known hallmarks of T cell help. T cell responses to autoantigens, including DNA, have been reported only incidentally in SLE patients. Nevertheless, in murine SLE, naked DNA and complexed DNA (nucleosomes) are known to be recognized by T cells. This study aimed to characterize the antinucleosome response and its clinical impact on human SLE. METHODS: Nucleosomes were prepared from chicken erythrocytes. Sera from SLE and control patients were investigated by enzyme-linked immunosorbent assay (ELISA) for nucleosome-specific antibody responses. Peripheral blood mononuclear cells (PBMC) from SLE and control patients were analyzed by a kinetic T cell proliferation assay. PBMC were subsequently analyzed for nucleosome-specific T cell proliferation. RESULTS: Of 136 SLE patients, 56% were seropositive for antinucleosome antibodies. In contrast, only 3% of 309 control patients (with rheumatoid arthritis, mixed connective tissue disease, undifferentiated connective tissue disease, Lyme borreliosis, scleroderma, Sjögren's syndrome, ulcerative colitis, hepatitis B virus infection, or human immunodeficiency virus infection) were seropositive. Thus, the antinucleosome ELISA had a sensitivity of 56%, a specificity of 97%, and a diagnostic confidence of 90% when applied to SLE. It was therefore superior to an anti-DNA ELISA that demonstrated a 69% diagnostic confidence in the same population. Antinucleosome reactivity in SLE patients correlated significantly with disease activity (P < 0.0001), nephritis (P < 0.002), and psychosis (P < 0.02). When proliferation assays were applied, 14 of 26 SLE patients (54%) were positive for nucleosome-specific T cells that proliferated in response to their cognate antigen. A suppressed response was elicited in 3 SLE patients (12%); in these patients, the PBMC response to nucleosomes was lower than the proliferation of PBMC in the presence of culture medium only. PBMC from the remaining 9 SLE patients (35%) were nonresponsive to nucleosomes in either way. Responding, nonresponding, and suppressed populations differed from each other significantly (P < 0.0001). None of the PBMC from 7 healthy donors and 10 control patients could be stimulated with nucleosomal antigens. CONCLUSION: We present evidence that nucleosomes are major autoantigens in human SLE and that antinucleosomal antibodies are highly specific for the disease. The antinucleosome ELISA has been shown to be superior to the anti-dsDNA ELISA and may thus be a significantly better tool for diagnosing SLE. Nucleosome-specific T cells in SLE patients may help B cells class switch to IgG and undergo affinity maturation.

Adult↗
PubMed2000

[Protection of autogenous cartilage transplants from resorption using membrane encapsulation].

In reconstruction of cartilage defects, autogenous transplantation is known as a reliable and experienced method. Although a clinical application has not been reported until now, tissue engineering permits in vitro production of autogenous cartilage transplants. Nevertheless, in both methods the cartilage is exposed to individually varying resorptive mechanisms. Among other methods for in vivo tissue protection, the encapsulation with a semipermeable polyelectrolytecomplex membrane could guarantee sufficient protection against resorptive influences. Human septal cartilage was encapsulated (group 1) with polyelectrolytecomplex membranes and subcutaneously implanted on the back of thymusaplastic nude mice. Cartilage implants without encapsulation (group 2) were used as control. Scanning electron microscopy and histochemical investigations were performed 1, 4, 8, 12 and 16 weeks after implantation. Group 1 showed no signs of resorption and chronic inflammation at all. In contrast, group 2 presented, correlating to the time of implanta-tion, increasing signs of cell death and fibrotic transformation, representing an increased activity of resorption. In conclusion, tissue encapsulation with a polyelectrolytecomplex membrane could ensure a sufficient protection of human cartilage transplants from resorptive influences. For the plastic-reconstructive surgeon the desired result becomes more calculable.

Animals↗
PubMed2000

Macroencapsulation of human cartilage implants: pilot study with polyelectrolyte complex membrane encapsulation.

Autogenous cartilage transplantation is a generally accepted method in reconstructive surgery. A promising alternative to this established method could be represented by in vitro engineering of cartilage tissue. In both methods of autogenous transplantation, host response induces reduction of transplant size and transplant instability to an unforeseeable extent. To investigate if polyelectrolyte complex (PEC) membranes were able to avoid host-induced effects on implanted tissues without neglecting the tissue metabolism, human septal cartilage was encapsulated with polyelectrolyte complex membranes and subcutaneously implanted on the back of nude mice. Septal cartilage implants, without encapsulation served as control group. Histochemical and electron microscopic investigations were performed 1, 4, 8 and 16 weeks after implantation. In the case of an intact PEC-membrane no interactions between the host and the implant could be observed. In some implants, the capsule was torn in several areas and signs of chronic inflammation with the cartilage having been affected mildly could be observed. Implanted cartilage protected with PEC-encapsulation showed no signs of degeneration and significantly lower level of after effects of chronic inflammation than implanted cartilage without PEC-encapsulation. Therefore, it could be expected, that PEC membrane encapsulation offers a novel approach to protect cartilage implants from host response after autogenous transplantation.

Animals↗
PubMed2000

Segmental bone repair by tissue-engineered periosteal cell transplants with bioresorbable fleece and fibrin scaffolds in rabbits.

The biological bone healing depends on the presence of osteochondral progenitors and their ability for proliferation. Isolated periosteal cells were seeded into biodegradable PGLA polymer fleece or fibrin beads and cultivated for 14 days after prior monolayer culture. On 12 New Zealand white rabbits 8 mm metadiaphyseal ulna defects were created bilaterally and subsequently filled with cell-fibrin beads, with polymers seeded with cells compared to controls with fibrin beads and polymers alone and untreated defects. A semiquantitative grading score was applied for histomorphological and radiological analysis after 28 days. Histologically intense bone formation was observed in both experimental groups with cell transplants only. The histological and radiological scoring was superior for both experimental groups. Control groups revealed only poor healing indices and untreated defects did not heal. The highest histological score was noted in the group with polymer fleeces containing periosteal cells. Applying the radiographic score system we determined a significant difference between experimental groups and controls without cells. The radiographic and histological scores for both experimental groups containing periosteal cells differed not significantly. The results strongly encourage the approach of the transplantation of pluripotent mesenchymal cells within a suitable carrier structure for the reconstruction of critical size bone defects.

Animals↗
PubMed2000

Interactions of autonomic nervous, neuroendocrine, and immune systems in rheumatoid arthritis.

In general, it is assumed that the two pathways (i.e., HPA axis and sympathetic nervous system) probably act cooperatively to maintain homeostasis. The previously mentioned studies clearly point to a disturbance in the interaction between the ANS, the HPA axis, and the immune system in chronic rheumatic diseases (Fig. 2). Even early on in the course of RA, these changes can be observed. Along with the results obtained in animal models, an important role of neuroendocrine interactions in the pathogenesis of RA is proposed. Further studies are required to establish the exact contribution of the ANS in the initiation and perpetuation of RA. To date, it is quite obvious that neuropeptides play a part in the orchestration of the various molecules (e.g., cytokines) exerting modulatory effects on immune cells. One can speculate that therapeutic implications are likely to result from investigations on the ANS-immune interactions. Based on early observations that blocking catecholamine actions ameliorate symptoms of RA, it is quite promising to follow this avenue in investigating ANS-immune interactions of various time points of the disease. Conversely, further studies are required to determine the contribution of the HPA axis to the onset of RA. Results from ongoing studies are eagerly awaited so as to establish new therapeutic options. In the future,it may be possible to interfere with the inflammatory process in RA by an exactly timed neuroendocrine intervention right at or even before the onset of disease. Therapy with steroids in RA might be better planned based on the genetically determined reactivity of an individual's HPA axis. In this respect, a recent report by Masi et al is of special interest. Based on the current literature on the disturbances in the neuroendocrine, immune, and microvascular systems found in early RA, the authors hypothesize that an imbalance in the interactive homeostasis of these systems develops during a long preclinical phase and eventually leads to the outbreak of the disease in genetically predisposed individuals. This interesting hypothesis includes the perspective that individuals prone to develop RA may be identified in a preclinical phase and treated prophylactically. In any event, results from all these studies are promising in two ways: to gain more insight in the pathogenic process of RA and to establish novel therapies to help the patients bear their burden of a chronic rheumatic disease.

Arthritis, Rheumatoid↗
PubMed2000

Bioenergetics of human peripheral blood mononuclear cell metabolism in quiescent, activated, and glucocorticoid-treated states.

The first quantitative findings on the energy metabolism of human immune cells are presented. In quiescent peripheral blood mononuclear cells (PBMC) protein biosynthesis and Na+,K+-ATPase activity each accounted for 8% of cellular oxygen consumption. Stimulation with 25, 50, and 75 microg Con A/ml (1.25, 2.5 or 3.75 microg/10(6) cells) increased total oxygen consumption within seconds by 8, 36, and 53%, respectively. After addition of 75 microg Con A/ml, the proportion of cellular oxygen consumption due to protein biosynthesis, Na+,K+-ATPase activity, and Ca2+-ATPase activity was 15% each and that due to DNA/RNA synthesis was 8%. On the basis of these findings the immediate effects of five different glucocorticoids on cellular energy metabolism were investigated. The various glucocorticoids exerted basically the same inhibitory effects on Con A-stimulated cellular respiration and individual ATP-consuming processes, but differed significantly in potency. Similar to previous studies on rat thymocytes, the relative potencies of the glucocorticoids were found to be: prednylidene (1.7) > dexamethasone (1.5) > methylprednisolone (1.0) > prednisolone (0.3) > betamethasone (< 0.2). Given their rapidity of onset, these effects must be nongenomically mediated. The differences between the relative potencies of the various glucocorticoids for these effects and those for the classical genomic effects have important clinical implications, in particular for high-dose systemic and local glucocorticoid therapy.

Calcium-Transporting ATPases↗
PubMed2000

Tissue engineered cartilage repair using cryopreserved and noncryopreserved chondrocytes.

The objective of this study was to reconstruct full thickness cartilage defects in rabbit knees with in vitro engineered cartilage tissue based on noncryopreserved and cryopreserved chondrocytes in polymer fleece scaffolds. Osteochondral defects in rabbits were filled with polymer cylinders with noncryopreserved or cryopreserved allogeneic chondrocytes and compared with empty defects and defects filled with polymers alone. The defects were evaluated macroscopically and histologically 4 and 12 weeks after surgery. Transplant samples were graded using a semiquantitative score system. Successful healing was defined as complete integration of a hyalinelike and structurally intact cartilage into the defect and occurred in 71% of the group with noncryopreserved chondrocytes after 4 weeks and 100% of the rabbit knees after 12 weeks, whereas hyalinelike cartilage was seen in 71% of the group with cryopreserved chondrocytes after 4 weeks, and in 85% after 12 weeks. No newly formed cancellous bone was present in the subchondral bone. In the control groups, no cartilagelike tissue was seen. Transplantation of chondrocytes in polymer fleece constructs is a suitable approach for joint cartilage repair. Noncryopreserved chondrocytes are preferred to cryopreserved chondrocytes because of their regenerative potential. In vitro engineered cartilage offers broad opportunities for optimization of cartilage transplantation based on the controlled use of morphogenic and biologically active factors such as transforming growth factor-beta and bone morphogenetic proteins.

Animals↗
PubMed2000

Monocytes from systemic lupus erythematous patients are severely altered in phenotype and lineage flexibility.

OBJECTIVE: Cells of the myeloid lineage comprise a very heterogeneous population with many phenotypes and functional activities including macrophages and dendritic cells. To investigate the status, differentiative potential and lineage commitment of monocytic cells in systemic lupus erythematosus (SLE) patients, this study isolated and cultured peripheral blood monocytes from patients and healthy donors. METHODS: Monocytes were isolated by gradient centrifugation and adherence to plastic dishes. The cells were then cultured for three days, partially supplemented with GM-CSF and interleukin 4 (IL4) to obtain dendritic cells. The differentiation status was monitored by the expression of surface markers using flow cytometry and cytokine secretion. RESULTS: Monocytes from SLE patients expressed significantly lower numbers of the monocytic marker CD14 and HLA-DR while secreting significantly more tumour necrosis factor alpha (TNFalpha) than monocytes from healthy donors. The addition of GM-CSF and IL4 resulted in an inhibition of TNFalpha secretion, but was not sufficient to generate monocytederived dendritic cells. CONCLUSION: Monocytes from SLE patients are severely altered in phenotype and function and have a limited differentiation flexibility towards the accessory type of monocytic cells.

Adult↗
PubMed2000

Increased serum soluble CD14, ICAM-1 and E-selectin correlate with disease activity and prognosis in systemic lupus erythematosus.

To improve monitoring of immunological and disease activity, we determined soluble markers of activity of the monocyte/macrophage system (sCD14) and the vascular endothelium (sE-selectin, sICAM-1) in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) in comparison to patients with infections or sepsis. Concentrations of sCD14, sICAM-1 and sE-selectin (soluble CD14, ICAM-1 and E-selectin, respectively) were measured in serum samples from patients with SLE and pSS, patients with sepsis, different infectious diseases and healthy controls using ELISA systems. Elevated levels of sE-selectin and sICAM-1 were detected in patients with SLE as well as sepsis, in contrast to patients with a localized infection (SLE and sepsis, respectively, versus infection P<0.001; Kruskal-Wallis test). Levels of sCD14 were persistently elevated in sera from patients with SLE, whereas these values decreased rapidly after effective therapy in patients with sepsis or infection. A continuous elevation of all of these three parameters was associated with a fatal outcome in patients with sepsis as well as in patients with SLE. Combined elevation of sCD14, sICAM-1 and sE-selectin correlates with the prognosis in patients with active SLE and indicates a remarkable immune activation involving the monocyte/macrophage system and the endothelium comparable to an activation found only in patients with sepsis.

Adolescent↗