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C M Lockwood

Publications and source records attributed to C M Lockwood.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effect of anti-neutrophil cytoplasm autoantibodies on the intracellular calcium concentration of human neutrophils.

BACKGROUND: The discovery of circulating autoantibodies to neutrophil cytoplasm antigens (ANCA) has implicated autoimmune mechanisms in the pathogenesis of systemic vasculitis although it is uncertain whether these play a primary role or arise secondary to neutrophil injury. EXPERIMENTAL DESIGN: We examined the pathophysiologic effect of ANCA on intracellular cytosolic-free calcium concentration (Ca2+)i in neutrophils by preincubating cells with ANCA-positive IgG or F(ab')2 preparations followed by stimulation with calcium ionophore (A23187). The mechanism by which ANCA may affect (Ca2+)i was studied by analyzing the production of platelet-activating factor (PAF), an intracellular messenger which is the mediator through which A23187 acts. RESULTS: ANCA-positive F(ab')2 induced a small but insignificant increase in (Ca2+)i. Preincubation of neutrophils with ANCA-positive IgG or F(ab')2 reduced the calcium mobilization induced by subsequent stimulation with A23187 compared with experiments performed with antibody preparations from ANCA-negative disease or healthy controls. The suppression of A23187-induced calcium mobilization was dose-dependent and correlated with the serum ANCA levels at clinical presentation. ANCA did not bind PAF but reduced the binding of PAF to neutrophils, suggesting that ANCA may prevent the expression of PAF receptor on activated neutrophils. The preincubation of neutrophils with increasing concentrations of F(ab')2 preparation resulted in reduced membrane and supernatant concentrations of PAF, an effect that was more prominent with ANCA-positive F(ab')2. CONCLUSIONS: Our data suggest ANCA may potentially mediate a pathophysiologic effect on neutrophils through interference with the signal transduction pathways utilized in neutrophils' activation. One of the possible mechanisms underlying the suppressive effect of ANCA on A23187-induced calcium mobilization may be mediated through the reduction of PAF synthesis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy.

Monoclonal antibodies that target T cells offer an alternative to conventional immunosuppressive drugs in the management of autoimmune disease. "Humanisation" of such monoclonal antibodies makes their clinical use less likely to be prone to the risk of cross-species sensitisation than treatment with rodent antibodies. We describe humanised monoclonal antibody therapy in four patients with severe systemic vasculitis unresponsive to immunosuppressive drugs. Substantial and sustained benefit was seen in three of the four patients, although one of these three patients developed anti-idiotypic antibodies that had to be removed by plasma exchange.

Antibodies, Anti-Idiotypic↗
PubMed1993

Association of ANCA isotype and affinity with disease expression.

The association of ANCA isotype and affinity with disease expression is reviewed and new data on IgA ANCA levels and affinity in relation to disease activity are presented. Differences in the IgG ANCA subclass distribution exist between active disease and remission, with high affinity IgG3 ANCA present at the onset of disease. IgM ANCA, with or without associated IgG ANCA, correlates with pulmonary haemorrhage and disappears at remission. IgA ANCA are mainly found in patients presenting with Henoch-Schönlein purpura (HSP), and are directed against a distinct autoantigen of approximately 50 kD. The level and affinity of IgA ANCA also correlate with disease activity in HSP. Isotype as well as antibody specificity appear to be major determinants of disease expression.

Adult↗
PubMed1993

ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin.

The presence of anti-idiotype antibodies (anti-id) to anti-neutrophil cytoplasm autoantibodies (ANCA) in intravenous immunoglobulin (IVIg) and remission sera from patients with systemic vasculitis, and the use of IVIg as an alternative therapeutic agent in open studies, has suggested a role for idiotypic regulation in the normal control of these disorders. Clinical benefit with IVIg has been reported in 15/16 patients, with sustained remission in eight. The ability of IVIg to produce lasting remission has been associated with a fall in ANCA levels and stimulation of endogenous immunoglobulin production. IVIg has the potential to influence the pathogenetic process in patients with vasculitis at several stages, and an influence on the idiotypic regulation of ANCA may explain the observed clinical responses and point to possible targets for more specific immunotherapy in the future.

Animals↗
PubMed1993

Anti-idiotype antibodies to anti-myeloperoxidase autoantibodies in patients with systemic vasculitis.

The presence of anti-idiotype antibody (anti-id) activity to anti-myeloperoxidase autoantibodies (anti-MPO) was measured by assessing binding of IgG in patients' sera to F(ab')2 fragments of polyclonal heterologous anti-MPO antiserum. Thirteen paired acute and remission sera and three groups of sequential sera from patients with systemic vasculitis were studied. The levels of anti-MPO fell as disease activity subsided with treatment. However, levels of anti-id activity against these anti-MPO rose as patients entered remission. This effect was still seen after controlling for binding to F(ab')2 constant regions and after polyethylene glycol precipitation of immune complexes. In the sequential studies, levels of anti-MPO and anti-MPO anti-id tended towards a reciprocal relationship. These observations point to dynamic interactions between autoantibody and complementary anti-idiotype antibodies in this system and a role for idiotypic networks in the regulation of anti-neutrophil cytoplasm antibodies.

Acute Disease↗
PubMed1993

Lactoferrin co-purifies with myeloperoxidase and is recognised by anti-neutrophil cytoplasm antibodies.

Thirty-five sera with binding greater than 20% in a myeloperoxidase (MPO, Calbiochem) ELISA were tested in Western blot analyses. 5/35 blotted MPO, but 5/35 blotted lactoferrin (LF) contaminating the commercial MPO preparation. All the anti-LF positive sera, but none of the anti-MPO positive sera, also exhibited anti-nuclear binding on Hep2 cells. Three of the patients with anti-LF antibodies had vasculitis affecting areas additional to the pulmonary-renal involvement which characterised the patients with anti-MPO antibodies.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Anti-neutrophil cytoplasm antibodies (ANCA) increase neutrophil adhesion to cultured human endothelium.

ANCA have been demonstrated to activate normal neutrophils in vitro. This study demonstrates that ANCA positive IgG and Fab2 fragments increase the adhesion of normal neutrophils to cultured human umbilical vein endothelium (HUVEC), and that preincubation of the endothelial monolayers with tumour necrosis factor (TNF) to activate the endothelium enhances this effect. Preincubation of neutrophils with anti-CD18 monoclonal antibodies inhibited adhesion, suggesting that the observed effect was integrin mediated.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Further characterization of an animal model of systemic vasculitis.

The demonstration of vasculitis and anti-myeloperoxidase antibodies in the mercuric chloride treated Brown Norway rat provides a useful, though limited, animal model of systemic vasculitis. We describe some preliminary experiments on the effect of transfer of serum from mercuric chloride treated rats and of two forms of immunotherapy: intravenous immunoglobulin and an anti-CD4 antibody. Transfer of serum did not lead to tissue injury and neither of the two forms of therapy proved beneficial in this model.

Animals↗
PubMed1993

ANCA and anti-GBM antibodies in RPGN.

ANCA and anti-GBM antibodies can occur together in RPGN. These patients are rare and have two distinct populations of antibodies and the ANCA specificity tends to be for myeloperoxidase more often than expected.

Antibodies↗
PubMed1993

Pooled intravenous immunoglobulin in the management of systemic vasculitis.

Investigation into the therapeutic use of intravenous immunoglobulin (IVIg) in systemic vasculitis was prompted by the detection of anti-idiotype antibodies reactive with ANCA in IVIg and the proven ability of IVIg to reduce the incidence of coronary artery aneurysms in Kawasaki disease. The efficacy and safety of IVIg (Sandoglobulin) was assessed in an open study of 26 patients with active systemic vasculitis. Eight weeks after IVIg 13 patients were in full and 13 in partial remission, clinical benefit was maintained in 18 twelve months later and was reflected by changes in C-reactive protein and ANCA.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Computed tomography of the lung in Wegener's granulomatosis.

Computed tomography of the thorax was performed in 30 patients with Wegener's granulomatosis to define the anatomical basis of pulmonary involvement. A wide variety of parenchymal and bronchial abnormalities was demonstrated in addition to the cavitary nodules commonly described. The high incidence (40%) of bronchial abnormalities in these patients may suggest that bronchocentric injury is more important in the pathogenesis of lung involvement in this disease than has previously been considered. Serial scans in individual patients showed broad correlation between the extent of the pulmonary abnormalities and the clinical and immunological markers of disease activity.

Adult↗
PubMed1993

Clinical significance of anti-endothelial cell antibodies in systemic vasculitis: a longitudinal study comparing anti-endothelial cell antibodies and anti-neutrophil cytoplasm antibodies.

Ten patients with systemic vasculitis, all positive for anti-neutrophil cytoplasm antibody (ANCA), were followed for a mean of 36 weeks to determine the prevalence of anti-endothelial cell antibodies (AECAs) and the relationship between AECAs, ANCAs, and disease activity. Anti-endothelial cell antibodies were detected in eight (80%) patients at some time during the study. The levels of both AECAs and ANCAs changed with time, and these autoantibodies were present in 48% and 63% of the total 100 serum samples, respectively. Eighteen clinical remissions were observed; in 16 (88.9%) cases the level of ANCAs dropped. Fifteen (83.3%) of the 18 remissions were among the AECA-positive patients and the level of AECAs decreased in 13 (86.7%) instances (P = not significant). There were 11 episodes of disease relapse; all were associated with an increase in the level of ANCAs. Nine (81.8%) of the 11 relapses were among AECA-positive patients, and the level of AECAs increased in eight (88.9%) cases (P = not significant). Serum levels of AECAs appeared less suppressible by cyclophosphamide therapy compared with ANCAs, and patients who were persistently positive for AECAs despite being ANCA-negative during remissions were at risk of subsequent relapse. Disease recrudescense was not observed in patients persistently tested negative for both AECAs and ANCAs. Intravenous immunoglobulin therapy was used in four patients and resulted in clinical improvement in all cases, but with variable changes in the levels of AECAs and ANCAs. We conclude that AECAs are commonly detected in patients with systemic vasculitis and their levels show a relationship to disease activity similar to that for ANCAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Serum soluble interleukin 2 receptor levels in anti-neutrophil cytoplasmic autoantibodies--positive systemic vasculitis.

Systemic vasculitis is characterized by the presence of autoantibodies to neutrophil cytoplasmic antigens (ANCA). The role of T-lymphocytes in systemic vasculitis remains uncertain. In the present study, we attempted to explore the role of T-lymphocytes in systemic vasculitis by measuring the serum soluble interleukin 2 receptor (sIL2R) levels in seven vasculitic patients and comparing the sequential measurements with the titres of ANCA which satisfactorily reflect the disease activity. The serum levels of both ANCA and sIL2R were elevated at clinical presentation. Contrary to ANCA, the serum sIL2R remained elevated in most patients despite clinical remission following immunosuppressive therapy. These findings suggest that T-lymphocytes may be activated in the acute phase of the disease. The finding of elevated serum sIL2R levels in most patients during clinical remission indicates that it is not a good measure of the disease activity and tends to argue against the role of T-lymphocytes as a major effector mediating inflammatory injuries in systemic vasculitis.

Aged↗
PubMed1992

T and B cell responses to neutrophil cytoplasmic antigens in systemic vasculitis.

The systemic vasculitides (SV) are characterized by the presence of autoantibodies to neutrophil cytoplasmic antigens (ANCA). The role of T cells in SV is uncertain. We studied human and murine T cell responses to human neutrophil cytoplasmic antigens in vitro. T cells from mice immunized with the neutrophil extract showed dose-dependent antigen-specific proliferation, restricted by the MHC class II E molecule. Myeloperoxidase (MPO) was not an important target antigen for murine T cells. Peripheral blood lymphocytes (PBLs) were obtained from 36 patients with SV, 31 before the start of immunosuppressive therapy, and from 11 healthy controls. T cell responses to the neutrophil extract in vitro did not differ between patients and controls: there were only low levels of antigen-specific proliferation, and this could not be amplified by in vitro selection. In 3 patients and 2 normals, PBLs were also tested after the depletion of CD8+ cells; this did not unmask T cell reactivity to neutrophil extract. The lack of demonstrable T cell reactivity to this antigen preparation may indicate that T cells do not play an important effector role in these diseases. A solid-phase spot ELISA was adapted to demonstrate autoantibody-producing B cells in vitro. Low numbers of ANCA-producing B cells could be demonstrated in the majority of patients. B cells producing antibody to MPO could be demonstrated in most patients and in three laboratory staff, but not in normals from outside the laboratory. In 2 patients, sequential B cell spot ELISAs were performed during the introduction of therapy, and autoantibody-producing B cells rapidly decreased in number. This assay may therefore be useful in monitoring the effects of treatment at the cellular level.

Animals↗