Biomedical subjects
D K Peters
Publications and source records attributed to D K Peters.
UK clinical research.
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Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies.
To determine whether plasma exchange was of additional benefit in patients treated with oral immunosuppressive drugs for focal necrotizing glomerulonephritis (without anti-GBM antibodies), we performed a randomized controlled trial with stratification for renal function on entry. Forty-eight cases were analyzed, 25 in the treatment group (plasma exchange, prednisolone, cyclophosphamide and azathioprine) and 23 in the control group (drug therapy only). There was no difference in outcome in patients presenting with serum creatinine less than 500 mumol/liter (N = 17), or greater than 500 mumol/liter but not on dialysis (N = 12), all but one of whom had improved by four weeks. However, patients who were initially dialysis-dependent (N = 19) were more likely to have recovered renal function (P = 0.041) if treated with plasma exchange as well as drugs (10 of 11) rather than with drugs alone (3 of 8). Long-term follow-up showed that improvement in renal function was generally maintained. The results of this trial confirm that focal necrotizing glomerulonephritis related to systemic vasculitis responds well to immunosuppressive drugs when treatment is started early, and suggest that plasma exchange is of additional benefit in dialysis-dependent cases.
Factors distinguishing samples of lesbian and heterosexual women.
This study utilized non-clinical samples of women and examined historical, familial, sexual, and attitudinal variables to assess differences between groups endorsing heterosexual or homosexual orientations. Drawing from social learning theory, researchers expected the lesbian group to report more negative childhood sexual experiences with males, more positive childhood sexual experiences with females, more accepting parental attitudes toward sexuality and sexual experimentation, and more distant relationships with parents. Results indicate that, rather than childhood sexual experiences distinguishing groups, respondents' current attitudes are significant between-group discriminators. These findings are consistent with the recent body of literature that suggests that sexual orientation cannot be explained in terms of early sexual trauma or negative heterosexual experiences.
Effects of ancrod and rtPA on fibrin accumulation, glomerular inflammation and renal function in nephrotoxic nephritis.
We have compared the effects of ancrod and recombinant tissue plasminogen activator (rtPA) on nephrotoxic nephritis induced in pre-immunized rabbits by the administration of nephrotoxic globulin (NTG; sheep anti-rabbit glomerular basement membrane). We used three different doses of NTG: in each experiment three groups of six rabbits were preimmunized with normal sheep globulin and given NTG: group A received no further treatment; group B received rtPA, 2 mg/kg 12 hourly; group C received ancrod 2 U/kg 12 hourly. Animals were bled daily for estimation of plasma fibrinogen and serum creatinine, then killed on day 5 and kidneys removed for histology. 1 ml/kg of NTG caused massive glomerular necrosis, all three groups having severe renal failure. With 0.5 ml/kg of NTG, ancrod and rtPA both effectively prevented fibrin deposition in Bowman's space, but all animals had severe proliferative glomerulonephritis and marked renal failure. With 0.25 ml/kg of NTG, control animals developed severe proliferative nephritis and advanced renal failure, ancrod provided almost complete protection, and the rtPA group had renal injury and functional impairment intermediate between the other two groups. We conclude that renal failure in severe nephrotoxic nephritis is fibrin-independent, but in less fulminant nephritis renal function can be protected by defibrination with ancrod. rtPA is capable of reducing glomerular fibrin accumulation as effectively as ancrod, but provides inferior protection of renal function.
Binding and internalization of biotinylated interleukin-2 in human lymphocytes.
The binding, internalization, and fate of interleukin-2 (IL-2) were studied in phytohemagglutinin (PHA)-activated human lymphocytes using biotinylated recombinant IL-2 (rIL-2). Streptavidin adsorbed to 18-nm colloidal gold beads (Au18-streptavidin) and streptavidin covalently bound to horseradish peroxidase (HRP-streptavidin) were used to follow the movement of biotinylated rIL-2 within cells over a 4-hour period. Results obtained from either probe were similar. Biotinylated rIL-2 was taken up in coated pits, transferred to a series of small uncoated vesicles and tubules in the peripheral cytoplasm of the cell, then concentrated and sequestered in uncoated vesicles, multivesicular bodies (MVB), and dense bodies (DB) in the peripheral and juxtanuclear cytoplasm of the cell. Occasionally, MVB containing Au18-streptavidin, or HRP-streptavidin, appear to have fused with the plasma membrane of the cell. No labeling of the Golgi cisternae, nuclear envelope, or nucleus was observed. Results from a competitive receptor binding assay and a cell proliferation assay indicate that both the affinity of rIL-2 for high affinity rIL-2 receptors and the proliferative activity of rIL-2 were negligibly affected by the biotinylation procedure. These studies suggest that in activated lymphocytes, IL-2 is bound to receptors on the cell surface, gathered in coated pits, internalized by receptor-mediated endocytosis, concentrated in the endosomal compartments, and delivered to lysosomes for degradation.
Autoimmunity and the pathogenesis of glomerulonephritis.
Self-tolerance is maintained by: thymic influences on developing T cells; peripheral mechanisms that can tolerise post-thymic T cells; and to a variable extent the tolerisation of potentially autoreactive B cells. The presence of autoreactive T cells in normal individuals suggests that mechanisms to control the activity of such cells may be important. Failure of any of these processes may lead to autoimmunity. The relationship between glomerulonephritis and the mechanisms leading to breakdown of self-tolerance remains elusive. An important observation is that autoimmune diseases are strongly associated with particular products of the major histocompatibility complex (MHC). This association may reflect the intimate involvement of the MHC in thymic T cell education. Another explanation is that T cells only recognise antigens presented in the context of MHC molecules. Although there has been progress in identifying the targets recognised by autoantibodies in vasculitis and anti-GBM disease, nothing is known about the T cells involved. Despite our ignorance, therapy aimed specifically at the T cell can be effective. This approach is being supplemented by attempts to engage immunoregulatory mechanisms, such as idiotype-antiidiotype interactions. The hope is that such treatments, or combinations thereof, will allow a more focused suppression of the autoimmune response, in contrast to the non-specific (and therefore potentially dangerous) methods of immunosuppression available at present.
Towards new therapeutic strategies in renal disease.
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The immunogenetic basis of autoimmunity.
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Symposium on the pathogenetic mechanisms in nephritis.
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Autoimmunity and nephritis.
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Monoclonal rheumatoid factor-IgG immune complexes. Poor fixation of opsonic C4 and C3 despite efficient complement activation.
Monoclonal IgM rheumatoid factor forms complexes with IgG in essential mixed cryoglobulinemia. We demonstrate that such complexes fix C3 and C4 poorly, although efficient fluid-phase C3 conversion can occur. Fixation of small amounts of C4 may be sufficient to generate a C3 convertase, but may prevent subsequent fixation of C3 by competing for binding sites on the complex. These complexes bind inefficiently to normal erythrocyte complement receptor type 1 (CR1) in vitro, and are undetectable on erythrocytes of patients with essential mixed cryoglobulinemia in vivo. Clearance of such phlogistic complexes from tissues by CR1-bearing cells may be inefficient.
Monoclonal antibodies to restricted and cross-reactive idiotopes on monoclonal rheumatoid factors and their recognition of idiotope-positive cells.
Four human monoclonal rheumatoid factors (MRF) were used to raise a panel of mouse monoclonal antibodies (mAb) which were selected in a solid-phase radioimmunoassay for binding to MRF but not normal IgM. Three mAb, each raised against a different MRF, bound to the majority of MRF and also to most polyclonal RF. Four other mAb bound selectively to the MRF against which they were raised and to no other MRF, and rarely to any polyclonal RF. Competition studies using cold and radiolabeled mAb further indicated that these mAb recognize distinct and different epitopes on MRF. RF activity of MRF was inhibited by 3 of the 4 mAb binding to a single MRF and 2 of the 3 mAb binding to multiple RF. It was thus concluded that of this panel of mAb 3 recognized cross-reactive idiotopes and the remainder demonstrated highly restricted idiotopes on MRF. These mAb identified MRF idiotope-bearing cells in the peripheral blood of 3 of the MRF donors (and a further subject with type II essential cryoglobulinemia), with a frequency ranging from 0.3-10% of all mononuclear cells with the mAb to restricted idiotopes or 1.5-17% with mAb to cross-reactive idiotopes. These anti-idiotopic mAb should thus provide a highly specific means of identifying and monitoring MRF-producing cells in vivo.
A lysine-binding protein in SLE sera inhibits the binding of immune complexes to normal erythrocyte CR1 (complement receptor type 1).
The binding of 125I-labelled immune complexes (IC) to normal human erythrocyte CR1 (complement receptor type 1) by sera from patients with SLE was found to be significantly decreased compared to normal sera. In 13/29 patients, there was an inhibitor which decreased the binding of opsonized IC in normal sera to normal erythrocytes. It was found in each of the nine patients who had clinically active disease. The inhibitor was shown to be a globulin that was labile at 56 degrees C and bound to lysine; low concentrations of tranexamic acid and of lysine abolished the effects of the inhibitor which suggests that it possesses lysine-binding sites: these may block the CR1-binding site on IC opsonized with complement. This inhibitor may decrease the efficiency of IC carriage by erythrocyte CR1.
The role of complement and its receptor in the elimination of immune complexes.
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Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro.
Plasma samples from patients with nephritic factor (NeF) were examined for their C3 converting activity. C3, C3dg, C5 and the fluid phase terminal complement complex (TCC) were quantified. All patients had evidence of C3 activation with low plasma C3 and high C3dg. Some patients had normal C5 and normal TCC levels, and thus no evidence of terminal pathway activation in vivo; others, with slower C3 conversion in vitro, had low C5 levels with TCC either elevated or in the upper normal range, suggesting in vivo activation of the terminal pathway. These observations were confirmed by in vitro experiments using purified NeFs. It is concluded that considerable activation of C3 may occur in vivo without a simultaneous activation of the terminal pathway, and that NeF is heterogeneous with regard to its ability to activate complement.
C3 nephritic factor (C3NeF): dissociation of cell-bound and fluid phase stabilization of alternative pathway C3 convertase.
Fluid phase C3 conversion by C3 nephritic factor (C3NeF) is usually easily detectable and forms the basis of the C3NeF screening test. We have described a group of patients with membranoproliferative glomerulonephritis or partial lipodystrophy and hypocomplementaemia who have an unusual C3NeF which stabilizes cell-bound C3 convertase of the alternative pathway (C3bBb) but causes such weak fluid phase C3 conversion that a C3NeF screening test is negative. These patients have low concentrations of C5 in serum.