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A J Rees

Publications and source records attributed to A J Rees.

At least 37 records · Page 2Linked to original sources
PubMed1997

Scleroderma, D-penicillamine treatment, and progressive renal failure associated with positive antimyeloperoxidase antineutrophil cytoplasmic antibodies.

Progressive renal failure in patients with scleroderma is a sinister development that is usually attributed to impaired renal blood flow. In some exceptional cases, the underlying pathology is a crescentic glomerulonephritis, which has been associated with positive antineutrophil cytoplasmic antibodies, and in particular antimyeloperoxidase antibodies. The prognosis in such cases has been very poor. We report such a patient whose renal function has improved and stabilized on immunosuppressive therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes.

Anti-glomerular basement membrane (anti-GBM) disease is caused by autoimmunity to a component of glomerular basement membrane. The major autoantigen has been identified as the NC1 domain of the alpha 3 chain of type IV collagen, and patients are characterized by the presence of specific autoantibodies to this molecule. In common with other autoimmune disorders, there is a strong association with HLA genes, with up to 80% of patients inheriting an HLA-DR2 haplotype. To examine the genetic basis of susceptibility to anti-GBM disease in more detail, the HLA-DRB and DQB alleles inherited by 82 patients were analyzed using sequence specific oligonucleotides. This identified a hierachy of association of DRB1 genes with anti-GBM disease, including susceptibility (DRB1*15, DRB1*04), neutral (DRB1*03) and protective (DRB1*07) alleles. Analysis of inherited haplotypes, particularly DRB1*04 and DRB1*07 carrying haplotypes, provided further evidence that the primary association was with genes at the DRB1 locus. Comparison of the sequences of the positively and negatively associated alleles showed that polymorphic residues in the second peptide binding region of the HLA Class II antigen binding groove segregated with disease. This work supports the hypothesis that the HLA associations in anti-GBM disease reflect the ability of certain Class II molecules to bind and present peptides derived from the autoantigen to T helper cells.

Alleles↗
PubMed1997

Interleukin-4 ameliorates experimental glomerulonephritis and up-regulates glomerular gene expression of IL-1 decoy receptor.

Monocytes/macrophages and pro-inflammatory cytokines such as interleukin (IL)-1 are important in the pathogenesis of acute glomerulonephritis. The aim of this study was to examine whether IL-4, a cytokine with anti-inflammatory activity, could modulate glomerular inflammation and reduce injury in vivo. Treatment with recombinant rat IL-4 in a model of anti-glomerular basement membrane (GBM) antibody mediated glomerulonephritis in rats reduced glomerular injury. Albuminuria was less (73% less at day 4) and a lower proportion of glomeruli had capillary thrombi (79% less at day 4). In IL-4 treated rats, there was a moderate reduction in the number of macrophages in the glomeruli and also suppression of pro-inflammatory activities of the macrophages. Northern blot analysis of glomerular RNA showed that treatment with IL-4 up-regulated mRNA levels of type II IL-1 receptor (IL-1RTII). IL-1RTII, also known as IL-1 decoy receptor, may act as a decoy molecule to inhibit the effect of IL-1 beta. To our knowledge, this is the first demonstration of (i) recombinant IL-4 reducing glomerular inflammation in vivo and (ii) a treatment that increases IL-1RTII expression in association with reduction of tissue injury in vivo.

Animals↗
PubMed1997

Abrogation of glomerular injury in nephrotoxic nephritis by continuous infusion of interleukin-6.

Interleukin-6 (IL-6) has been reported to have pro- and anti-inflammatory effects. It has also been shown to cause mesangial cell proliferation in vitro and has been suggested as a mediator of injury in proliferative nephritis. We have assessed the effects of continuous infusion of human recombinant (hr) IL-6, by osmotic minipump, on the degree of glomerular injury, and on glomerular and interstitial cell proliferation, in the accelerated autologous phase of nephrotoxic nephritis. Two groups of rats were pre-immunized with 1 mg of normal rabbit IgG in Freund's complete adjuvant. One week later, nephritis was induced by an intravenous injection of 1 ml of rabbit nephrotoxic serum. One day before the induction of nephritis, group 1 (N = 9) was subcutaneously implanted with osmotic minipumps filled with 50 micrograms (200 microliters) of IL-6 (equivalent to a dose of 6 micrograms/day), while in group 2 (N = 11) the minipumps were filled with 200 microliters of normal saline. In group 3 (N = 6) normal rats were infused with 50 micrograms of IL-6 alone. The rats were killed seven days after implantation of minipumps. The administered hrIL-6 was detectable in the circulation within the pathophysiological range, and induced a hepatic acute phase response, as assessed by alpha 2-macroglobulin levels. Continuous treatment with IL-6 resulted in a significant reduction in albuminuria (from 195 +/- 37 mg/20 hr to 60 +/- 15 mg/20 hr on day 1, and from 494 +/- 52 mg/20 hr to 238 +/- 30 mg/20 hr on day 7, P < 0.002) and in the prevalence of glomerular capillary thrombosis (from 19 +/- 3% to 5 +/- 1%, P < 0.002). There was also a reduction in macrophage infiltration (ED1 + ve cells from 524 +/- 34 to 466 +/- 14 per 50 glomeruli, P < 0.02) and activation (ED3 + ve cells from 106 +/- 13 to 42 +/- 5 per 50 glomeruli, P < 0.002). Immunohistology showed fewer interstitial Ia + ve cells (OX3 and OX4) in the IL-6 treated group. Similar results were obtained in a second set of experiments in which the IL-6 treatment was extended until day 14. Kidney sections taken from nephritic rats infused with IL-6 showed no increase in glomerular or interstitial cell proliferation when stained with antibodies to proliferating cell nuclear antigen. There was no difference in the deposition of rabbit IgG or rat IgG along the glomerular basement membrane (GBM), and the titer of rat anti-rabbit IgG was similar in the IL-6 and control treated rats. Infusion of IL-6 alone in normal rats had no functional or pathological effects. In conclusion, these results show that IL-6 has powerful anti-inflammatory effects in a rat model of anti-GBM nephritis, and does not induce mesangial cell proliferation in vivo.

Animals↗
PubMed1997

Influence of endotoxin contamination on anti-GBM antibody induced glomerular injury in rats.

It is accepted that the main determinant of glomerular injury in experimental nephrotoxic nephritis is the administered dose of anti-glomerular basement membrane (GBM) antibody. However, there are other factors that can enhance the severity of such injury including small doses of bacterial lipopolysaccharide (LPS). In the present study, we have assessed whether preparations of anti-GBM antibody contaminated with different concentrations of endotoxin could influence the severity of glomerular injury in the heterologous phase of nephrotoxic nephritis. We have also examined the efficacy of different laboratory methods to isolate an endotoxin-free anti-GBM antibody, and to purify anti-GBM antibody preparations from endotoxin. Preparations of anti-GBM antibody (nephrotoxic globulin) isolated from nephrotoxic serum by the sodium sulphate precipitation method contained variable concentrations of endotoxin. Administration of these preparations in equal doses into clean rats, which had no established acute phase response, markedly aggravated the severity of glomerular injury. However, preparations contained less than 50 pg/ml of endotoxin appeared to have no significant effect on such injury. Furthermore, isolation of anti-GBM antibody from nephrotoxic serum by affinity chromatography, using Staphylococcus protein-A column, proved to be a reliable method not only for the isolation of an IgG (nephrotoxic antibody) free from other serum contaminants, but also for purification of endotoxin contaminated preparations of anti-GBM antibody. These observations have practical implications in studying models of nephritis as our results show that the glomerular injury, which is usually considered to be a sole function of the mass of antibody bound to GBM, is profoundly influenced by minor endotoxin contamination of the anti-GBM antibody.

Animals↗
PubMed1997

Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo.

Mesangial cell proliferation and matrix overproduction characterize many progressive glomerular diseases. Based on currently available data, the role of interleukin-6 (IL-6) in mediating mesangial cell proliferation and matrix production is controversial. The present study attempts to clarify this issue by showing that: (1) IL-6 knock out mice develop a normal glomerular architecture and in particular a normal mesangium. (2) Mesangioproliferative glomerulonephritis induced by Habu snake venom is equally severe in IL-6 knock out mice as in control mice. (3) A continuous seven-day intraperitoneal infusion of 50 micrograms recombinant human IL-6 into rats with a prior minimal (subnephritogenic) injury to mesangial cells does not induce glomerular cell activation, cell proliferation, matrix production, leukocyte influx, platelet influx or proteinuria. (4) A continuous seven-day IL-6 infusion into rats with mesangioproliferative nephritis (anti-Thy 1.1 nephritis) increases matrix protein transcription in the absence of detectable effects on matrix protein accumulation and otherwise has no effect on the natural course of the disease. We conclude from these findings that IL-6 is not an important mediator of mesangial cell proliferation and matrix overproduction in vivo, and that currently little rationale exists to advocate anti-IL-6 therapy in mesangioproliferative disease states.

Animals↗
PubMed1996

Direct identification of naturally processed autoantigen-derived peptides bound to HLA-DR15.

Biochemical analysis of HLA class II-associated peptides from antigen-pulsed cells is a potentially useful approach to the analysis of antigen processing and presentation because it examines directly which antigen-derived peptides are presented. This is especially advantageous in the analysis of self-antigen presentation where conventional approaches utilizing antigen-specific T cells may be biased by the presence of self-tolerance. However, successful biochemical analysis has been reported for only one exogenous antigen and no autoantigens. We have used a novel analytical approach coupling biochemical data with the reported properties of class II-associated peptides to characterize the peptides derived from a clinically relevant autoantigen presented on the disease-associated class II type. Incubating the target of autoimmune attack in patients with Goodpasture's disease, the 230-amino acid NC1 domain of the alpha3 chain of type IV collagen (Goodpasture antigen, alpha3(IV)NC1), with human B cells homozygous for HLA-DR15, the allele carried by 80% of patients, we find that alpha3(IV)NC1 is presented as at least two sets of three to five peptides centered on common core sequences (nested sets). Synthetic peptides containing these core sequences bind to HLA-DR15 with intermediate affinity (IC50, 1.1-6 microM).

Amino Acid Sequence↗
PubMed1996

Differential expression of macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 in experimental glomerulonephritis.

We examined the relation between glomerular expression of chemokines from alpha-subfamily (macrophage inflammatory protein-2, MIP-2) and beta-subfamily (monocyte chemoattractant protein-1, MCP-1) and infiltration of neutrophils and monocytes in antibody mediated glomerulonephritis in rats. In the accelerated model of nephrotoxic nephritis (NTN), glomerular expression of MIP-2 and MCP-1 genes correlated with the sequential migration of neutrophil and monocyte influx, respectively. These relationships were investigated further in the heterologous phase of NTN by applying various treatments known to modulate the severity of injury. Pretreatment with bacterial lipopolysaccharide resulted in greater injury, MIP-2 expression increased 25- to 50-fold, and the glomerular neutrophil count increased two- to fourfold. Both MIP-2 mRNA levels and neutrophil infiltration were reduced by additional pretreatment with IL-6, IL-1 receptor antagonist, soluble IL-1 receptor or soluble TNF receptor (Spearman correlation coefficient r = 0.897, P < 0.005). In the heterologous phase of NTN, different pre-treatments only resulted in trivial changes in MCP-1 expression and monocyte infiltration. In conclusion, glomerular MIP-2 gene expression correlates with neutrophil infiltration both temporally during the evolution of nephritis, and when glomerular injury is modified by treatment. Glomerular MCP-1 gene expression correlates with monocyte influx. The data show chemokines of alpha- and beta-subfamilies co-operative to cause selective and sequential migration of different leukocyte subsets during development of antibody mediated glomerulonephritis.

Animals↗
PubMed1996

Vasculitis and the kidney.

This review analyzes the current literature on small vessel vasculitis affecting the kidney, and emphasizes the important contribution of anti-neutrophil cytoplasmic antibodies to recent advances in understanding. There is a very strong correlation between the presence of these auto-antibodies and the types of systemic vasculitis that cause crescentic glomerulonephritis with scanty immune deposits. Despite this, it is not yet clear whether anti-neutrophil cytoplasmic antibodies cause vasculitis or merely reflect its presence. However, the recent demonstration of anti-neutrophil cytoplasmic antibodies in spontaneous murine models of vasculitis, and the development of a model of vasculitis caused by immunity to myeloperoxidase strengthen the case for a pathogenic role. Regardless of whether they are pathogenic, sequential measurement of anti-neutrophil cytoplasmic antibody titres have proved extremely useful in the management of patients with systemic vasculitis. They are a considerable help in diagnosis, but perhaps they are even more important as a guide to maintenance immosuppressive therapy; relapses are rare when anti-neutrophil cytoplasmic antibodies cannot be detected, and are common when their titres are rising. Other ways to minimize exposure to cyclophosphamide are also reviewed.

Animals↗
PubMed1996

Goodpasture's disease and Alport's syndromes.

Goodpasture's, or anti-glomerular basement membrane, disease is an uncommon, usually severe disease caused by autoimmunity to a component of certain basement membranes. Alport's syndrome is an inherited, degenerative disorder that affects specific basement membranes. The two are linked by the involvement of type-IV collagen (basement membrane collagen) in their pathogenesis.

Anti-Glomerular Basement Membrane Disease↗
PubMed1996

Inhibiting inflammatory cytokines.

Acute glomerulonephritis is a common cause of renal dysfunction and ultimately renal failure. The inflammation involved is a tightly regulated response with pro- and anti-inflammatory cytokines playing key roles. Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are the principal pro-inflammatory cytokines produced by intrinsic cells and infiltrating leukocytes. IL-1 and TNF can be directly antagonized using IL-1 receptor antagonist (IL-1ra) or binding proteins such as soluble receptors or antibodies. Alternatively, cytokines with anti-inflammatory properties can be used to decrease IL-1 and TNF synthesis, increase the production of their natural antagonists and deactivate inflammatory cells such as macrophages. This review will focus on these anti-inflammatory cytokines, principally IL-4, IL-6, IL-10 and IL-13, and highlight recent research of their activities in existing models of renal disease. The results of these experiments offer a promising new avenue of treatment.

Animals↗
PubMed1995

Malignant disease in patients with long-term renal transplants.

The incidence of de novo malignancy was analyzed in 274 renal transplant recipients whose graft had functioned for at least 3 years and who had been followed for 2622 patient-years and individually for up to 29 years. The actuarial incidence and relative risks (RR) of tumor development (compared with National statistics) were calculated. Subgroup analysis was performed according to age, sex, the number of years and type of immunosuppression, and the tumor type. Seventy one tumors occurred in 54 patients. Skin tumors were the most common, followed by lymphoma, renal, bladder, and bronchial carcinoma. The actuarial cumulative risks of tumor development were 18.4% (95% confidence interval [CI] 12.4-24.3%) at 10 years and 49.6% (95% CI 36.3-62.0%) at 20 years. The overall RR of developing a tumor was 6.2 but was higher for men (RR 7.3) than women (RR 4.9). The RR of developing skin cancers, but not other malignancies, increased from 6.6 at 5 years to 20 after > 15 years. There was no evidence that cyclosporine-treated patients had an increased incidence of tumors, indeed the risk may be less in patients treated with cyclosporine and low-dose azathioprine than in those treated with azathioprine and prednisolone alone after more than 5 years.

Adolescent↗
PubMed1995

Relationship between disease activity and anti-neutrophil cytoplasmic antibody concentration in long-term management of systemic vasculitis.

Autoantibodies directed against neutrophil cytoplasmic antigens (ANCA) are valuable in the diagnosis of primary systemic vasculitis, and immunofluorescence studies suggest that changes in ANCA concentration reflect changes in disease activity. We used enzyme-linked immunosorbent assays to examine retrospectively the relationship between ANCA concentration and disease activity in 56 patients with systemic vasculitis. We included patients with Wegener's granulomatosis, microscopic polyangiitis, idiopathic rapidly progressive glomerulonephritis, and Churg-Strauss syndrome, and examined separately the initial treatment period (mean length of follow-up, 26 months) and long-term management (mean length of follow-up, 59 months). Levels of ANCA decreased during induction therapy with prednisolone and cyclophosphamide, with or without plasma exchange. During follow-up, 27 relapses were documented in 20 patients (10 with Wegener's granulomatosis, nine with microscopic polyangiitis, and one with Churg-Strauss syndrome), occurring between 4 and 183 months (mean, 62 months) after initial presentation. Patients in whom ANCA were detectable 1 year or more after treatment were at particular risk of clinical relapse. Proteinase 3-directed ANCA appeared to be associated with a higher rate of relapse (44% of patients relapsed) than myeloperoxidase-directed ANCA (13% of patients relapsed). Twenty-four of the 27 relapses occurred in the presence of detectable ANCA; in 21 of these, ANCA concentration was high or rising. The temporal relationship between changes in ANCA concentration and clinical relapse varied considerably between patients; in seven patients, ANCA remained at high levels for many months (range, 14 to 67 months) before eventual relapse. One patient showed high concentrations of ANCA over a period of 11 years without relapse. In five patients, increases in the ANCA level were not temporally associated with relapse (although four of these patients relapsed on other occasions.) We conclude that monitoring ANCA by enzyme-linked immunosorbent assays is of value in the long-term management of patients with Wegener's granulomatosis, microscopic polyangiitis, idiopathic rapidly progressive glomerulonephritis, and Churg-Strauss syndrome. Increases in ANCA and persistently high levels point to the risk of relapse and indicate the need for frequent clinical review and continuing maintenance immunosuppression. However, our results suggest that ANCA assays should always be used in conjunction with other indices of disease activity and should not be the sole basis for changing therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1995

Modulation of antibody-mediated glomerular injury in vivo by IL-1ra, soluble IL-1 receptor, and soluble TNF receptor.

The severity of glomerular injury in the heterologous phase of NTN is dependent on proinflammatory cytokines including TNF alpha and IL-1 beta, and can be enhanced by LPS. We have previously shown that passive immunization against IL-1 beta and TNF partially abrogated the LPS effect in this model. In the present work, we have assessed the effects on glomerular injury of blocking and binding of IL-1 to its receptor by rh IL-1 receptor antagonist (IL-1ra) and by neutralizing IL-1 and TNF with rm soluble IL-1 receptor type1 (sIL-1Rt1) and rh sTNF receptor (sTNFr p55), respectively. Pretreatment with either IL-1ra, sIL-1Rt1, or sTNFr partially abrogated the effects of LPS and reduced albumin excretion from 45 +/- 8, 66 +/- 9, and 101 +/- 17 mg/24 hr at 13 +/- 4 (P < 0.02), 14 +/- 4 (P < 0.001), and 21 +/- 7 mg/24 hr (P < 0.001), respectively. Similarly, these inhibitors reduced the prevalence of glomerular capillary thrombi and the intensity of glomerular neutrophil infiltration. Glomerular thrombosis was reduced from 18 +/- 3%, 28 +/- 5%, and 25 +/- 7% to 3 +/- 2% (P < 0.002), 6 +/- 2% (P < 0.001), and 3 +/- 2 (P < 0.001), respectively, and glomerular neutrophil infiltration was reduced from 46 +/- 3, 54 +/- 2, 59 +/- 8 to 19 +/- 2 (P < 0.001), 25 +/- 2 (P < 0.001), and 28 +/- 2 neutrophils/50 glomeruli in section, respectively. Coadministration of both soluble receptors of IL-1 and TNF caused a further decrease in glomerular injury. The protective effect was also noticed at four hours after induction of nephritis, and even when these inhibitors were administered after the LPS injection and at the same time of induction of nephritis. All three treatments reduced circulating TNF concentration (down to 20%, 34%, and 0%, respectively) but without detectable glomerular TNF gene expression. Glomerular IL-1 beta mRNA levels were also reduced by 41%, 53%, and 67%, respectively, when assessed by densitometric analysis of Northern blots. In contrast, the glomerular expression of IL-1ra was not affected by its exogenous administration but was mildly reduced by sIL-1Rt1 and sTNFr, which demonstrates the potential role for host derived IL-1ra as an endogenous negative feedback mediator in the glomerulus. These results confirm the direct involvement of IL-1 and TNF in LPS-enhanced hNTN and demonstrate the potency of these inhibitors in modulating injury even when administered after LPS and in time of induction of nephritis. They were more specific and effective than passive immunization with polyclonal antibodies, and this demonstrates their potential usefulness in the management of nephritis.

Animals↗
PubMed1995

Analysis of T cell responses to the autoantigen in Goodpasture's disease.

Goodpasture's disease is a rare form of glomerulonephritis characterized by the production of autoantibodies to the glomerular basement membrane (GBM). In order to understand the development of autoimmunity to the GBM, it is important to examine mechanisms underlying T cell responses to the autoantigen. A MoAb P1, with the same specificity as patients' autoantibodies, was used to affinity-purify the antigen from collagenase-digested human GBM. This material was enriched in the NC1 domain of the alpha 3 chain of type IV collagen (alpha 3(IV)NC1), known to be the principal target of anti-GBM antibodies, but also contained lower quantities of alpha 4(IV)NC1. In proliferation assays, T cells from 11/14 patients with Goodpasture's disease showed significant responses (SI > or = 2.0) to affinity-purified human GBM. Peak responses were demonstrated at 7 or 10 days at antigen concentrations of 10-30 micrograms/ml. As in other autoimmune disorders, the presence of autoantigen-reactive T cells was also demonstrated in 5/10 healthy volunteers. Tissue typing revealed that all patients possessed HLA-DR2 and/or -DR4 alleles, while normal individuals whose T cells responded possessed DR2 and/or DR7 alleles. The specificity of the T cell response in Goodpasture's disease was further investigated using monomeric components of human GBM purified by gel filtration and reverse phase high performance liquid chromatography (HPLC). Two antigenic monomer pools were obtained, which were shown by amino-terminal sequence analysis to contain alpha 3(IV)NC1 and alpha 4(IV)NC1, respectively. In all patients tested, significant T cell proliferation was observed in response to one or both of these alpha (IV)NC1 domains. These results demonstrate that patients with Goodpasture's disease possess T cells reactive with autoantigens known to be recognized by anti-GBM antibodies.

Adult↗
PubMed1995

Molecular analysis of HLA class II genes in Goodpasture's disease.

A molecular analysis of HLA class II genes was undertaken in order to characterize the previously reported association between HLA-DR2 and glomerulonephritis caused by antibodies to glomerular basement membrane (Goodpasture's disease). Genomic DNA was prepared from 53 patients with Goodpasture's disease and analysed by: (i) Southern blotting using cDNA probes to DRB, DQA and DQB genes, after digestion with TaqI endonuclease; (ii) allele-specific oligonucleotide probing of specifically amplified DNA; and (iii) nucleotide sequencing of relevant alleles. The patients had a greatly increased frequency of DRw15 (a subspecificity of DR2) which was present in 75.5% of patients and 31% of controls (p < 0.0001). The frequency of DR4 was also increased, especially in patients without DRw15. Overall, 90.5% of the patients had either DRw15 or DR4. In contrast, the frequency of DR1 was significantly reduced (patients 5.6%, controls 20.7%, p < 0.01). Differences in the frequencies of DQA and DQB alleles could all be explained by linkage disequilibrium. Nucleotide sequences of relevant alleles were identical to those previously published. Comparison of derived amino acid sequences of expressed DR beta chains showed that the DR beta chains of DRw15 and DR4 shared a six-amino-acid motif from positions 26-31, that included four polymorphic amino acids none of which are shared with DR1. A sequence-specific oligonucleotide detected this amino-acid motif in 45/49 (91.8%) patients tested. Thus, this particular motif, which lies on the floor of the antigen binding groove, has a stronger association with Goodpasture's disease than any individual allele, and may be of pathogenic significance.

Alleles↗
PubMed1995

High incidence of end-stage renal disease in Indo-Asians in the UK.

In a retrospective survey, we show that the incidence of end-stage renal disease (ESRD) is significantly raised among immigrant Indo-Asians referred to two UK renal units (p < 0.001). In addition to the expected increase in diabetic nephropathy, glomerulonephritis and chronic pyelonephritis are also seen more frequently in Indo-Asians. The most striking finding was a five-fold increase in ESRD of uncertain cause (p < 0.001) presenting with small smooth kidneys, which was strongly associated with active, mostly non-renal tuberculosis. The causes of this generalized increased susceptibility to renal disease are unknown. These findings have important implications both for primary health care screening and for planning the provision of renal replacement therapy.

Adolescent↗