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Biomedical subjects

A J Rees

Publications and source records attributed to A J Rees.

At least 55 records · Page 3Linked to original sources
PubMed1994

Molecular epidemiological study of invasive pulmonary aspergillosis in a renal transplantation unit.

The molecular epidemiology of an outbreak of invasive pulmonary aspergillosis which occurred on a renal transplantation unit was investigated. Restriction fragment length polymorphism and random amplified polymorphic DNA analyses were used to characterise the isolates of Aspergillus fumigatus from the patients (2 isolates from each of 2 patients) and from the environment (11 isolates). While the isolates from the environment could be readily distinguished from each other by both methods, each patient appeared to be infected with a single strain. These findings lend support to the suggestion that certain isolates of Aspergillus fumigatus are more pathogenic than others.

Aspergillosis↗
PubMed1994

Influence of an established acute phase response on the severity of experimental nephritis.

Small doses of lipopolysaccharide (LPS) induced an acute phase response (APR), and a number of studies have also shown that this greatly enhances the severity of glomerular injury in the heterologous phase of nephrotoxic nephritis (hNTN), an experimental model of anti-glomerular basement membrane (GBM) disease. Here, we examined the influence of pre-existing subclinical infection and raised APR, assessed by plasma alpha 2-macroglobulin (alpha 2-M) concentration, on the degree of injury in this model of nephritis. Studies were initially performed to determine the normal range of alpha 2-M in rats and its modulation by IL-6 and different doses of LPS. Plasma concentration of alpha 2-M was found to be variable and dependent on the weight of the rats. Single injections of either LPS or IL-6 had a comparable effect, and continuous perfusions of LPS caused a progressive increase in alpha 2-M which peaked at 48 h and declined gradually over 1 week. Following induction of nephritis with 10 mg of anti-GBM antibody, rats with raised alpha 2-M had 14 +/- 3 mg/24 h albuminuria compared with 4 +/- 1 mg/24 h in rats with normal alpha 2-M (P < 0.001, Wilcoxon). Injection of 20 mg anti-GBM antibody caused 36 +/- 11 mg/24 h albuminuria compared with 16 +/- 4 mg/24 h (P < 0.001), respectively. However, all these rats remained active and none of them died. In contrast, injection of 0.25 microgram LPS before induction of nephritis with 10 mg anti-GBM antibody, in rats with raised alpha 2-M, caused severe albuminuria (115 +/- 23 mg/24 h) compared with rats having normal levels of alpha 2-M (72 +/- 15 mg/24 h, P < 0.05). Furthermore, rats with raised alpha 2-M also had severe systemic manifestations characterized by pulmonary haemorrhage and extensive glomerular thrombosis, and many of them died. These results demonstrate the potential effect of pre-existing subclinical infection and raised APR on severity of glomerular injury which may affect the outcome of experimental studies.

Acute-Phase Reaction↗
PubMed1994

Glomerular expression of interleukin-1 receptor antagonist and interleukin-1 beta genes in antibody-mediated glomerulonephritis.

Interleukin-1 (IL-1) is a powerful proinflammatory cytokine whose function is modulated by a natural IL-1 receptor antagonist (IL-1ra). There are few data about kinetics of in vivo synthesis of IL-1ra at tissue level, except in response to bacterial endotoxin. The purpose of this study was to examine the kinetics of local expression of IL-1ra gene in relation to IL-1 beta gene in a model of anti-glomerular basement membrane antibody-mediated glomerulonephritis. Rats were killed in groups of 5 or 6 at 0, 4, 6, 24, 48, and 96 hours after induction of glomerulonephritis. Messenger RNA for IL-1ra and IL-1 beta was undetectable by Northern blot in normal glomeruli but increased markedly 4 to 6 hours after induction of nephritis. The increase in IL-1ra mRNA was more sustained than that of IL-1 beta mRNA. In situ hybridization showed that IL-1 beta mRNA increased diffusely within glomeruli, while IL-1ra mRNA was expressed more discretely. Expression of these mRNA in noninflamed tissues, spleens and lungs, was different, particularly increase in IL-1ra mRNA was more substantial than that of IL-1 beta. These observations suggest that differential expression of IL-1ra and IL-1 beta might focus inflammation in glomeruli while protecting more distant sites. They also raise the possibility of reducing glomerular injury by therapeutic measures that upregulate glomerular synthesis of IL-1ra while reducing that of IL-1 beta.

Animals↗
PubMed1993

Significance of autoantibodies to purified proteinase 3 in systemic vasculitis.

Proteinase 3 was purified from human neutrophils and used in ELISA to examine sera from 150 patients with systemic vasculitis. It was found to be the major target of autoantibodies in Wegener's granulomatosis, and anti-proteinase 3 antibodies were also found in some patients with microscopic polyarteritis. Anti-proteinase 3 antibodies were associated with a chronic relapsing course.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Relationship between disease activity and ANCA level by ELISA in the long-term management of vasculitis.

Solid-phase immunoassays were used to examine the relationship between ANCA concentration and disease activity during follow-up of 63 patients with systemic vasculitis. ANCA levels fell with induction therapy. Relapses during long-term follow-up were generally associated with high or rising ANCA concentrations, although the temporal relationship between clinical relapse and changes in ANCA was variable.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Modulation of antibody-mediated glomerular injury in vivo by interleukin-6.

We have shown previously that pretreatment with small doses of bacterial lipopolysaccharide (LPS), human recombinant interleukin-1 beta (hrIL-1 beta) and human recombinant tumor necrosis factor-alpha (hrTNF) increase injury in the heterologous phase of nephrotoxic nephritis (NTN). All three pretreatments induce synthesis of interleukin-6 (IL-6) which in some systems down-regulates synthesis of IL-1 and TNF. We have now investigated the influence of IL-6 on injury in both heterologous and autologous phases of NTN in rats. Injection of hrIL-6 in doses sufficient to induce hepatic synthesis of acute phase proteins (assessed by plasma alpha 2-macroglobulin concentration) had no effect on glomerular injury in the heterologous phase of NTN (albuminuria in NTAb alone 9 +/- 6; LPS/NTAb 34 +/- 10 and IL-6/NTAb 2 +/- 1 mg/24 hr, P < 0.001, Wilcoxon test). In contrast, IL-6 pretreatment partially abrogated the effect of LPS on albumin excretion (NTAb 4 +/- 2; LPS/NTAb 85 +/- 11 and IL-6/LPS/NTAb 32 +/- 6 mg/24 hr, P < 0.002), percentage of glomerular capillary thrombi (3 +/- 1%; 39 +/- 8%; and 6 +/- 1%, P < 0.001) and glomerular neutrophil infiltrate (29 +/- 3; 58 +/- 5; and 34 +/- 2 neutrophils/50 glomeruli in section, P < 0.001, respectively) at 24 hours. The effect of IL-6 was also evident four hours after induction of nephritis and was associated with a marked reduction in glomerular concentration of mRNA for IL-1 beta and TNF, without change in that of tubulin. Serum TNF concentrations were also significantly reduced at four hours in IL-6 treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Renal transplantation following immunoadsorption in highly sensitized recipients.

Five highly sensitized patients, with panel reactivity greater than 80% for 1.75-5 years, were treated by extracorporeal staphylococcal protein-A immunoadsorption, prednisolone, and cyclophosphamide. The five patients underwent treatment of 18-40 (mean 31) liters of plasma, respectively in 4-7 (mean 5.6) sessions. This reduced the titer of cytotoxic antibodies to sensitizing antigens to < 1/8 in all cases and abolished reactivity to crossreacting antigens. Two patients required retreatment following resynthesis of cytotoxic antibodies. All five patients have been transplanted, and four of these now have stable serum creatinines of 168 mumol/L at 34 months, 208 mumol/L at 29 months, 96 mumol/L at 5 months, and 125 mumol/L at 3 months posttransplantation. One patient had primary graft dysfunction due to acute tubular necrosis; the kidney was removed after eight weeks and showed cortical necrosis without evidence of acute rejection.

Adult↗
PubMed1993

In vitro production of tumor necrosis factor by monocytes cultured from dialysis patients.

Cellular release of cytokines may be responsible for certain complications of extracorporeal dialysis including the increased susceptibility to infection found in dialysis patients. In order to study this further, we have evaluated the in vitro production of tumor necrosis factor (TNF) by peripheral blood monocytes (PBMC) to stimulation by lipopolysaccharide (LPS) from dialysis patients with end-stage renal failure (ESRF). The patients were subdivided into two groups according to the type of dialysis; those undergoing hemodialysis (HD) (N = 12) and those performing continuous ambulatory peritoneal dialysis (CAPD) (N = 9). Results were compared with those of controls taken from healthy laboratory staff (N = 7). The experiments show that the secretion of TNF by PBMC's in response to LPS is significantly augmented in patients undergoing HD when compared to those on CAPD (81.3 +/- 38.7 U/ml vs. 18.2 + 13.3 U/ml, mean +/- SD, P < 0.001); and controls (81.3 +/- 38.7 U/ml vs. 18.1 +/- 6.6 U/ml, P < 0.001). There was no significant difference between the CAPD group and controls. In vitro monocyte production of TNF fell following a single HD session (81.3 +/- 38.7 U/ml before HD and 50.5 +/- 28.7 U/ml after HD, P < 0.05). We conclude from this study that TNF release from PBMC's in vitro is augmented in patients with chronic renal failure receiving chronic HD but not in a similar group receiving CAPD. Interestingly, TNF release from monocytes collected immediately following a dialysis was suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Familial IgA nephropathy: a study of HLA class II allogenotypes in a Chinese kindred.

We have studied the restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) class II DQ, DR pattern of a Chinese family with IgA nephropathy (IgAN). The three affected and one apparently unaffected sibling shared the same DR and DQ pattern. The subjects were homozygous for DRw12, DQw7, DQ alpha 1b. The DQw7 allele was further confirmed by polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) probing. This study confirms that IgAN can run in a family and is consistent with the possible immunopathogenetic effects of MHC class II antigens on IgAN.

Adult↗
PubMed1992

HLA class II specificities in vasculitis with antibodies to neutrophil cytoplasmic antigens.

HLA class II genes were examined in patients with small vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) using restriction fragment length polymorphism and allele specific oligonucleotide typing. Fifty-nine patients were studied, 34 with Wegener's granulomatosis and 25 with microscopic polyarteritis, and their results were compared with those from 1103 British Caucasoid controls. The frequency of HLA-DQw7 was significantly increased in patients with vasculitis (patients 53%; controls 27.8%, chi 2 17.8, Pc less than 0.0025, relative risk 2.9), and all the DQw7 bearing haplotypes commonly found in Caucasoid populations contributed to the increase. By contrast, the frequency of HLA-DR3 bearing haplotypes was decreased in the patients (patients 6.8%; controls 21.6%, chi 2 6.7, P less than 0.01). HLA specificities were similar in the groups of patients presenting with Wegener's granulomatosis and microscopic polyarteritis and with different types of ANCA assessed by indirect immunofluorescence. However, patients with the DQw7, DR4 haplotype were significantly more likely to have transiently positive tests for ANCA than patients with other DQw7 bearing haplotypes, whereas patients with DR2 bearing haplotypes were more likely to have persistently positive ANCA. These results show that HLA class II genes are associated with small vessel vasculitis and may influence the duration of the associated autoimmune response.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1992

Passive immunization against tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta protects from LPS enhancing glomerular injury in nephrotoxic nephritis in rats.

Glomerular injury caused by injection of heterologous anti-glomerular basement membrane antibodies (anti-GBM Ab) is increased in rats pretreated with small doses of bacterial lipopolysaccharide (LPS). We have investigated the involvement of tumour necrosis factor-alpha (TNF-alpha), IL-1 alpha and IL-1 beta in this phenomenon by passive immunization against these cytokines. Anti-TNF-alpha or anti-IL-1 beta antibodies given 1.5 h before the induction of nephritis significantly decreased injury in this model, whether assessed by the magnitude of albuminuria, the prevalence of glomerular capillary thrombi or the intensity of glomerular neutrophil infiltrate. Albuminuria in anti-GBM Ab alone was 11 +/- 3, LPS/anti-GBM Ab 87 +/- 22, and anti-TNF-alpha antibodies/LPS/anti-GBM Ab 21 +/- 6 mg/24 h (mean +/- s.e.) P < 0.05. Passive immunization with antibodies to IL-1 beta had a similar effect (anti-GBM Ab, 0.6 +/- 0.1, LPS/anti-GBM Ab, 92 +/- 19, anti-IL-1 beta antibodies/LPS/anti-GBM Ab 39 +/- 8 mg/24 h, P < 0.05). The prevalence of glomerular capillary thrombi was also reduced significantly by these treatments; from 22 +/- 5% to 4 +/- 1% in the case of anti-TNF-alpha antibodies and 28 +/- 5% to 13 +/- 4% with anti-IL-1 beta antibodies. Similarly, the glomerular neutrophil infiltrate was also reduced by these treatments; from 42 +/- 3 to 25 +/- 1 in the case of anti-TNF-alpha and 47 +/- 2 to 30 +/- 1 with anti-IL-1 beta antibodies. In contrast, passive immunization against IL-1 alpha had no effect on either albumin excretion (4 +/- 3, 83 +/- 22 and 77 +/- 24 mg/24 h), glomerular capillary thrombi (2 +/- 1; 19 +/- 5 and 16 +/- 3) or glomerular neutrophil infiltrate (22 +/- 3; 47 +/- 5 and 48 +/- 5 from the three groups respectively). These results demonstrate that enhanced antibody mediated injury in the kidney is modulated by TNF-alpha and IL-1 beta but not by IL-1 alpha.

Animals↗
PubMed1992

Human mesangial cells synthesize interleukin 1 alpha but not interleukin 1 beta, interleukin 1 receptor antagonist, or tumour necrosis factor.

There is controversy over whether mesangial cells synthesize and release IL-1 and TNF, and many of the positive experiments were performed before specific reagents and molecular probes were available. Consequently we have stimulated human mesangial cells using protocols known to stimulate the synthesis of other cytokines. No mRNA for IL-1 beta or TNF could be detected in quiescent or proliferating mesangial cells irrespective of whether they had been exposed to cytokines or not. In contrast mRNA for IL-1 alpha was detected in cells stimulated with IL-1 beta 10 ng/ml or with TNF 500 ng/ml; IL-1 alpha was also detected in cell lysates from stimulated mesangial cells. We could not detect mRNA for IL-1 receptor antagonist in any of the cell preparations. These results suggest that mesangial cells are unlikely to be a major source of IL-1 beta or TNF.

Cells, Cultured↗
PubMed1992

Type II essential mixed cryoglobulinaemia: presentation, treatment and outcome in 13 patients.

The long-term clinical course of patients with primary Type II essential mixed cryoglobulinaemia is unclear as many reports fail to separate this group from patients with Type III disease. We have reviewed 13 patients with Type II essential mixed cryoglobulinaemia who presented to the Hammersmith Hospital between 1976 and 1990. All patients had a cryoglobulin level greater than 0.1 mg/ml (range 0.27-6.50 mg/ml), and characterization of the cryoglobulin in all cases revealed the presence of a monoclonal IgM kappa component with rheumatoid factor activity together with polyclonal IgG. All patients had evidence of activation of the classical pathway of complement with greatly reduced levels of C4, while C3 levels were moderately reduced in three patients. All patients had skin disease and joint symptoms were reported by nine patients, with erosive arthritis in one. Eight patients had peripheral sensorimotor neuropathy. Renal disease was observed in 10 patients, manifesting as raised creatinine level, proteinuria or haematuria. Renal tissue was examined in eight patients: in six the appearances were those of a mesangiocapillary glomerulonephritis Type I while in the other two patients there was a mesangioproliferative glomerulonephritis, in one diffuse and in the other focal and segmental. Glomerular capillary 'hyaline thrombi' were found in six biopsies, extracapillary proliferation was found in three and evidence of vasculitis was found in all eight. Liver biopsy showed macronodular cirrhosis in one patient, while a second with recurrent episodes of jaundice showed only chronic inflammatory changes. No patient was positive for hepatitis B surface antigen; however one patient had low titre anti-hepatitis B surface antibody. Normochromic normocytic anaemia was present in nine patients. Bone marrow examination was carried out in 13 patients at presentation to our unit: 10 showed no evidence of a lymphoproliferative disorder, while three suggested the presence of a non-Hodgkin's lymphoma (some years after original presentation in all three). Unusual clinical features included one patient with retinal vasculitis and one patient with severe pulmonary haemorrhage.

Adult↗
PubMed1991

The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians.

The frequencies of the MHC class II HLA-DR and DQ alleles in 36 Caucasian patients with IgA nephropathy (IgAN) were analyzed by RFLP analysis and allele specific oligonucleotide (ASO) probing of specifically amplified genomic DNA. The class II alleles HLA-DR4 (52.7%) and DR5 (30.5%) were increased in the patient group compared to 1103 UK Caucasoid controls, but these increases were not statistically significant. However, there was a significant increase in the HLA-DQw7 allele frequency (71%) (c = 27.8%, chi 2 = 29.2, P less than 0.001, Relative Risk = 6.17). This can be explained by linkage disequilibrium between the DQw7 allele at the DQB1 locus and DRB1 genes of some DR4 and all DR5 haplotypes. The polymorphic portion of the DQ alpha chains from DR4, DQw7 and DR5, DQw7 haplotypes differ but they have identical DQ beta chains. DNA encoding DQw7 allele at the DQB1 locus was sequenced in two patients and was identical to that previously published. We conclude that the DQw7 allele at the DQB1 locus is strongly associated with susceptibility to IgAN in Caucasians.

Alleles↗