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A R Clarkson

Publications and source records attributed to A R Clarkson.

At least 19 recordsLinked to original sources
PubMed2001

Restricted gammadelta T-cell receptor repertoire in IgA nephropathy renal biopsies.

BACKGROUND: We have previously reported that gammadelta T cells are involved in the progression of IgA nephropathy (IgAN) to renal failure. Our current study examined the diversity of the CDR3 region of the gammadelta T-cell receptor (TCR), and characterized the junctional sequences of gammadelta chain TCR transcripts from T cells infiltrating renal biopsies from patients with IgAN and in peripheral blood T cells (PBLs) from the same patients. METHOD: RNA extracted from renal biopsies and PBLs of IgAN patients (N = 15) was transcribed and then amplified with primers specific for the four Vgamma and six Vdelta families. Controls were renal biopsies from thin basement membrane disease (N = 6) and a sample from a kidney with suppurative pyelonephritis. CDR3 length spectratyping and sequencing of TCR gammadelta-chain were used to analyze the diversity of CDR3 region of these receptors. RESULTS: CDR3 spectratyping of gammadelta TCR junctional diversity demonstrated that TCR gammadelta chains (Vgamma1-3 and Vdelta1-3) expressed by T cells from PBLs of IgAN patients and the infected kidney showed highly diverse junctional lengths that were broadly distributed. In contrast, the junctional lengths of Vgamma1 (Vgamma2, 3, 4, 5, and 8 genes) and Vdelta1 transcripts in the T cells infiltrating kidneys with IgAN were much more restricted than those of PBLs. Renal biopsies from thin basement membrane disease demonstrated no significant signal for any Vgamma or Vdelta family. Sequence analysis of Vgamma1 and Vdelta1 transcripts from those patients with restricted CDR3 spectratyping profiles confirmed oligoclonal expansion of gammadelta T cells infiltrating the kidneys in those IgAN patients and also revealed recurrent junctional amino acid motifs in the TCR Vdelta1 chain in the kidney with IgAN. CONCLUSION: The data show that gammadelta T cells infiltrating the kidneys of IgAN patients use a restricted subset of gammadelta T cells, indicating clonal expansion of individual gammadelta T cells in the kidneys with IgAN. The feature of recurrent junctional amino acid motifs in Vdelta1 T cells may indicate antigen-driven selection.

Adult↗
PubMed2000

Excellent long-term graft survival in low risk, primary renal allografts treated with prednisolone-avoidance immunosuppression.

Primary avoidance of oral corticosteroids for renal transplant recipients is uncommon. The South Australian renal transplant service used a double therapy (DT) regimen of cyclosporin and azathioprine from August 1986 to July 1996 for low risk (first graft, PRA < 50%) allografts. Oral corticosteroid, prednisolone (P), was reserved for severe rejection or two mild rejection episodes, but could be later withdrawn at the physician's discretion. This regimen is associated with more early acute rejection (Russ et al., Clin Transplant 1990: 4: 26). We have now analysed long-term patient survival (PS) and graft survival (GS) for this group. Of 448 transplants in South Australia between August 1986 and July 1996, 295 commenced DT regimen. Ninety-four (31.8%) never received P at any stage post-transplantation (group 1), 96 (32.5%) were placed on P and later weaned (group 2), and 97 (33%) remained on long-term P (group 3). Technical losses, eight (2.7%), within 30 d of transplantation, were excluded from sub-group analysis. PS for the total DT cohort at 1, 5 and 9 yr post-transplantation was 97, 88 and 74%, respectively. GS over the same time period was 88, 75 and 55%, respectively. There was no statistically significant difference in survival compared to other 'low risk' grafts in the rest of Australia during the same time period. Mean serum creatinine concentration (CrC) for the DT group at 3 and 6 months and 1, 3, 5 and 10 yr was not significantly different to the rest of the Australian 'low risk' grafts. In the DT cohort, there were 334 acute rejections ( < 90 d) in 206 patients (70%), but only 42 (12.5%) required anti-lymphocyte antibody therapy (OKT3 or ATG) for rejection. PS at 9 yr was not statistically significantly different between groups 1 and 2, but both groups survived better than group 3 (p < 0.0043). GS for group 1 at 1, 5 and 9 yr post-transplantation was 90, 81 and 73%, respectively; for group 2, 98, 87 and 66%, respectively; and for group 3, 84, 63 and 29%, respectively. Statistical significance was reached in group 1 versus 3 (p < 0.001) and group 2 versus 3 (p < 0.001). In summary, a DT regimen in low risk, first renal allografts gives excellent long-term patient and GS and minimises long-term P, despite a high rate of early acute rejection.

Acute Disease↗
PubMed1999

Clozapine-induced acute interstitial nephritis.

Drug hypersensitivity reactions commonly cause acute interstitial nephritis (AIN). Clozapine, a new antipsychotic, can cause fatal bone-marrow toxicity. We report clozapine-induced AIN as another serious adverse drug reaction.

Acute Disease↗
PubMed1999

Conserved T-cell receptor beta chain CDR3 sequences in IgA nephropathy biopsies.

BACKGROUND: We have previously reported that both alpha beta and gamma delta T cells are involved in the progression of IgA nephropathy (IgAN) to renal failure. To determine whether the T-cells seen in the interstitium represent a generalized inflammatory response or whether they are proliferating oligoclonally in response to a particular antigen, we analyzed the TCR Vbeta gene usage by T cells infiltrating renal biopsies from patients with IgAN. METHODS: Fourteen IgAN patients were divided by clinical criteria into stable and progressive groups (7 in each group). Reverse transcription-polymerase chain reaction (RT-PCR) and cloning were used to characterize the expression of TCR Vbeta families in renal biopsies and in peripheral blood lymphocytes. RESULTS: TCR Vbeta8 was significantly and preferentially expressed in most IgAN kidney biopsies compared with peripheral blood lymphocytes from both IgAN patients and healthy controls (P < 0.001). TCR Vbeta8 expression was more marked in progressive biopsies than in stable biopsies (P < 0.05). Spectratyping of Vbeta8 RT-PCR products from T cells infiltrating the kidney showed an intense spectratype band at the shortest range of amplified CDR3s in the renal biopsies of four patients. Analysis of nucleotide and deduced amino acid sequences of Vbeta8 PCR products derived from intense spectratype bands from these renal biopsies revealed a high concordance across the CDR3 region. A conserved amino acid (leucine) at the first position of the nongermline-encoded nucleotides and diversity (ND) junction of Vbeta8 was found at a frequency of 95% in multiple sequences obtained from the renal biopsies of all four patients examined. CONCLUSIONS: The preferential use of Vbeta8 with marked similarities in the CDR3 region by some renal infiltrating T cells suggests clonal expansion of T cells in the kidneys of some IgAN patients. Conserved amino acids in the TCR CDR3 hypervariable region may contribute to the recognition of a particular antigen or set of antigens.

Adult↗
PubMed1995

No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis.

It has been recently reported that in type 1 diabetes the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene is associated with the presence of diabetic nephropathy. Tissue angiotensin I-converting enzyme is determined by I/D polymorphism, and it has been speculated that in diabetes differences of local angiotensin II availability determine the risk of renal disease. Since angiotensin II is thought to play an important role in the evolution of renal disease in general, we tested whether genotype distribution of the I/D polymorphism is also different in patients with immunoglobulin A-glomerulonephritis (IgA-GN). Furthermore we compared IgA-GN patients with (1) stable renal function or (2) terminal renal failure to investigate a potential role of the I/D polymorphism in the renal prognosis. We examined 122 patients with biopsy-confirmed IgA-GN who had stable renal function and 82 dialysis-dependent or transplanted patients with biopsy-confirmed IgA-GN. Furthermore, in 134 healthy individuals used as controls we analyzed the DNA for normal distribution of genotypes and allele frequencies. The polymorphic region was amplified using polymerase chain reaction with specific primers. Alleles were detected on 2% agarose gels. Genotype distributions and allele frequencies were not significantly different between controls and patients with IgA-GN and stable renal function. Furthermore, no significant difference in genotype distribution was detected between patients with IgA-GN and stable renal function compared with patients with IgA-GN and end-stage renal failure, although a trend for a higher frequency of DD-homozygotes was noted in the latter group (P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Infiltration of the kidney by alpha beta and gamma delta T cells: effect on progression in IgA nephropathy.

We have studied renal biopsies from three groups of patients to determine if alpha beta T cells or gamma delta T cells are present, and whether their presence is correlated with disease progression in IgA nephropathy (IgAN). Group one comprised thin basement membrane disease biopsies (non-immunological control, N = 7); group two were patients with IgAN and stable renal function one year following biopsy (stable, N = 7); and group three were IgAN patients with rapidly declining renal function after one year (progressive, N = 7). Immunohistochemical staining using monoclonal antibodies (CD3, TcR beta, TcR delta) and molecular studies utilizing polymerase chain reaction amplification of cDNA transcribed from biopsy RNA, with primers specific for either the alpha beta TcR or gamma delta TcR, were undertaken. On immunohistochemistry a significant increase in CD3 + cells in progressive biopsies was seen (vs. control P = 0.002, vs. stable P = 0.002). The progressive biopsies infiltrate consisted of both alpha beta TcR (vs. control P = 0.001, vs. stable P = 0.003) and gamma delta TcR cells (vs. control P = 0.01). The RNA study demonstrated an increase in TcR C alpha transcription in the progressive (vs. control P = 0.003) biopsies. Increased TcR C delta transcription was seen in the progressive group (vs. control P = 0.01, vs. stable P = 0.02). We confirm that the presence of lymphocytes in IgAN biopsies predicts progressive disease. While alpha beta T cells are found in both stable and progressive disease, the presence of gamma delta T cells is only associated with progressive IgAN.

Adult↗