Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of glomerulosclerosis was studied in murine chronic graft-versus-host disease (GvHD), which is a model for human systemic lupus erythematosus. The authors investigated the distribution patterns of six components of the extracellular matrix (ECM), i.e., laminin, fibronectin, collagen types I, III, IV, and VI during the course of the disease. All of these ECM components except collagen type I were found in the glomeruli of normal mice, where all of them were intrinsic constituents of the mesangium. Laminin, fibronectin, and collagen type IV were also found in the glomerular capillary walls. Starting 6 weeks after the induction of GvHD and continuing at week 8, the onset of an expansion of the mesangial matrix was observed. At the same time, the amounts of laminin, fibronectin, and collagen types IV and VI increased. Ten weeks after the onset of the disease, glomerulosclerosis developed. Traces of the interstitial collagen type I were found in sclerotic glomeruli. The levels of four ECM components, i.e., collagens III, IV, VI, and laminin were markedly decreased in the sclerotic glomeruli as compared with week 8. In contrast, the amount of fibronectin in the sclerotic glomeruli increased dramatically. Immunoelectron microscopic examination showed fibronectin in the sclerotic lesions, in contrast to laminin, collagen type I, and collagen type IV. It is concluded that the sclerotic lesions in murine chronic GvHD contain fibronectin. The small amounts of the ECM components laminin, as well as collagens III, IV, and VI in the sclerotic glomeruli in GvHD, might represent remnants of mesangial material and collapsed capillary walls. These components are probably replaced by increased production and/or accumulation of collagen type I and fibronectin.
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PMID:A histologic study of the extracellular matrix during the development of glomerulosclerosis in murine chronic graft-versus-host disease. 158 Mar 27

Previous studies have revealed quantitative alterations in laminin-1 expression at the mRNA and protein levels during the development of glomerulonephritis and glomerulosclerosis in chronic graft-versus-host disease in mice, a model for lupus nephritis. We have now studied the qualitative alterations in laminin expression with two monoclonal antibodies that recognize epitopes on either the E8 or the P1 fragment of laminin-1. Both of these fragments are involved in cell-matrix and matrix-matrix interactions. In normal glomeruli these laminin epitopes are present only in the mesangial matrix; during embryogenesis, however, they are also present in the glomerular basement membrane. The distribution of laminin epitopes was first studied by using immunofluorescence in kidneys of mice with graft-versus-host disease at different points in time after disease induction. Reflection contrast and immunoelectron microscopy were performed after in vivo injection of the horseradish peroxidase-coupled monoclonal antibodies. In glomeruli of mice 8 weeks after disease induction, both injected antibodies bound specifically in electron-dense immune deposits in the mesangium and subepithelially along the glomerular basement membrane as well as in the expanded mesangial matrix. At 11 and 12 weeks after disease induction, when focal and segmental glomerulosclerosis had developed, the antibodies additionally bound in the matrix subendothelially along the glomerular basement membrane and at the periphery of end-stage sclerotic lesions. To study changes in the distribution of laminin epitopes over time, mice were injected with either monoclonal antibody before induction of graft-versus-host disease. The antibodies were detected 8 and 12 weeks later in the mesangial matrix of mice with lupus nephritis. Once segmental glomerulosclerosis had developed, the antibodies were additionally detected within the thickened glomerular capillary wall. The specific binding of anti-laminin monoclonal antibodies in electron-dense immune deposits further substantiates the hypothesis that anti-laminin autoantibodies participate in glomerular immune complex formation in this model, as suggested by earlier studies. Furthermore, our results show that the distribution of glomerular laminin epitopes in the matrix is altered during the development of glomerular disease. These changes in the structure of the glomerular basement membrane may contribute to the abnormal cell-matrix and matrix-matrix interactions during the development of glomerular disease in this model for lupus nephritis.
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PMID:Qualitative alterations in laminin expression in experimental lupus nephritis. 754 36

The prognosis of patients showing glomerulosclerosis as a complication of an immunologically mediated kidney disease is poor. To improve the diagnosis and treatment of these patients, it is important to understand the processes involved in the development of glomerulosclerosis. In this study, we investigated the molecular composition of experimental end-stage glomerular sclerotic lesions and their pathogenesis in chronic graft-versus-host disease (GvHD) in the mouse and chronic serum sickness in the rat. Accumulation studies were performed to determine the degree of specific trapping of constituents from the circulation. Two different models were investigated to determine whether differences in disease initiation resulted in different compositions of the glomerulosclerotic lesions. In both models, glomerulosclerosis was preceded by expansion of the mesangial matrix and thickening of the glomerular basement membrane (GBM). The end-stage sclerotic lesions consisted mainly of fibronectin, which appeared to displace the other extracellular matrix (ECM) components peripherally in the mesangial matrix and GBM. The abundance of fibronectin in the lesions was not reflected in the mRNA levels for this component. Indeed, antibodies directed against the cellular form of fibronectin did not stain positive in the end-stage lesions. These findings, together with accumulation studies, suggest that specific accumulation rather than de novo synthesis of fibronectin plays a major role in the development of experimental glomerulosclerosis, which appears to be independent of the pathway of induction.
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PMID:Specific accumulation of exogenous fibronectin in experimental glomerulosclerosis. 763 29

The influence of cyclosporine A (CsA) treatment on the development of glomerulonephritis and glomerulosclerosis was investigated in chronic graft-versus-host disease (GvHD), a murine model for lupus nephritis. The renal disease is characterized by the formation of IgG-containing electron-dense deposits along the glomerular basement membrane (GBM) and in the mesangium, followed by the onset of proteinuria which starts, varying per individual mouse, about six weeks after the induction of the disease. Glomerular mRNA levels for matrix molecules were increased from week 4, preceding mesangial matrix expansion and GBM thickening which occurred from week 6. These initial events finally led to development of glomerulosclerosis, and end-stage renal failure. Groups of mice received three intraperitoneal (i.p.) injections per week with different doses of CsA, and treatment was started 2, 4, or 6 weeks after induction of the disease. Treatment with 10 or 50 mg CsA/kg/week did not influence the development of glomerulonephritis or glomerulosclerosis. Injection of 100 mg CsA/kg/week delayed the onset of proteinuria only when treatment was started in week 2. In week 6 some mice had already developed proteinuria whereas others had not. Treatment with 250 mg CsA/kg/week starting in week 6 abrogated glomerulonephritis and glomerulosclerosis only in those animals which were not yet proteinuric at that time. This, despite comparable increased autoantibody levels against DNA, GBM, and renal tubular epithelium (RTE) in both treated and untreated GvHD mice. Further increase in proteinuria and development of glomerulosclerosis could not be prevented if the mice already had developed proteinuria when CsA treatment was started. Dot blot analysis and in situ hybridization showed significantly decreased mRNA levels for alpha 1(I) and alpha 1(IV) collagen in kidneys of CsA-treated mice as compared to those of untreated mice 12 weeks after induction of the disease, if the highest dose of CsA was administered before the onset of proteinuria. No effect on these whole-kidney mRNA levels was observed in mice which had already developed proteinuria before CsA injections were started. Increased mRNA expression for matrix molecules in this group and in untreated GvHD mice was observed mainly in the interstitium. The kidneys of the treated GvHD mice and those of mice injected with 250 mg CsA/kg/week without induction of GvHD showed no morphological signs of CsA nephrotoxicity. We conclude that treatment with 250 mg CsA/kg/week prevents the development of glomerulonephritis and glomerulosclerosis in this model of lupus nephritis, if started before the onset of proteinuria.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prevention of glomerulosclerosis by early cyclosporine treatment of experimental lupus nephritis. 770 25

Increased mRNA and protein expression of extracellular matrix (ECM) components, including fibronectin, occurs during the development of glomerulonephritis and glomerulosclerosis in immunologically mediated kidney diseases. However, in addition to these quantitative changes in ECM expression, qualitative changes in these molecules may contribute to malformations in the composition of the glomerular matrix. These qualitative changes may include alterations in the splicing pattern of the V-region of fibronectin, since this region plays a role in its accumulation. The splicing patterns of this region have been studied in chronic graft-versus-host disease (GvHD) in mice, a model of lupus nephritis, and in chronic serum sickness (CSS) in rats, a model of immune complex nephritis. Cloning of the mouse fibronectin V-region from kidney tissue revealed 96.1 per cent homology with the corresponding domain in rat fibronectin. PCR (polymerase chain reaction) analysis of RNA from isolated glomeruli revealed three isoforms of this region in both mouse and rat fibronectin, namely inclusion or exclusion of the whole region, or exclusion of only the CS1 domain. In both models, increased exclusion of the V-region was observed early in the disease. However, in GvHD the splicing pattern returned to normal, whereas in CSS the shift persisted during the course of the experiment. Differentiated expression of fibronectin isoforms may exert an important effect on the structure and biological function of the glomerulus and may thus play a role in the development of glomerulonephritis and glomerulosclerosis.
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PMID:Cloning of the mouse fibronectin V-region and variation of its splicing pattern in experimental immune complex glomerulonephritis. 869 28

Susceptibility to systemic lupus erythematosus (SLE) and, in particular, lupus nephritis is strongly influenced by genetic factors. Previous studies have shown that MHC-related antigens influence the development of SLE. In the current study, we set out to investigate how non-MHC genes influence the pathogenesis of glomerulonephritis in chronic graft-versus-host disease (GVHD) in mice, a model for lupus nephritis. For the induction of GVHD we used parent-to-F1 hybrid mouse strain combinations. DBA/2, BALB/c, BALB.D2 and C57B1/10.D2 (BL10.D2) donor lymphocytes carrying an H-2d haplotype were injected into H-2b/d F1 hybrids of BL10 mice, which differed only at non-MHC loci. Within these hybrid strains the development of immune complex glomerulonephritis was investigated by monitoring the occurrence of autoantibodies in the circulation, deposition of immunoglobulins in the glomeruli, development of albuminuria, and glomerulosclerosis. In diseased DBA/2 mice albuminuria developed 6 weeks after induction of the disease. Mice with a BALB background developed a lupus-like syndrome characterized by albuminuria starting 8 weeks after induction of the GVHD. During the development of the GVHD, polyclonal B cell activation occurred in both the DBA/2 and BALB/c strains, resulting in the formation of autoantibodies. Only the strain combination using DBA/2 mice developed anti-GBM antibodies. In DBA/2 and BALB strain combinations immune complexes were detected in a granular pattern along the glomerular capillary walls. In the DBA/2 recipients a linear pattern of immunoglobulin depositions preceded the granular phase. This study demonstrates that: (i) non-MHC genes govern the pathogenesis of immune complex nephritis in this model by influencing the autoantibody profile; and (ii) the presence of anti-GBM antibodies in the early stages of the disease is a conditio sine qua non for the development of full-blown glomerulonephritis and glomerulosclerosis in this model.
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PMID:Non-MHC genes determine the development of lupus nephritis in H-2 identical mouse strains. 891 72

A 13-yr-old boy was diagnosed as T cell lymphoma. After the second remission, he underwent BMT from an HLA-identical, MLC negative sibling donor. After BMT, he developed grade II acute GVHD. GVHD was improved by pulsed steroid therapy using prednisolone. About 12 months after BMT, he developed bronchiolitis obliterans, sicca syndrome, and leukoderma, which were related to chronic GVHD. Pulsed steroid therapy was carried out twice, and his condition improved. Twenty-seven months after BMT, he developed nephrotic syndrome. A renal biopsy was performed, and the diagnosis was histologically membranous nephropathy and focal glomerular sclerosis. The response to steroids was not satisfactory. After 5 weeks, dipyridamole was added, but proteinuria persisted. Proteinuria disappeared 8 weeks after the addition of cyclosporine. The second biopsy after 5 months of treatment revealed an improvement in the renal lesions. The patient showed a low T4 to T8 ratio of T-lymphocytes at the onset of nephrotic syndrome. However after treatment with cyclosporine, the ratio gradually increased. These findings suggested the nephrotic syndrome in this patient was related to renal involvement in the course of chronic GVHD.
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PMID:[Nephrotic syndrome related to chronic graft versus host disease after allogeneic bone marrow transplantation in a patient with malignant lymphoma]. 899 26

Mice with chronic graft-versus-host disease (GvHD) induced by injection of DBA/2 lymphocytes into (DBA/2 x C57BL/10) F1 hybrids (DBA/2 GvHD) develop a lupus-like glomerulonephritis with global glomerulosclerosis 12 weeks after induction of the disease. In two other strain combinations with similar H-2 incompatibilities [BALB/c into BALB/c x BL10 (BALB/c GvHD) and BALB.D2 into BALB.D2 x BL10 (BALB.D2 GvHD)], GvHD induction leads to lupus nephritis without global glomerulosclerosis. This study investigated the identity of kidney-infiltrating leukocytes and their involvement in the development of glomerulosclerosis in these three strain combinations. In mice with DBA/2 GvHD, a significant increase in glomerular CD11a-positive cells was found 4 weeks after disease induction. Mice with BALB/c or BALB.D2 GvHD did not show an increase in glomerular CD11a-positive cells at any time point. In the interstitium, CD11a-positive cells were observed 4 weeks after disease induction only in mice with DBA/2 GvHD. In mice with BALB.D2 GvHD, no increase was found in interstitial CD11a-positive cells. In mice with BALB/c GvHD, interstitial CD11a-positive cells were found from week 4 onward. Further immunohistochemical analysis of the glomerular CD11a-positive cells in mice with DBA/2 GvHD showed that these cells were neither polymorphonuclear leukocytes (PMN), nor CD3-positive (T cells), B220-positive (B cells), or F4/80-positive (macrophages). They were all CD45-positive (leukocytes) and MHC class II-positive. In conclusion, we have shown in this model of chronic lupus nephritis that glomerular influx of as yet unidentified CD11a-positive leukocytes is associated with the development of glomerulosclerosis.
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PMID:Association between leukocyte infiltration and development of glomerulosclerosis in experimental lupus nephritis. 960 15

Expansion of the glomerular mesangial matrix (MM), thickening of the glomerular basement membrane (GBM), and eventually the development of glomerulosclerosis are often seen in immunologically mediated kidney diseases. In addition to quantitative changes in the extracellular matrix (ECM), qualitative changes in ECM molecules may contribute to alterations in the composition of the glomerular matrix. The expression of collagen IV, alpha 1-5(IV) mRNA, and polypeptides was therefore investigated during the development of chronic graft-versus-host disease (GvHD) in mice, a model for lupus nephritis, and in chronic serum sickness (CSS) in rats, a model for membranous nephropathy. Immunohistochemical studies showed increased mesangial expression of alpha 1 and alpha 2 early in the disease, but only late in the GBM. In contrast, alpha 3 and alpha 4 increased in the GBM during disease, but not in the MM. The mRNA levels for all collagen IV chains were increased in isolated glomeruli before morphological alterations were detectable. The mRNA increase was earlier and more profound for alpha 3, alpha 4 and alpha 5 than for alpha 1 and alpha 2. Expression of alpha 3(IV) was greatest in GvHD, whereas expression of alpha 4 was greatest in CSS. As determined by in situ hybridization (ISH), alpha 1 mRNA was observed dispersed in the glomerulus, but alpha 3, alpha 4, and alpha 5 mRNAs were mainly located in cells at the periphery of the glomerular tuft. The changes in the relative abundance of collagen IV mRNA in disease states may perturb the collagen IV network, altering glomerular structure and function, and may thereby play a central role in the development of glomerulonephritis and glomerulosclerosis.
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PMID:Differential expression of collagen IV isoforms in experimental glomerulosclerosis. 961 84

A 5-year-old girl developed severe proteinuria and microscopic hematuria 17 months after allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia. These nephrotic symptoms occurred during cyclosporin tapering, in the absence of other signs of chronic graft-versus-host disease (GVHD). A renal biopsy revealed focal segmental glomerulosclerosis. After methylprednisolone therapy, the proteinuria gradually decreased. The altered or disordered immune regulation that occurred after BMT may have resulted in the development of nephrotic syndrome.
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PMID:Nephrotic syndrome in a bone marrow transplant recipient without chronic graft-versus-host disease. 1092 58


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