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)

We evaluated the preventive effects of a novel nonpolyglutamatable antifolate, MX-68, on two experimental murine models of systemic lupus erythematosus (SLE); NZBxNZW F1 (BWF1) mice and chronic graft-versus-host disease (GVHD) mice, in comparison with classical antifolate methotrexate (MTX). The oral administration of 2 mg/kg MX-68, three times a week from 12 to 40 or 60 weeks of age, significantly delayed the onset of proteinuria and prolonged the life-span of BWF1 mice. The elevation of serum blood urea nitrogen (BUN) and cholesterol levels resulting from the development of lupus nephritis was also inhibited. However, MX-68 did not suppress the increase of serum anti-DNA or anti-TNP antibodies or total IgG isotype (IgG1, IgG2 and IgG3) levels. In chronic GVHD mice, MX-68 given three times a week from the day of first cell injection, for 9 weeks, dose-dependently delayed the appearance of proteinuria. The elevation of BUN and cholesterol levels was also inhibited. Furthermore, in the 4 mg/kg MX-68 group, the production of IgG anti-DNA and anti-TNP antibodies was significantly inhibited, but this was not observed in the 2 mg/kg MX-68 and the 4 mg/kg MTX groups. These beneficial effects of MX-68 were much greater than those of MTX in both models. These results suggest that MX-68 might be a more useful drug for the treatment of SLE.
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PMID:Preventive effect of a novel antifolate, MX-68, in murine systemic lupus erythematosus (SLE). 927 76

The purpose of this article is to review a set of recently obtained data concerning matrix and matrix adhesion molecules in renal disease. Our goal is not to cover the entire topic, but rather to focus on findings obtained with an experimental model for chronic lupus nephritis, evoked in mice by inducing graft-versus-host disease (GVHD). The overall aim of these studies was to investigate the role of adhesion molecules as targets for autoantibodies, in the recruitment of inflammatory cells, and in the accumulation of matrix in kidney disorders. In addition, we set out to discover how matrix proteins in renal diseases differ from normal matrix molecules both quantitatively, in their increased frequency, and qualitatively, in their intramolecular structure. The advances in understanding and methodology described in this review imply a substantial capability for greater insight into the pathogenesis of kidney disease; for making better use of renal biopsies, such as in applying competitive reverse-transcriptase-polymerase chain reaction (RT-PCR) in RNA analysis for matrix; and in developing more effective treatment strategies for patients with kidney disease.
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PMID:Matrix and adhesion molecules in kidney pathology: recent observations. 935 73

Mice with chronic graft-versus-host disease (GvHD), induced by injection of DBA/2 lymphocytes into (C57BL10*DBA/2)F1 hybrids, develop a lupus-like syndrome with immune complex glomerulonephritis. Circulating autoantibodies are reactive with various self-antigens, including DNA, renal tubular epithelium (RTE), and laminin-1. To elucidate the reactivity of autoantibodies with renal antigens in experimental lupus nephritis further, the reactivity of the autoantibodies was studied in more detail by generating hybridomas from GvHD spleen cells. Hybridomas were selected for reactivity with RTE and laminin-1 coated on nitrocellulose sheets. Four stable clones were obtained (GV1-GV4). Monoclonal antibody (mAb) GV1 showed no reactivity on kidney sections, while GV2 stained the brush border of proximal tubular epithelial cells. Both GV1 and GV2 reacted only with RTE in ELISA. GV3 showed a nuclear staining pattern, while GV4 stained matrix structures on F1 kidney sections. GV3 and GV4 both reacted with RTE, laminin-1, ssDNA, and dsDNA in ELISA. Growth of hybridomas in mice, but not passive transfer of the mAbs, led to glomerular Ig binding for mAbs GV3 and GV4 without development of proteinuria. Our results show that in addition to anti-nuclear autoantibodies cross-reactive with renal antigens, autoantibodies reactive with renal antigens and not with DNA are generated during chronic GvHD. Based on these results, combined with those of earlier experiments, we conclude that a combination of autoantibodies against multiple epitopes is necessary for the induction of glomerular damage in this model for lupus nephritis.
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PMID:Characterization of reactivity of monoclonal autoantibodies with renal antigens in experimental lupus nephritis. 939 43

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

Increasing amounts of evidence support the involvement of inflammation and immunity in atherogenesis, but mediators of communication between the major cell types in atherosclerotic plaques are poorly defined. Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand CD40L (also known as CD154 or gp39). The interaction of CD40 with CD40L figures prominently in both humoral and cell-mediated immune responses. CD40L-positive T cells accumulate in atheroma, and, by virtue of their early appearance, persistence and localization at sites of lesion growth and complication, activated T cells may coordinate important aspects of atherogenesis. Interruption of CD40L-CD40 signalling by administration of an anti-CD40L antibody limits experimental autoimmune diseases such as collagen-induced arthritis, lupus nephritis, acute or chronic graft-versus-host disease, multiple sclerosis and thyroiditis. Ligation of CD40 on atheroma-associated cells in vitro activates functions related to atherogenesis, including induction of proinflammatory cytokines, matrix metalloproteinases, adhesion molecules and tissue factor. However, the role of CD40 signalling in atherogenesis in vivo remains unknown. Here we determine whether interruption of CD40 signalling influences atherogenesis in vivo in hyperlipidaemic mice. Treatment with antibody against mouse CD40L limited atherosclerosis in mice lacking the receptor for low-density lipoprotein that had been fed a high-cholesterol diet for 12 weeks. This antibody reduces the size of aortic atherosclerotic lesions by 59% and their lipid content by 79%. Furthermore, atheroma of mice treated with anti-CD40L antibody contained significantly fewer macrophages (64%) and T lymphocytes (70%), and exhibited decreased expression of vascular cell adhesion molecule-1. These data support the involvement of inflammatory pathways in atherosclerosis and indicate a role for CD40 signalling during atherogenesis in hyperlipidaemic mice.
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PMID:Reduction of atherosclerosis in mice by inhibition of CD40 signalling. 967 6

Mice with chronic graft-versus-host disease (GvHD) develop a lupus-like disease with severe immune complex glomerulonephritis. Previous studies with this model have shown that anti-laminin autoantibodies are involved in immune complex formation and that glomerular laminin expression alters qualitatively. The present study investigated glomerular laminin chain expression and autoantibody reactivity with matrix antigens during disease development in mice with chronic GvHD, killed before and 6, 8, 10, and 11 weeks after disease induction, using antibodies raised against laminin chain peptides, in immunofluorescence and western blotting studies. Decreased glomerular expression of the laminin beta1 chain, unaltered expression of the laminin beta2 and gamma1 chains, and increased expression of the laminin alpha1 chain and filamin/actin-binding protein 280 (ABP 280) were found during disease progression. Furthermore, 4 weeks after disease induction, autoantibodies appeared which were reactive with laminin alpha1, beta1, beta2, and gamma1 chains, and filamin in rat mesangial cell matrix. Ten weeks after disease induction, autoantibodies reacted with filamin, and beta2 and gamma1 laminin chains. Autoantibodies reacted with laminin chains only and not with other proteins in matrices extracted from glomeruli of normal and diseased mice. Staining with H50, an anti-laminin alpha1 chain/anti-filamin monoclonal autoantibody derived from an MRL/lpr mouse with spontaneous lupus nephritis, confirmed these observations and showed identical anti-laminin/anti-filamin autoantibody reactivity in two different models for lupus nephritis. In summary, differential glomerular expression of laminin chains was found during the development of chronic GvHD. Concomitantly with expression of the laminin alpha1 chain and/or filamin in the glomerulus, anti-laminin alpha1 and/or anti-filamin reactivity was present, pointing towards a role for (neo) antigen expression in the epitope spreading of the immune response. Furthermore, glomerular expression of laminin beta1 decreased in conjunction with decreased presence of anti-laminin beta1 reactivity, presumably due to antigen masking or shedding of immune complexes into the urine. These changes in anti-laminin chain autoantibodies, with concomitant alterations in the glomerular expression of laminin chains, may aggravate progressive immune injury in this model for lupus nephritis.
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PMID:Differential expression of laminin chains and anti-laminin autoantibodies in experimental lupus nephritis. 1105 25

Acute, lethal graft-versus-host disease (GvHD) develops in B6D2F1 hybrid recipients of wild-type, C57BL/6, parental strain grafts; however, when interferon-gamma (IFN-gamma) gene knockout (gko) donors are used, the disease is prolonged and associated with a higher level of engraftment, particularly of T cells. Lesions containing large, mixed cellular infiltrates develop in the skin, liver, pancreas, salivary gland, lung and kidney. In our current study, we wished to determine whether GvHD features a preponderance of T helper 2 (Th2) cytokines in the absence of donor-derived IFN-gamma, and whether autoantibody production, commonly associated with chronic GvHD, also occurs. Because mitogen responsiveness is consistently suppressed in mice with acute GvHD, we wished to measure this response in recipients of IFN-gamma gko grafts. Our findings indicate that spleen cells from the latter produce interleukin (IL)-4, IL-5 and IL-13 in culture, but respond poorly to concanavalin A (Con A) and lipopolysaccharide (LPS). Their sera contain anti-nuclear antibodies (ANA), some of which are specific for double-stranded (ds)DNA and are predominantly immunoglobulin (Ig)M and IgG1. We also noted the presence of numerous eosinophils in the infiltrates developing within the target organs. In some respects, this syndrome bears resemblance to both systemic lupus erythematosus (SLE) and chronic GvHD. However, histological evidence of glomerulonephritis is lacking and proteinuria fails to develop in recipients of IFN-gamma gko grafts, suggesting that IFN-gamma may be necessary for the development of lupus nephritis. On a broader scope, our findings underscore the importance of IFN-gamma in the pathogenetic mechanism of GvHD, and demonstrate that the absence of this cytokine promotes the development of chronic GvHD and autoimmunity.
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PMID:Murine graft-versus-host disease induced using interferon-gamma-deficient grafts features antibodies to double-stranded DNA, T helper 2-type cytokines and hypereosinophilia. 1184 16

Bone marrow transplantation is becoming a powerful strategy for the treatment of hematologic disorders (leukemia, aplastic anemia, etc.), congenital immunodeficiencies, metabolic disorders and also autoimmune diseases. Using various animal models for autoimmune diseases, we have previously found that allogeneic (not autologous) bone marrow transplantation can be used to treat autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, immune thrombocytic purpura, insulin-dependent diabetes mellitus, chronic glomerulonephritis and certain types of non-insulin-dependent diabetes mellitus. In contrast, we have found that the transplantation of T-cell-depleted bone marrow cells or partially purified hemopoietic stem cells from autoimmune-prone mice to normal mice leads to the induction of autoimmune diseases in the recipients. These findings have recently been confirmed even in humans; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and Crohn's disease were resolved after allogeneic bone marrow transplantation. However, there have recently been reports on the rapid recurrence or persistence of autoimmune diseases after autologous bone marrow transplantation. Conversely, the adoptive transfer of autoimmune diseases such as myasthenia gravis, insulin-dependent diabetes mellitus and Graves' disease by allogeneic bone marrow transplantation from donors to recipients has been reported. Owing to these findings, we have proposed that autoimmune diseases are "stem cell disorders." We have thus succeeded in treating autoimmune diseases in various autoimmune-prone mice, except MRL/lpr mice, by conventional bone marrow transplantation. The MRL/lpr mouse itself is radiosensitive (<8.5 Gy), while the abnormal hemopoietic stem cells of the MRL/lpr mouse are radioresistant (>8.5 Gy); conventional bone marrow transplantation (8.5 Gy plus bone marrow transplantation) has a transient effect on autoimmune diseases, which recur three months after the bone marrow transplantation. However, bone marrow transplantation plus bone grafts (to recruit donor stromal cells) completely prevents the recurrence of autoimmune diseases in MRL/lpr mice. Donor-derived stromal cells (including mesenchymal stem cells) thus seem to play a crucial role in successful allogeneic bone marrow transplantation, since there is a major histocompatibility complex restriction between hemopoietic stem cells and stromal cells. We have, however, found that the combination of bone marrow transplantation plus bone grafts has no effect on the treatment of autoimmune diseases in MRL/lpr mice, since MRL/lpr mice become more radiosensitive after the onset of lupus nephritis due to the development of uremic enterocolitis. To reduce the cytotoxic effect of radiation on the intestine, we carried out fractionated irradiation and devised a new strategy. We injected allogeneic whole bone marrow cells (including a small number [<3%] of T cells, hemopoietic stem cells and stromal cells) from donors directly into the intra-bone marrow of recipients so that donor-derived hemopoietic cells including stromal cells could effectively accumulate in the bone marrow. All the MRL/lpr mice survived more than one year (>60 weeks after birth) without the recurrence of autoimmune diseases, and immunological functions were completely restored even when the radiation dose was reduced to 5 Gy x 2. These findings suggest that intra-bone marrow injection-bone marrow transplantation can be used to treat intractable autoimmune diseases under reduced radiation doses without using any immunosuppressants.Intra-bone marrow injection-bone marrow transplantation seems to be the best strategy for allogeneic bone marrow transplantation: 1) no graft-versus-host disease develops even if T cells are not depleted from the bone marrow; 2) no graft failure occurs even if the dose of radiation as the conditioning for bone marrow transplantation is reduced to 5 Gy x 2; 3) hemopoietic recovery is rapid; and 4) T-cell functions are completely restored even in donor-recipient combinations across the major histocompatibility complex barriers. Using cynomolgus monkeys, we have recently established a new method (the "perfusion method") for collecting bone marrow cells from the long bones (femur, humerus, etc.) without peripheral blood contamination. This method has various advantages: 1) no graft-versus-host disease develops even in cynomolgus monkeys, since the percentage of T cells in the bone marrow cells collected is less than 3%; 2) a large number of bone marrow cells can be collected quickly and safely; and 3) the bone marrow cells collected contain stromal cells including mesenchymal stem cells. We therefore believe that this method (intra-bone marrow injection-bone marrow transplantation in conjunction with the perfusion method) will become a powerful new strategy for not only allogeneic bone marrow transplantation but also organ transplantation in conjunction with bone marrow transplantation. Furthermore, this method could become a valuable strategy in regeneration therapy for injured organs and tissues (myocardial infarction, cerebral infarction, Alzheimer's disease, etc.), since it can efficiently reconstitute the recipient with both donor-derived hemopoietic stem cells and mesenchymal stem cells.
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PMID:Bone marrow transplantation: a new strategy for intractable diseases. 1253 88

Fibronectin (FN) is the main extracellular matrix component in glomerulosclerotic lesions. There are different FN isoforms that result from alternative splicing at the EDA and EDB regions of FN mRNA. Increased inclusion of EDA and EDB, which can be elicited by TGFbeta, may be conducive to the development of glomerulosclerosis (GS). TGFbeta and IL-4 have previously been shown to play a role in the development of GS. In this study, the mRNA splicing patterns for EDA+ and EDB+ fibronectin were investigated in vivo in various experimental sclerotic glomerulopathies, in vitro in rat mesangial cells (MC) that were stimulated by TGFbeta or transfected with IL-4, and in human kidney biopsies with GS from patients with various kidney diseases. Analysis of glomerular FN mRNA demonstrated inclusion of both ED regions in rats with anti-Thy1 nephritis or chronic serum sickness and in mice with anti-GBM glomerulonephritis. Inclusion of both the EDA and EDB regions was associated with glomerular TGFbeta expression. In contrast, in mice with Th2-mediated graft-versus-host disease, a model for lupus nephritis, the FN transcripts included neither the EDA nor the EDB region, and renal TGFbeta expression was absent. Compared to normal MCs in culture, MCs transfected with IL-4 produced lower amounts of FN and demonstrated less EDA inclusion, while MC that had been treated with TGFbeta showed increased production of FN and more EDA inclusion. Renal biopsies from patients with renal diseases, except those taken from patients with lupus nephritis, showed higher TGFbeta levels, higher FN levels, and more EDA inclusion than controls. TGFbeta may be a key player in the development of GS by inducing local FN production and alternative splicing of FN mRNA. In lupus glomerulonephritis, in which the involvement of TGFbeta in GS is less prominent, Th2 cytokines such as IL-4 probably account for increased intrarenal collagen synthesis and subsequent FN accumulation from the circulation. In conclusion, neither alternative FN splicing, nor a high transcription level of TGFbeta, appears to be a general prerequisite for the development of GS.
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PMID:Alternatively spliced isoforms of fibronectin in immune-mediated glomerulosclerosis: the role of TGFbeta and IL-4. 1537 54


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