Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-gamma and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.
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PMID:Conversion of alloantigen-specific CD8+ T cell anergy to CD8+ T cell priming through in vivo ligation of glucocorticoid-induced TNF receptor. 1662 87

Chronic graft-versus-host disease (GVHD) induced in (C57BL/6 x DBA/2) F1 (BDF1) mice by the injection of DBA/2 mouse spleen cells represents histopathological changes associated with systemic lupus erythematosus (SLE), primary biliary cirrhosis (PBC) and Sjogren's syndrome (SS), as indicated by glomerulonephritis, lymphocyte infiltration into the periportal area of the liver and salivary glands. We determined the therapeutic effect of hepatocyte growth factor (HGF) gene transfection on lupus using this chronic GVHD model. Chronic GVHD mice were injected in the gluteal muscle with either HVJ liposomes containing 8 microg of the human HGF expression vector (HGF-HVJ liposomes) or mock vector (untreated control). Gene transfer was repeated at 2-week intervals during 12 weeks. HGF gene transfection effectively prevented the proteinuria and histopathological changes associated with glomerulonephritis. While liver and salivary gland sections from untreated GVHD mice showed prominent PBC- and SS-like changes, HGF gene transfection reduced these histopathological changes. HGF gene transfection greatly reduced the number of splenic B cells, host B cell major histocompatibility complex class II expression, and serum levels of IgG and anti-DNA antibodies. IL-4 mRNA expression in the spleen, liver, and kidneys was significantly decreased by HGF gene transfection. CD28 expression on DBA/2 CD4+ T cells was decreased by the addition of recombinant HGF in vitro. Furthermore, IL-4 production by DBA/2 CD4+ T cells stimulated by irradiated BDF1 dendritic cells was significantly inhibited by the addition of recombinant HGF in vitro. These results suggest that HGF gene transfection inhibited T helper 2 immune responses and reduced lupus nephritis, autoimmune sialoadenitis, and cholangitis in chronic GVHD mice. HGF may represent a novel strategy for the treatment of SLE, SS and PBC.
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PMID:Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease. 1685 27

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+ T cells rapidly fall into anergy to host cells, while donor CD4+ T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+ T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+ T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+ regulatory T cells (Treg cells) are critical in maintaining the donor CD8+ T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of Treg cells in determining cGVHD versus aGVHD.
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PMID:Maintenance of CD8+ T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease. 1707 65

During pregnancy maternal and fetal cells commute back and forth leading to fetal microchimerism in the mother and maternal microchimerism in the child that can persist for years after the birth. Chimeric fetal and maternal cells can be hematopoietic or can differentiate into somatic cells in multiple organs, potentially acting as targets for 'autoimmunity' and so have been implicated in the pathogenesis of autoimmune diseases that resemble graft-versus-host disease after stem cell transplantation. Fetal cells have been found in women with systemic lupus erythematosus, both in the blood and a target organ, the kidney, suggesting that they may be involved in pathogenesis. Future studies will address how the host immune system normally tolerates maternal and fetal cells or how the balance may change during autoimmunity.
Lupus 2006
PMID:Microchimeric cells in systemic lupus erythematosus: targets or innocent bystanders? 1715 57

Although defects in apoptosis have been linked to both human and murine lupus, the exact mechanisms remain unknown. Moreover, it is not clear whether such defects are primary or secondary events in disease pathogenesis. To address these issues, we used an induced model of murine lupus, the parent-into-F(1) model of chronic graft-versus-host disease (cGVHD) in which a lupus-like phenotype highly similar to human systemic lupus erythematosus is reliably induced in normal F(1) mice. We addressed the role of nuclear Ags modified by caspases during apoptosis as potential targets of the autoantibody response and our results identify poly(ADP-ribose) polymerase 1 (PARP-1) as a frequently targeted autoantigen. Additional proteins cleaved during apoptosis were also targeted by the immune response. Importantly, female mice exhibited significantly greater numbers of apoptotic cells in germinal centers and higher serum anti-PARP-1 Ab levels compared with male cGVHD mice. Serum anti-PARP-1 levels in male cGVHD mice could be elevated to levels comparable to those of female cGVHD mice by the injection of apoptotic syngeneic F(1) splenocytes early in the disease course. These results provide a mechanism by which lupus autoantibodies target apoptotic molecules. Specifically, T cell-driven polyclonal B cell activation characteristic of systemic lupus erythematosus is sufficient to saturate otherwise normal apoptotic clearance mechanisms, permitting apoptotic material to accumulate, serve as autoantigens, and drive autoantibody production.
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PMID:Apoptotic splenocytes drive the autoimmune response to poly(ADP-ribose) polymerase 1 in a murine model of lupus. 1718 44

Finding effective treatments for patients with systemic sclerosis (SSc) remains one of the final frontiers in therapeutic discovery. Although remarkable progress has been made in the symptomatic treatment of various organ system manifestations, little is available that treats the underlying disease process. SSc patients do not respond to many of the medications that provide benefit in related diseases, such as systemic lupus erythematosus, polymyositis and chronic graft-versus-host disease. Current research has not even clarified whether the complex pathogenesis starts primarily in vascular, immunological or connective tissues. Herein are discussed selected emerging therapeutics and therapeutic approaches designed to target the underlying immunological and fibrotic disease processes. Distinctive fibrotic features and data from translational research consistently place transforming growth factor-beta (TGFbeta) as a central mediator in SSc. The discovery of agents targeting TGFbeta, its activation or its intracellular signaling suggest that TGFbeta pathway inhibitors efficacious for the treatment of SSc may soon be identified. IL-4 and IL-13 are other fibrotic mediators produced during immune activation that might be targeted for SSc therapy, and therapeutics targeting these interleukins are also being developed. Immune dysregulation, leading to overproduction of these or other fibrotic mediators might respond to currently available immunosuppressives: mycophenolate, cyclosporine, tacrolimus or sirolimus, alone or in combination. Nucleic acid-containing immune complexes may also contribute to toll-like receptor mediated immune dysregulation in SSc, suggesting that agents targeting the innate immune system may ameliorate SSc. Thus, the complexity of SSc pathogenesis provides a plethora of targets for urgently needed new therapies.
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PMID:Targeting fibrosis in systemic sclerosis. 1721 85

The clinical and histological presentation of inflammatory disease in the skin is exceedingly heterogeneous. Nonetheless, most inflammatory dermatoses can be classified according to five stereotypical tissue-reaction patterns: the spongiotic, the lichenoid, the psoriasiform, the vesiculo-bullous and the vasculopathic. By means of potent antigen-presenting cells, cytokine and chemokine cascades and a skin-specific cutaneous lymphocyte antigen (CLA)-positive lymphocyte population, the skin is able to respond very efficiently to pathogens that threaten the individual. Inflammatory skin diseases follow the rules and routes of the physiological reaction to inflammation but however for various reasons the immune response may be inadequate, enhanced or chronic. In allergic contact dermatitis, which is a prototype of the spongiotic reaction pattern, the inflammation is directed against an otherwise harmless antigen, for which the body is sensibilized. Lichenoid dermatitis (like erythema multiforme, graft versus host disease or lupus erythematodes) is based on a primary cytotoxic reaction against the basal epithelial cell, due to alterations in its antigenic make-up or due to an altered immune response. In psoriasis, an example of psoriasiform dermatitis, the interaction between inflammatory cells, antigen presenting cells and epithelial cells is disturbed.
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PMID:[The immune system of the skin and stereotyped reaction patterns in inflammatory skin diseases]. 1722 34

Several autoimmune diseases are thought to be mediated in part by interleukin (IL)-18. Many are those with associated increased interferon-gamma (IFNgamma) levels such as systemic lupus erythematosus, macrophage activation syndrome, rheumatoid arthritis, Crohn's disease, psoriasis, and graft-versus-host disease. In addition, ischemia, including acute renal failure in human beings, appears to involve IL-18. Animal studies also support the concept that IL-18 is a key player in models of lupus erythematosus, atherosclerosis, graft-versus-host disease, and hepatitis. Unexpectedly, IL-18 plays a role in appetite control and the development of obesity. IL-18 is a member of the IL-1 family; IL-1beta and IL-18 are related closely, and both require the intracellular cysteine protease caspase-1 for biological activity. The IL-18 binding protein, a naturally occurring and specific inhibitor of IL-18, neutralizes IL-18 activities and has been shown to be safe in patients. Other options for reducing IL-18 activities are inhibitors of caspase-1, human monoclonal antibodies to IL-18, soluble IL-18 receptors, and anti-IL-18 receptor monoclonal antibodies.
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PMID:Interleukin-18 and the pathogenesis of inflammatory diseases. 1733 92

Regulatory T cells (Treg) encompass a heterogeneous family of T cells implicated in maintenance of tolerance to self antigens. Treg cells might be qualitatively and/or quantitatively deficient in human autoimmune diseases, including multiple sclerosis, graft versus host disease, systemic lupus erythematosus, type I diabetes, and rheumatoid arthritis. In animal models of autoimmunity, infusion of ex vivo-expanded Treg cells and/or in vivo enhancement of Treg cell suppressor function by pharmacological agents and cytokines attenuate disease manifestations and restore tolerance. However, Treg cells represent a double-edged sword, as Treg cells with specificity for tumour-associated antigens contribute to cancer pathogenesis and progression. In vivo depletion of Treg cells by monoclonal antibodies and/or selected drugs is an encouraging therapeutic strategy which improves tumour eradication in animal models of cancer. In addition, elimination and/or functional inactivation of Treg cells might boost anti-tumour immunity in tumour-bearing hosts receiving anti-cancer vaccination. The present review discusses Treg cell manipulation as a novel therapeutic strategy in cancer and autoimmunity, conditions characterised by a common regulatory basis.
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PMID:The Janus face of CD4+CD25+ regulatory T cells in cancer and autoimmunity. 1734 53

Clinical data from case reports of nephrotic syndrome including allogenetic hematopoietic stem cell transplantation (HSCT) suggest that there may be some relationship between chronic graft-versus-host disease (GVHD) and membranous nephropathy (MN). It is widely recognized T cells are crucial for the development of GVHD, and that T helper (Th) cells differentiate into at least two subsets, Th1 and Th2. The polarized situation between Th1 and Th2 cells is established to be important in animal models and human autoimmune diseases. In a chronic GVHD murine model a Th2 cell plays a pivotal role for the pathogenesis. In MRL/lpr mice, which is particularly valuable model for systemic lupus erythematosus, developed diffuse proliferative glomerulonephritis (DPGN) in Th1 environment and MN in Th2 environment. Similarly, Th2 cells may be predominantly activated in chronic GVHD, production and deposition of IgG4 in the glomeruli may develop MN. A hypothesis is: when the patient in period of chronic GVHD developed immune complex-mediated disease, IgG4 might be mainly produced in Th2 environment, and the deposition of IgG4 in the glomeruli may result in the formation of MN.
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PMID:Membranous nephropathy is developed under Th2 environment in chronic graft-versus-host disease. 1739 13


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