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)

Transferring DBA/2 spleen cells into (C57BL/10xDBA/2) F1 (referred to as BDF1) mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th(2) cytokines, hypergammaglobulinemia, and immune complex-mediated glomerulonephritis that resembles systemic lupus erythematosus. DNA motif consisting of an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines (CpG ODN) induces Th(1) cytokine production in mice. This study examines the effect of administering CpG ODN to mice undergoing chronic GVHD, based on the premise that altering Th(1)/Th(2) activity might beneficially impact on disease progression.GVHD BDF1 mice injected with DBA/2 spleen cells were treated with weekly intraperitoneal injection of 50 microg CpG ODN. This treatment significantly suppressed the production of IgG anti-DNA autoantibody and reduced the development of glomerulonephritis. Serum IgG2a titers were higher in the CpG ODN than in non-CpG control group, whereas IgG1 titers were unchanged. As predicted, IFN-gamma levels were significantly higher in the CpG ODN-treated group, while IL-4 levels were lower, resulting in a shift in the Th(1)/Th(2) cytokine ratio. Results suggest that CpG ODN administration may be of therapeutic benefit in chronic GVHD.
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PMID:Therapeutic effect of CpG motifs on the development of chronic graft-versus-host disease in mice. 1244 Nov 43

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

There are few reports describing the association between antiphospholipid antibodies, including the lupus anticoagulant, and bone marrow or peripheral stem cell transplantation. Autoimmune syndromes and autoantibodies such as lupus anticoagulant and anticardiolipin antibodies have been described following allogeneic bone marrow or peripheral blood stem cell transplantation, particularly in patients who develop chronic graft-versus-host disease (GVHD). The association between Lupus anticoagulant and acute GVHD has not been previously described. We report a patient who developed a de novo lupus anticoagulant on day +34 after a matched-related allogeneic peripheral stem cell transplant. No clinical evidence of systemic thrombosis was observed and the lupus anticoagulant disappeared following immunosuppressive therapy with a combination of steroids and infliximab.
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PMID:Acute graft-versus-host disease (aGVHD) presenting with an acquired lupus anticoagulant. 1262 95

Description of the molecular phenotypes of pathobiological processes in vivo is a pressing need in genomic biology. We have implemented a high-throughput real-time PCR strategy to establish quantitative expression profiles of a customized set of target genes. It enables rapid, reproducible data acquisition from limited quantities of RNA, permitting serial sampling of mouse blood during disease progression. We developed an easy to use statistical algorithm--Global Pattern Recognition--to readily identify genes whose expression has changed significantly from healthy baseline profiles. This approach provides unique molecular signatures for rheumatoid arthritis, systemic lupus erythematosus, and graft versus host disease, and can also be applied to defining the molecular phenotype of a variety of other normal and pathological processes.
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PMID:Customized molecular phenotyping by quantitative gene expression and pattern recognition analysis. 1284 47

Inorganic mercury (iHg) is known to induce autoimmune disease in susceptible rodent strains. Additionally, in inbred strains of mice prone to autoimmune disease, iHg can accelerate and exacerbate disease manifestations. Despite these well-known links between iHg and autoimmunity in animal models, no association between iHg alone and autoimmune disease in humans has been documented. However, it is possible that low-level iHg exposure can interact with disease triggers to enhance disease expression or susceptibility. To address whether exposure to iHg can alter the course of subsequent acquired autoimmune disease, we used a murine model of acquired autoimmunity, lupus-like chronic graft-versus-host disease (GVHD), in which autoimmunity is induced using normal, nonautoimmune prone donor and F1 recipient mice resistant to Hg-induced autoimmunity. Our results indicate that a 2-week exposure to low-dose iHg (20 or 200 micro g/kg every other day) to donor and host mice ending 1 week before GVHD induction can significantly worsen parameters of disease severity, resulting in premature mortality. iHg pretreatment clearly worsened chronic lupus-like disease, rather than GVHD worsening iHg immunotoxicity. These results are consistent with the hypothesis that low-level, nontoxic iHg preexposure may interact with other risk factors, genetic or acquired, to promote subsequent autoimmune disease development.
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PMID:Low-dose exposure to inorganic mercury accelerates disease and mortality in acquired murine lupus. 1289 45

CD4+ helper T cells play a critical role in the production of the antinuclear autoantibodies that characterize systemic lupus erythematosus in mice and humans. A key issue is whether this help is derived from a diverse repertoire of autoreactive CD4+ T cells or from a select number of T cells of limited specificity. We used the chronic graft-versus-host disease model to define the diversity of the CD4+ T cell repertoire required to induce the autoantibody response. By transferring clonally restricted versus clonally diverse populations of MHC class II-reactive CD4+ T cells, we show that the loss of B cell tolerance to nuclear antigens has two distinct components with different CD4+ cell requirements. Activation of limited repertoires of CD4+ T cells was sufficient for the expansion of anergized anti-double-stranded DNA B cells and production of IgM autoantibodies. Unexpectedly, we found that CD4+ T cell diversity was necessary for CD4+ T cell trafficking into the follicle and for the generation of isotype-switched IgG autoantibodies. Importantly, combining two limited repertoires of T cells provides sufficient CD4+ T cell diversity to drive antinuclear Ab production. These data demonstrate that a diverse CD4+ T cell repertoire is required to generate a sustained effector B cell response capable of mediating systemic autoimmunity.
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PMID:Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance. 1459 62

Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cell (DC) precursors, represent the key effectors in antiviral innate immunity and triggers for adaptive immune responses. IPCs play important roles in the pathogenesis of systemic lupus erythematosus (SLE) and in modulating immune responses after hematopoietic stem cell transplantation. Understanding IPC development from hematopoietic progenitor cells (HPCs) may provide critical information in controlling viral infection, autoimmune SLE, and graft-versus-host disease. FLT3-ligand (FLT3-L) represents a key IPC differentiation factor from HPCs. Although hematopoietic cytokines such as interleukin-3 (IL-3), IL-7, stem cell factor (SCF), macrophage-colony-stimulating factor (M-CSF), and granulocyte M-CSF (GM-CSF) promote the expansion of CD34+ HPCs in FLT3-L culture, they strongly inhibit HPC differentiation into IPCs. Here we show that thrombopoietin (TPO) cooperates with FLT3-L, inducing CD34+ HPCs to undergo a 400-fold expansion in cell numbers and to generate more than 6 x 10(6) IPCs per 10(6) CD34+ HPCs within 30 days in culture. IPCs derived from HPCs in FLT3-L/TPO cultures display blood IPC phenotype and have the capacity to produce large amounts of interferon-alpha (IFN-alpha) and to differentiate into mature DCs. This culture system, combined with the use of adult peripheral blood CD34+ HPCs purified from G-CSF-mobilized donors, permits the generation of more than 10(9) IPCs from a single blood donor.
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PMID:Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors. 1467 Sep 16

Donor alloreactive CD4(+) T cells are important to the pathogenesis of chronic graft-versus-host disease (cGVHD), but specific subsets of CD4(+) T cells responsible for GVHD have not been defined. We hypothesized that cGVHD might be associated with a preponderance of CD4(+) effector memory cells (CCR7(-)/CD62L(low), CD4(EM)). We analyzed CCR7 and CD62L expression on CD4(+) T cells from stem cell transplantation patients, who did or did not develop cGVHD, and healthy donors. Patients with cGVHD had a higher percentage of CD4(EM) cells (35.5% +/- 2.9%) than healthy donors (13.8% +/- 0.7%; P <.0001) or patients without cGVHD that received a transplant (21.7% +/- 2.1%; P <.01). Using corticosteroid dose as a surrogate marker for cGVHD severity, severe cGVHD was associated with a higher percentage of CD4(EM) cells. The proportion of CD4(EM) cells in corticosteroid-dependent patients with systemic lupus erythematosis or Wegener granulomatosis did not differ from patients without cGVHD that received a transplant. This finding implies that overrepresentation of CD4(EM) cells is a unique feature of cGVHD.
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PMID:Severe chronic graft-versus-host disease is characterized by a preponderance of CD4(+) effector memory cells relative to central memory cells. 1476 30

Methotrexate (MTX) is one of the immunosuppressory compounds applied in the prophylaxis and treatment of several diseases, including: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, graft-versus-host disease and, in combination with other drugs, neoplastic diseases. Studies in humans and in animal model, of clinical disease, have demonstrated that MTX diminishes the clinical symptoms of various immunological disorders. MTX, an antagonist of folic acid synthesis, causes apoptosis in activated cells, primarily in the G1 and S phases of the cell cycle. One of its actions, is inhibition of the synthesis or activity of several proinflammatory cytokines. At high doses, MTX is cytotoxic to hemopoietic cells; low doses, however, promote hemopoiesis. MTX also induces the differentiation of monocytic tumor cells, which may explain, in part, its therapeutic effects in the treatment of some disorders. The compound suppresses both cellular and humoral immune response and mitogen-induced lymphocyte proliferation. These effects are dose- and time-dependent. The strongest suppressory activity is exerted when MTX is applied 24 or 48 hours after immunization or mitogen stimulation. Administration of MTX in unfavorable conditions such as stress or other diseases, diminishes its tolerance and increases its toxicity. Side-effects of MTX may be ameliorated by application of pharmacological synthetic agents and plant extracts. In summary, MTX has been an effective agent in suppressing immunological disorders (for 50 years) and is still finding many applications.
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PMID:[Effect of methotrexate on the immune response in selected experimental models]. 1511 58

Recently stem cell transplantation has been suggested like novel treatment in some severe auto-immune diseases, specifically in severe and refractory to conventional treatment in systemic lupus erythematosus patients. Autologus hematopoietic steam cell transplantation has been used in systemic lupus erythematosus, because it does not represent risk of development in graft versus host disease, which is the most common and severe complication in alogenic transplant. This type of transplant is poorly used because of the difficulty to get donors and laboratory background. Patients under this type of treatment received high dosage of chemotherapy, followed by alogenic hematopoietic steam cell transplantation with or without T cell depletion. Most of cases have successes in treatment and some patients get clinical and serological remission even for 34 months. However, a longer following is necessary to obtain concluding results. This paper reviews those treatments in clinical cases reported in the literature.
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PMID:[Hematopoietic steam cell transplantation in the management of systemic lupus erythematosus resistant to treatment]. 1523 11


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