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)

The (NZW x BXSB)F1 (W/BF1) mouse is known to be an animal model of systemic lupus erythematosus (SLE) and immune thrombocytopenic purpura (ITP). These mice produce not only anti-DNA antibodies but also anti-platelet antibodies, resulting in decreased platelet counts. They show a high level of proteinuria, increased white blood cell (WBC) counts, hypertension, and myocardial infarction due to the high levels of anti-cardiolipin antibodies. When W/BF1 mice (4-5 months) were lethally irradiated and then reconstituted with T cell-depleted bone marrow cells of normal BALB/c mice (8 weeks), 60% of the mice survived more than one year. The WBC and platelet counts in the mice were normalized, and the levels of anti-DNA and anti-platelet antibodies decreased. The renal dysfunction was also ameliorated as indicated by a lower level of proteinuria, lower levels of serum creatinine (S-CRTN) and blood urea nitrogen (BUN), and by improved histology. The blood pressure (BP) of the treated W/BF1 mice decreased due to the improved renal functions. In contrast to the non-treated W/BF1 mice which died of myocardial infarction or renal failure by the age of 7 months, the treated W/BF1 mice showed no evidence of myocardial infarction even one year after BMT. This was due to the lower cardiolipin levels.
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PMID:Effect of bone marrow transplantation on antiphospholipid antibody syndrome in murine lupus mice. 778 96

Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with either a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id) or with a mouse monoclonal anti-idiotypic antibody specific for the 16/6 Id. Susceptibility to the induction of experimental SLE is genetically determined but is not linked to the MHC. In the present study we tested the susceptibility of BM chimeras of different donor-host combinations to the induction of SLE and found that high levels of anti-16/6 Id and anti-ssDNA antibodies were induced in BALB/c-->C57BL/6, BALB/c-->BALB/c and normal BALB/c mice as opposed to C57BL/6-->BALB/c chimeras and normal C57BL/6 mice. The low levels of the anti-16/6 Id and anti-ssDNA antibodies produced by C57BL/6-->BALB/c chimeras immunized with the 16/6 fully allogeneic BMT as such chimeras were shown to produce high levels of antibodies to a T cell-dependent antigen (the synthetic polypeptide (Phe,G)-A--L). These results demonstrate that the production of SLE-related autoantibodies is controlled by donor-type BM derived cells and not by host-type cells in the thymic stroma.
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PMID:Systemic lupus erythematosus-related autoantibody production in mice is determined by bone marrow-derived cells. 824 73

In addition to our center (Northwestern University, Chicago), several institutions in the United States (Fred Hutchinson Cancer Center, University of California at Los Angeles, and Medical College of Wisconsin) and Europe are activating protocols to transplant patients with SADS. In this age of cost-effectiveness, it will be difficult to arrange third-party reimbursement for a hematopoietic stem cell transplant that may lead to medical charges of between $100,000 and $200,000. However, the cost of standard medical care for patients with SADS is not trivial. Dialysis for an SLE patient with renal failure costs $40,000 per year, while the medical resources required to care for a patient with progressive multiple sclerosis may exceed $35,000 per year. Unique BMT regimen-related toxicities may occur, including intracranial hemorrhage in the SLE or rheumatoid arthritis patient who has vasculitis; acute neurologic decompensation in patients with multiple sclerosis, especially if the conditioning regimen contains neurotoxic agents that cross a compromised blood-brain barrier; respiratory failure in patients with myasthenia gravis; and increased renal or pulmonary toxicity in patients with scleroderma and parenchymal fibrosis. Scleroderma-associated gastrointestinal dysmotility and bacterial overgrowth may also lead to greater fungal and bacterial infections [76]. BMT is currently considered appropriate therapy for patients with chronic-phase Chronic myelogenous leukemia (CML) and indolent lymphomas who otherwise have a relatively long life expectancy of 5 and 10 years, respectively. The roughly similar long survival but greater functional impairment of patients with SADS may justify consideration of immune ablation and hematopoietic stem cell rescue.
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PMID:Immune ablation and hematopoietic stem cell rescue for severe autoimmune diseases (SADS). 907 9

With over 4 decades of seminal contributions to the development and application of BMT, Dr. Thomas stresses the importance of collaboration between rheumatologists and transplant clinicians in developing this evolving area of treatment. While the debate concerning the value of TBI in the conditioning regimen and the use of autologous or allogeneic stem cells will continue, he states there is simply no other way to answer these questions than to begin well designed clinical studies. As pointed out by Dr. Hahn, unexpected post-transplant complications may arise in patients with SSc and SLE and possibly require modifications to the transplant procedure similar to the experience in patients with other specific diseases. Other difficulties may be encountered, including restricted funding of the transplant procedure by insurance carriers. The emergence of managed care contracts and payer limitations in the United States described by Dr. Appelbaum could hinder the development of innovative, curative therapies. As initial clinical data are being collected, it is vital to actively support patient referral and participation in clinical studies that will ultimately establish the indications, risks, costs, and benefits of hematopoietic stem cell transplantation for autoimmune disease.
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PMID:The evolving role of blood and marrow transplantation for the treatment of autoimmune diseases. 915 Jan 10

A 36-year-old woman with RAEB-t and severe bone marrow fibrosis undergoing autologous BMT, developed a histologically documented GVHD-like skin rash. Thereafter, autoimmune thyroiditis, autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia and a lupus anti-coagulant (LAC) were diagnosed. The patient is still alive, symptom-free and in first complete remission (CR); however, all of the autoantibodies are still detectable, with the exception being the anti-erythrocyte antibody. The most outstanding feature of the present case is the polymorphism of the autoimmune events, in the absence of a coexisting systemic autoimmune disease. This patient has achieved long-term disease-free survival (DFS) in first CR despite high-risk MDS and the repeated immunosuppressant therapy required because of the complications described above; a GVL reaction somewhat similar to the autoimmune events may have contributed towards maintaining disease control.
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PMID:Multiple autoimmune events after autologous bone marrow transplantation. 915 54

We describe a patient with longstanding steroid-dependent systemic lupus erythematosus (SLE) in whom clinical and serological remission was achieved following high-dose therapy and autologous bone marrow rescue for high-grade non-Hodgkin's lymphoma. However, 3 years later, autoimmune disease re-presented in the form of immune thrombocytopenia (ITP), which had not previously been a feature of the SLE, necessitating reintroduction of steroid immunosuppression. Relapse of SLE is most likely, although de novo ITP post-BMT is also a possibility. The case suggests that severe long-standing autoimmune disease may be controlled by high-dose therapy and autologous stem cell reconstitution. However, further studies are required to determine the mechanism of re-emergence of autoimmunity and to evaluate optimal regimens and the potential value of such therapy in severe autoimmune diseases.
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PMID:Prolonged remission of longstanding systemic lupus erythematosus after autologous bone marrow transplant for non-Hodgkin's lymphoma. 920 20

Since Morton and Siegel's epochal experiments 30 years ago animal models have been successfully utilized both for transfer and resolution of autoimmune diseases (AID). More recently human lymphocyte xenografts have reproduced clinical AID in SCID mice. Allogeneic stem cell transplantation demonstrated therapeutic potential in fully developed autoimmune disease. Mixed allogeneic chimerism induced by a sublethal approach has also been shown to prevent and even reverse autoimmune insulitis in nonobese diabetic (NOD) mice. More unexpectedly it was found that experimental adjuvant arthritis (AA) and experimental allergic encephalomyelitis (EAE) could be cured by means of total body irradiation (TBI) followed by autologous hemolymphopoietic stem cell (HSC) transplantation. It was postulated that the newly developing T cells might be tolerant to self antigens. The transfer of AID from affected donors to recipients of allogeneic HSC transplants has been reported for many organ-specific AID, including diabetes (IDDM), thyroiditis, myasthenia gravis and thrombocytopenic purpura (AITP); rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were not transferred. Conversely patients with the combination of AID and a severe blood disease (leukemia, aplasia) were cured of both diseases following allogeneic BMT, with the notable exception of a relapse in a patient with RA despite full donor engraftment. Allogeneic transplants are certainly more promising as far as concerns a resolution of AID, because they may also exert a graft-versus-autoimmunity effect by gradually eradicating the recipient's lymphopoiesis, but transplant related mortality (TRM) is considered still too high to employ this procedure consistently. New non-myeloablative conditioning regimens, designed to allow the donor's immune system to take over, are already utilized for malignant and non-malignant hematologic diseases, and may become an attractive option for severe, refractory AID. For the time being, however, autologous procedures are still safer, and are being utilized in many projects worldwide. The EBMT/EULAR Registry has collected over 70 patient reports. The more numerous and favorable results have been obtained up to now in multiple scleosis and in systemic lupus erythematosus; the worst in refractory autoimmune thrombocytopenic purpura. No definite conclusions as to the efficacy of autologous HSC transplantation, from marrow or from blood, with or without T-cell depletion, may be drawn at this time, but the feeling is that real cures will be very difficult to obtain by this approach, and that corticosteroid-free remissions and a general lowering of the autoimmune potential will be more realistic goals. Accurate comparisons with already existing aggressive immunosuppressive protocols will become necessary, if possible by means of prospective randomized clinical studies.
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PMID:Stem cell transplantation for severe autoimmune diseases: progress and problems. 979 58

We report a 54-year-old woman who received interferon alpha for haematological relapse of Ph-positive CML, 7 years after allogeneic BMT from an HLA-identical brother. Eighteen months after relapse, cytogenetic and molecular remission was achieved. She received interferon therapy for 25 months and it was discontinued when she developed skin lesions on her face and trunk, dysphagia and fever with respiratory failure and bilateral patchy airspace consolidation of the lung without microbiologic findings. Histologic features showed discoid lupus erythematosis, oesophagitis with pseudomembranes and a mixed pattern of lymphocytic bronchiolitis involving the alveoli and interstitial spaces all compatible with chronic GVHD. The patient was commenced on immunosuppressive therapy with complete clinical and radiological resolution. The available evidence supports an atypical presentation of chronic GVHD and suggests a role for interferon alpha in the pathogenesis of GVHD. To the best of our knowledge, this is the first case reported of severe chronic GVHD occurring during the course of interferon therapy for relapsed CML.
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PMID:Atypical chronic graft-versus-host disease following interferon therapy for chronic myeloid leukaemia relapsing after allogeneic BMT. 1124 42

We present long-term outcomes of BXSB mice after non-myeloablative bone marrow transplants using major histocompatability complex (MHC)-matched cells. Groups differed in sources of donor lymphocytes or mesenchymal stromal cells (MSC). Unfractionated marrow cells from green fluorescent protein (GFP) transgenic (Tg) mice (BMT group) or from RAG1-/- B6 mice (RAG group) were injected intravenously (i.v.) into irradiated (550 cGy) hosts. As a source of mesenchymal cells, bone chips from GFP-Tg were injected intraperitoneally alone (MSC group) or along with i.v. bone marrow cells (BMT + MSC group). Controls were untreated mice (UnTx) or mice exposed to radiation only (Rad Cont). At 62 weeks post-transplant, surviving mice were harvested for histopathology, flow cytometry and real time polymerase chain reaction (RT-PCR). The mice from BMT + MSC group had the best outcomes for survival rates (71.4% vs. 43.8%), renal scores (2.9% vs. 28.8% glomerular sclerosis) and percent splenic monocytes (4.2 vs. 11.3%) compared with mice from Rad Cont. Improvement in RAG and BMT groups was less prominent but were comparable with one another. Although MSC alone were not sufficient to control the renal pathology, it limited the expansion of CD4(-)CD8(-) T cell populations without a change in Foxp3 expression. The results suggest the importance of the innate immune system in disease pathogenesis and a role for MSC in immunomodulation.
Lupus 2009 Aug
PMID:Long-term follow-up after non-myeloablative transplant of bone and marrow in BXSB mice. 1957 6

Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.
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PMID:Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. 2135 84


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