Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the CD5 mRNA expression and VH gene family usage in Epstein-Barr virus (EBV)-immortalized B-cell lines derived from the blood of patients with type 1 diabetes (IDDM) of recent onset and of patients with polyneuritis cranialis multiplex (cranial neuritis; CN). After immortalization with EBV, at least 10 cell lines from each subject were tested for surface CD5 and CD20. mRNA expression was studied using cDNA probes for the six VH families as well as for CD5. The EBV lines from the IDDM patients used the VHIV family more frequently and VHI and VHII families less frequently than lines from controls. EBV lines from CN patients expressed the VHI and VHII families more often than those of the controls. When the IDDM and CN lines were compared, the lines derived from IDDM patients were found to use VH families I and II less frequently and VH families IV and V more frequently than lines from CN patients. There were no significant differences in the mean numbers of CD5+ B cells in the cell lines tested. More than half of the lines from each patient expressed CD5 at the mRNA level. No correlation was seen between the expression of surface CD5 and the level of CD5 mRNA expression. There was, however, a positive correlation between the usage of VH families III, V and VI, and the CD5 mRNA expression. In conclusion, the usage of VH families I to VI seemed to differ in patients with IDDM and CN. No differences were seen in the surface CD5 expression, but the lines expressing CD5 mRNA preferentially used the VH families III, V and VI.
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PMID:CD5 and immunoglobulin VH gene expression in B-cell lines from patients with autoimmune diseases. 128 53

Immunotherapy has the potential to modify or re-balance the immune system and hence useful in the management of autoimmune conditions. This article aims to review clinically useful immunotherapies available for treatment of autoimmune conditions, with particular emphasis on Type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A Medline search for the period 1992 to 2002 (10 years) using the unrestricted keywords "immunotherapy AND autoimmune" was done. Full-length articles were selected for reviews based on the contents of their published abstracts. Additional Medline searches were focussed on the keywords "immunotherapy AND diabetes mellitus", "immunotherapy AND multiple sclerosis", "immunotherapy AND rheumatoid arthritis", and "immunotherapy AND systemic lupus erythematosus". Relevant publications referenced in the reviewed literature were further included for review, if not present in the original Medline search. Immunotherapy in Type I diabetes mellitus has focussed on the induction of tolerance to beta cell antigens, and in multiple sclerosis trials of anti-alpha 4 integrins and altered peptide ligand of myelin basic protein (MBP 83-99) showed initial promising results. The use of anti-cytokine therapy (anti-TNF alpha and IL-1Ra) in rheumatoid arthritis has improved the quality of life of patients with refractory disease. The use of anti-CD20 monoclonal antibody for in vivo B cells depletion and early trials of autologous peripheral stem cell transplants represent additional immunomodulatory treatment modalities for systemic lupus erythematosus patients. Better understanding of autoimmune conditions and advances in the production of humanized monoclonal antibodies, promises better immunotherapy in the near future.
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PMID:Immunotherapy in autoimmune diseases. 1252 Aug 21

Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the 'prediabetic' period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the beta-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.
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PMID:Prevention strategies for type 1 diabetes mellitus: current status and future directions. 1253 19

The levels and types of immune responses are determined dependent on the extent of pathogen invasion, reactions to antigens mediated by macrophage-dendritic cells, T cells and antibodies. Recently, accumulating evidence suggests that B cells also play an important role in the regulation of immune responses. Here we have made a review to present a role of B cells in determining the level of immune responses and discussed about the clinical significance of B cell-targeted therapy in patients with autoimmune diseases. Type 1 diabetes is a T cell-mediated autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells. We and other groups have elucidated that B cells play a critical role in the development of insulitis and diabetes, as B-cell-deficient NOD mice are protected from developing type 1 diabetes. B cells are essential for the T cell receptor clonotype spreading of islet-infiltrating T cells, indicating that B cells may play a role in determining the level of immune responses by antigen presentation to antigen specific T cells. There are now numerous case reports and small series of clinical trials regarding rituximab therapy in autoimmune diseases, such as refractory autoimmune hemolytic anemia, IgM antibody-associated polyneuropathy, systemic lupus erythematosus and rheumatoid arthritis. Rituximab is a genetically engineered chimeric anti-CD 20 monoclonal antibody that is approved for the treatment of lymphoma. CD20 is a B-cell surface antigen that is expressed only on pre- B and mature B cells. Thus, rituximab causes a selective transient depletion of the CD20+ B -cell subpopulation. Rationale and strategy for targeting B cells in the treatment of autoimmune diseases consist of the inhibition of antigen-presentation and co-stimulation that induces T cell expansion and activation. Further careful mechanistic studies are required to develop therapies in patients with autoimmune diseases.
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PMID:[B cells as key contributors in determining the level of immune responses -B-cell-targeted therapy in patients with autoimmune diseases]. 1599 5

Autoimmune diabetes is believed to be mediated primarily by T cells. However, B cells have been implicated in the pathogenesis of the disease in NOD mice. Although preclinical studies have been limited by the absence of anti-CD20 reagents that can induce B cell depletion in mice, a clinical trial using the B cell-depleting anti-CD20 monoclonal antibody rituximab (Rituxan) is underway in type 1 diabetes patients. In this issue of the JCI, Hu et al. describe the generation of transgenic NOD mice that express human CD20 on B cells (see the related article beginning on page 3857). They show that anti-CD20 therapy induces B cell depletion in these mice and offers some level of protection against diabetes. Although many questions remain unanswered, this mouse model represents the first opportunity to evaluate the potential value of rituximab as a novel therapy for autoimmune diabetes.
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PMID:B cell depletion: a novel therapy for autoimmune diabetes? 1806 33

The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.
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PMID:Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. 1806 22

NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by approximately 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcgammaRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 microg) in NOD mice, FcgammaRIII and FcgammaRIV compensated for inadequate FcgammaRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcgammaR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.
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PMID:B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions. 1829 8

The immunopathology of type 1 diabetes (T1D) has proved difficult to study in man because of the limited availability of appropriate samples, but we now report a detailed study charting the evolution of insulitis in human T1D. Pancreas samples removed post-mortem from 29 patients (mean age 11.7 years) with recent-onset T1D were analysed by immunohistochemistry. The cell types constituting the inflammatory infiltrate within islets (insulitis) were determined in parallel with islet insulin content. CD8(+) cytotoxic T cells were the most abundant population during insulitis. Macrophages (CD68(+)) were also present during both early and later insulitis, although in fewer numbers. CD20(+) cells were present in only small numbers in early insulitis but were recruited to islets as beta cell death progressed. CD138(+) plasma cells were infrequent at all stages of insulitis. CD4(+) cells were present in the islet infiltrate in all patients but were less abundant than CD8(+) or CD68(+) cells. Forkhead box protein P3(+) regulatory T cells were detected in the islets of only a single patient. Natural killer cells were detected rarely, even in heavily inflamed islets. The results suggest a defined sequence of immune cell recruitment in human T1D. They imply that both CD8(+) cytotoxic cells and macrophages may contribute to beta cell death during early insulitis. CD20(+) cells are recruited in greatest numbers during late insulitis, suggesting an increasing role for these cells as insulitis develops. Natural killer cells and forkhead box protein P3(+) T cells do not appear to be required for beta cell death.
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PMID:Analysis of islet inflammation in human type 1 diabetes. 1912 57

We describe the decline in islet function, in relation to HLA sensitization, in an islet transplant recipient and the recovery of this function after treatment with anti-CD20 monoclonal antibody and IV immunoglobulins. A 51-year-old woman with type 1 diabetes received one intraportal islet infusion. Following this transplantation, she became insulin independent. A search for HLA antibodies by using an ELISA technique remained consistently negative for HLA class I and II. It was only 2 years after the islet transplantation that this search became positive against class II antigens, reaching a peak of reactivity concomitantly with the appearance of a deterioration of glucose control requiring low-dose insulin therapy. Luminex screening and single-antigen assays then revealed the presence of both nondonor-specific and donor-specific antibodies against HLA class II molecules. This immunization, already present in the pretransplant serum, had increased during the 6 months preceding the clinical deterioration. Since these data nevertheless pointed to antibody-mediated rejection of the islet allograft, treatment with anti-CD20 monoclonal antibody and IV immunoglobulins was initiated. One month later, the search by ELISA for antibodies against HLA class II antigens became negative, the Luminex tests normalizing more gradually. As the result of an improvement in glucose control, the patient was again insulin-free.
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PMID:Evidence for humoral rejection of a pancreatic islet graft and rescue with rituximab and IV immunoglobulin therapy. 1952 77

Type 1 diabetes is characterized by the autoimmune-mediated destruction of the insulin-producing beta cells of the pancreatic islets of Langerhans. Several cells are potentially implicated in the selective destruction of beta cells, including the beta cells themselves, and T-lymphocytes and B-lymphocytes that are working as antigen-presenting cells. Both types of lymphocytes play also a role in the progressive loss of graft function after islet transplantation. Therefore, immunotherapy may represent a great opportunity to prevent, treat or even cure type 1 diabetes, and the input of monoclonal antibodies (mAb) appears crucial in such a strategy. The concept has first been validated in various animal models, especially the classical one of the NOD mouse. During recent years, promising results of a few clinical trials have been published with the administration of anti-CD3 mAbs targeting T lymphocytes at the time of diagnosis of type 1 diabetes. Results showed a more sustained residual insulin secretion during the following months associated with a reduction in insulin needs. Interesting results may also be expected from the use of anti-CD20 mAbs targeting B lymphocytes. Finally, when considering immunosuppressive therapies after beta-cell transplantation, mAbs, especially those blocking interleukin-2, are already used in clinical practice, but new trials are expected with mAbs targeting T or B lymphocytes. Thus, mAbs might be efficacious in a near future in the prevention (when administered early in the natural course of the disease, in high risk patients) and the treatment of type 1 diabetes, and therefore could avoid, or at least minimize, the constraints of intensive subcutaneous insulin therapy.
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PMID:[Monoclonal antibodies in diabetes: almost approaching the dream?]. 1964 69


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