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Autoimmune Diabetes (autoimmune + diabetes)
Kinds of Autoimmune Diabetes Selected AbstractsNo association of SUMO4 M55V with autoimmune diabetes in Asian-Indian patientsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2007S. K. Sedimbi Summary Autoimmune diabetes [type 1 diabetes mellitus (T1DM), latent autoimmune diabetes in adults (LADA) and part of malnutrition-related diabetes] has been shown to have genetic predisposition. Studies in IDDM 5 have lead to the discovery of a novel polymorphism 163 A,G, of SUMO4 (small ubiquitin-related modifier) gene, associated with risk to T1DM in Asians, but not in Caucasians. We studied patients with T1DM (n = 134), patients with LADA (n = 101), patients with malnutrition-modulated diabetes mellitus (n = 66) and patients with fibrocalculous pancreatic diabetes (n = 43) and healthy controls subjects (n = 114) from Cuttack, India. Polymerase chain reaction,sequence-specific primer (PCR-SSP) was used to amplify the 163 A,G sequences. Restriction fragment length polymorphism (RFLP) was performed using restriction enzyme Taq I (PCR-RFLP). Differences in the allelic frequencies of the A and the G alleles were tested statistically using Fisher's exact test or chi-squared test wherever appropriate. P -values were considered significant when equal to or less than 0.05. No significant association was detected between SUMO4 M55V and T1DM susceptibility in Asian-Indians. Comparison of the A and G alleles with HLA DR3-DR4 did not result in any significant P -values. No significant association was found between SUMO4 M55V and LADA or malnutrition-related diabetes mellitus (MRDM). Our results show that Asian-Indians with T1DM are different from other Asian populations. Asian-Indians show more similarity to Caucasians with respect to the association of SUMO4 M55V variant in T1DM. Association studies on Asian-Indian patients with LADA and MRDM showed no significant difference in the presence of the A and the G alleles when compared to healthy controls. [source] Prevention of diabetes: effect of mycophenolate mofetil and anti-CD25 on onset of diabetes in the DRBB ratPEDIATRIC DIABETES, Issue 6 2008Figen Ugrasbul Background:, Anti-CD25 and mycophenolate mofetil (MMF) treatment of patients with new-onset diabetes is currently being tested as one of the trials in TrialNet. We tested the effectiveness of MMF and anti-CD25 in preventing autoimmune diabetes in the diabetes-resistant biobreeding (DRBB) rat. Methods:, Autoimmune diabetes in the DRBB rat was induced with a Treg cell depletion regimen starting at 24,26 d of age. Treatment was started on the first day of the depletion regimen in the following groups: (i) control (vehicle); (ii) MMF 25 mg/kg/d intramuscularly daily for 8 wk; (iii) anti-CD25 0.8 mg/kg/d intraperitoneally 5 d/wk for 3 wk; and (iv) combination of MMF and anti-CD25. In a second set of experiments, treatments were started on day 5 of the depletion regimen (delayed treatment) with groups 1, 3, and 4. Rats that had diabetes-free survival for at least 30 d after the treatment was stopped underwent a second Treg depletion (redepletion). Results:, In each of the three treatment groups (n = 10/group), onset of diabetes was delayed or prevented in 20, 40 and 80% in groups 2, 3, and 4, respectively. After redepletion, diabetes-free survival was unchanged in group 2 and decreased to 10 and 30% in groups 3 and 4, respectively. With delayed treatment, groups 3 and 4 had 33 and 50% diabetes-free survival that decreased to 0 and 33% after redepletion. Summary:, MMF and anti-CD25 alone or in combination are effective in delaying and preventing diabetes in the DRBB rat especially if treatment is started before stimulation and expansion of the autoreactive T cells. [source] The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding ratPEDIATRIC DIABETES, Issue 1 2004Jadranka Popovic Abstract:, Background:, Autoimmune diabetes of the diabetes-resistant biobreeding (DRBB) rat shares similarities with diabetes in humans and has stages of diabetes that can be controlled and compared. FTY720 is an immunomodulator that has been efficacious in transplant and autoimmune models without inducing an immunosuppressed state. We determined the stages of diabetes that are affected by FTY720 in the DRBB rat. Methods:, Autoimmune diabetes was induced with RT6.1 T-cell-depleting antibody and polyIC starting at 4 weeks of age. FTY720 (1 mg/kg/d) was started at day 0, 5, 7, and 14 following the start of depletion. The rats that did not develop diabetes were maintained for 60 d following the last dose of FTY720 before undergoing a second course of depletion. Results:, FTY720 starting at day 0, 5, 7, and 14 of depletion prevented diabetes in 100, 100, 50, and 20% of the DRBB rats compared to 0% of the control rats. The surviving rats in the 5-, 7-, and 14-d groups developed diabetes after FTY720 treatment was stopped. Histological examination indicated insulitis in the control rats between day 7 and 11 of depletion and end-stage insulitis by day 18 of depletion compared to negligible insulitis in rats without diabetes. Redepletion in the surviving day 0 rats resulted in development of diabetes in 25% of these rats compared to none of the age-matched controls. Summary:, FTY720 can prevent autoimmune diabetes, if administered before and/or during stimulation and expansion of the autoreactive T cells or in the early stages of insulitis. The effectiveness diminishes with each successive stage of diabetes. [source] Preventative effects of the flowers of Inula britannica on autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocinPHYTOTHERAPY RESEARCH, Issue 4 2002Takao Kobayashi Abstract We have reported that an aqueous extract from the flowers of Inula britannica L. subsp. japonica Kitam. (IB) prevented immunologically induced experimental hepatitis in mice and suggested that the antihepatitic effect of IB is due to inhibition of IFN-, production. We then investigated the effects of IB on diabetes in mice induced by multiple low doses of streptozotocin (MLDSTZ), which is a mouse model for IFN-,-dependent autoimmune diabetes. C57BL/KsJ mice (male, 7 weeks) were provided with IB extract (500,mg/,kg/ day) in drinking water ad libitum, starting 7 days before the first STZ injection. Autoimmune diabetes was induced by MLDSTZ (40,mg/kg/day for 5 daily doses, i.p.). The IB treatment significantly suppressed the increase of blood glucose levels. Histological analysis of the pancreas showed that the degree of insulitis and destruction of ,-cells were reduced by IB treatment. The IFN-, production from stimulated splenic T lymphocytes was inhibited by the IB treatment. Moreover, the proportion of IFN-,-producing cells in the CD4+ population, which was increased by MLDSTZ, was significantly decreased by the IB treatment. These results suggest that IB has a preventative effect on autoimmune diabetes by regulating cytokine production. Copyright © 2002 John Wiley & Sons, Ltd. [source] Diabetes classification: grey zones, sound and smoke: Action LADA 1DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 7 2008R. D. G. Leslie Abstract Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes. KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area. Copyright © 2008 John Wiley & Sons, Ltd. [source] Rosiglitazone combined with insulin preserves islet , cell function in adult-onset latent autoimmune diabetes (LADA)DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 2 2005Zhiguang Zhou Abstract Background LADA is thought to result from the chronic autoimmune destruction of the insulin-producing pancreatic , cells. In addition to antidiabetic effects, the newly developed insulin sensitizer-thiazolidinediones have the potential to increase the insulin content of islet cells by downregulating local inflammation and autoimmune response. Therefore, we hypothesized that LADA patients might benefit from thiazolidinediones treatment. Methods LADA patients, with a fasting C-peptide (FCP) of 0.3 nmol/L or more, were enrolled and randomly assigned to receive subcutaneous insulin alone (insulin group, n = 12) or rosiglitazone plus insulin (insulin + RSG group, n = 11) to compare the impacts on islet , cell function. Plasma glucose, HbA 1c, fasting C-peptide (FCP) and C-peptide after 2 h 75-g glucose load (PCP) were determined every 6 months. GAD-Ab and C-peptide were measured with radioimmune assays. Islet , cell function was evaluated by PCP and ,CP(,CP = PCP-FCP). Results All of the 23 patients have been followed up for 6 months, 17 cases for 12 months and 14 for 18 months. (1) During 6 months' follow-up, there were no significant changes for ,CP and PCP levels in both groups. (2) PCP and ,CP levels in insulin + RSG group patients stayed steady during the 12 months' observation (P = 0.161 for both PCP and ,CP), while in the insulin alone group, both FCP (P = 0.021) and PCP (P = 0.028) levels decreased significantly. Furthermore, PCP (P = 0.004) and ,CP(P = 0.015) differences between 12th month and baseline were higher in insulin + RSG group than those in the insulin group. (3) When observed up to 18 months, PCP and ,CP levels in insulin + RSG group patients still stayed steady, while PCP and ,CP levels decreased more in the insulin alone group. Conclusions This pilot study suggests that rosiglitazone combined with insulin may preserve islet , cell function in LADA patients. Copyright © 2004 John Wiley & Sons, Ltd. [source] A new look at viruses in type 1 diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2003Hee-Sook Jun Abstract Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell-specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus-induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein-Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed. Copyright © 2002 John Wiley & Sons, Ltd. [source] Incorrect and incomplete coding and classification of diabetes: a systematic reviewDIABETIC MEDICINE, Issue 5 2010M. A. Stone Diabet. Med. 27, 491,497 (2010) Abstract Aims, To conduct a systematic review to identify types and implications of incorrect or incomplete coding or classification within diabetes or between diabetes and other conditions; also to determine the availability of evidence regarding frequency of occurrence. Methods, Medical Subject Headings (MeSH) and free-text terms were used to search relevant electronic databases for papers published to the end of August 2008. Two researchers independently reviewed titles and abstracts and, subsequently, the full text of potential papers. Reference lists of selected papers were also reviewed and authors consulted. Three reviewers independently extracted data. Results, Seventeen eligible studies were identified, including five concerned with distinguishing between Type 1 and Type 2 diabetes. Evidence was also identified regarding: the distinction between diabetes and no-diabetes, failure to specify type of diabetes, and diagnostic errors or difficulties involving maturity-onset diabetes of the young, latent autoimmune diabetes in adults, pancreatic diabetes, persistence of foetal haemoglobin and acquired immune deficiency syndrome (AIDS). The sample was too heterogeneous to derive accurate information about frequency, but our findings suggested that misclassification occurs most commonly in young people. Implications relating to treatment options and risk management were highlighted, in addition to psychological and financial implications and the potential impact on the validity of quality of care evaluations and research. Conclusions, This review draws attention to the occurrence and implications of incorrect or incomplete coding or classification of diabetes, particularly in young people. A pragmatic and clinically relevant approach to classification is needed to assist those involved in making decisions about types of diabetes. [source] The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitusDIABETIC MEDICINE, Issue 2 2008A. W. Van Deutekom Abstract Latent autoimmune diabetes in the adult (LADA) is a slowly progressive form of autoimmune diabetes, characterized by diabetes-associated autoantibody positivity. A recent hypothesis proposes that LADA consists of a heterogeneous population, wherein several subgroups can be identified based on their autoimmune status. A systematic review of the literature was carried out to appraise whether the clinical characteristics of LADA patients correlate with the titre and numbers of diabetes-associated autoantibodies. We found that the simultaneous presence of multiple autoantibodies and/or a high-titre anti-glutamic acid decarboxylase (GAD),compared with single and low-titre autoantibody,is associated with an early age of onset, low fasting C-peptide values as a marker of reduced pancreatic B-cell function, a high predictive value for future insulin requirement, the presence of other autoimmune disorders, a low prevalence of markers of the metabolic syndrome including high body mass index, hypertension and dyslipidaemia, and a high prevalence of the genotype known to increase the risk of Type 1 diabetes. We propose a more continuous classification of diabetes mellitus, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes. Future studies should focus on determining optimal cut-off points of anti-GAD for differentiating clinically relevant diabetes mellitus subgroups. [source] GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccinationDIABETIC MEDICINE, Issue 5 2007L. M. Bekris Abstract Aims Subcutaneous injection of recombinant human GAD65 (rhGAD65) in patients with latent autoimmune diabetes in adults (LADA) correlates with an increase in C-peptide levels. In this study we analysed the effect of rhGAD65 administration on the GAD65-specific autoimmune response. Methods Longitudinal serum samples obtained from LADA patients (n = 47) who received 4, 20, 100 or 500 µg alum-formulated rhGAD65 or placebo by subcutaneous injection twice (4 weeks apart) were analysed for their epitope recognition using GAD65-specific recombinant Fab and GAD65/67 fusion proteins. Results Overall, minor changes in the epitope pattern were observed using either approach. Only in the 500-µg dosage group was an increase in GAD65Ab level associated with a significant increase in the binding to a conformational epitope located at the middle part of GAD65. Conclusions Our data suggest that the apparent beneficial effects of 20 µg alum-formulated recombinant human GAD65 is not explained by changes in the GAD65Ab epitope pattern. [source] Breakpoints in immunoregulation required for Th1 cells to induce diabetesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Margaret Neighbors Abstract We describe a novel TCR-transgenic mouse line, TCR7, where MHC class,II-restricted, CD4+ T cells are specific for the subdominant H-2b epitope (HEL74,88) of hen egg lysozyme (HEL), and displayed an increased frequency in the thymus and in peripheral lymphoid compartments over that seen in non-transgenic littermate controls. CD4+ T cells responded vigorously to HEL or HEL74,88 epitope presented on APC and could develop into Th1 or Th2 cells under appropriate conditions. Adoptive transfer of TCR7 Ly5.1 T cells into Ly5.2 rat insulin promoter (RIP)-HEL transgenic recipient hosts did not lead to expansion of these cells or result in islet infiltration, although these TCR7 cells could expand upon transfer into mice expressing high levels of HEL in the serum. Islet cell infiltration only occurred when the TCR7 cells had been polarized to either a Th1 or Th2 phenotype prior to transfer, which led to insulitis. Progression from insulitis to autoimmune diabetes only occurred in these recipients when Th1 but not Th2 TCR7 cells were transferred and CTLA-4 signaling was simultaneously blocked. These findings show that regulatory pathways such as CTLA-4 can hold in check already differentiated autoreactive effector Th1 cells, to inhibit the transition from tolerance to autoimmune diabetes. See accompanying commentary at http://dx.doi.org/10.1002/eji.200636591 [source] Extracellular lysosome-associated membrane protein-1 (LAMP-1) mediates autoimmune disease progression in the NOD model of type 1 diabetesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005Marcelo De Carvalho Bittencourt Abstract Treatment (from 5 to 25,weeks of age) with a novel blocking monoclonal antibody, mAb I-10, directed against the plasma membrane (pm) form of LAMP-1, protected against development of autoimmune diabetes in the NOD mouse. A shorter course of treatment, i.e. from 5 to 12,weeks of age, significantly reduced the occurrence of insulitis as well as disease onset. Interfering with pm-LAMP-1 required continuous treatment as tolerance was not observed when treatment was stopped, and no higher proportion of cells with a T regulatory phenotype (e.g. CD4+CD25+) were induced. The mechanism appears to involve modulating a proinflammatory cytokine, as the proportion of pancreatic-infiltrating IFN-,-positive cells was significantly reduced in the mAb I-10-treated group. These results demonstrate an unexpected role for pm-LAMP-1 in autoimmune disease progression, and suggest that further investigation should be performed to understand how this molecule modulates IFN-,-driven responses. [source] Partial and transient modulation of the CD3,T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic miceIMMUNOLOGY, Issue 1 2010Devangi S. Mehta Summary It has been established that a total of 250 ,g of monoclonal anti-mouse CD3 F(ab,)2 fragments, administered daily (50 ,g per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing , cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab,)2 in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3,T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4+, CD8+ and CD4+ FoxP3+ T cells. Four doses of 2 ,g (total dose 8 ,g) induced 53% remission of diabetes, similarly to the 250 ,g dose regimen, whereas four doses of 1 ,g induced only 16% remission. While the 250 ,g dose regimen produced nearly complete and sustained modulation of the CD3 ,TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4+ and CD8+ T cells decreased, whereas the proportions of CD4+ FoxP3+ T cells increased; these effects were transient. Mice with greater residual ,-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3,TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. [source] Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodiesIMMUNOLOGY, Issue 4 2008Tyler R. Hall Summary Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96·11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96·11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96·11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96·11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne. [source] No association of SUMO4 M55V with autoimmune diabetes in Asian-Indian patientsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2007S. K. Sedimbi Summary Autoimmune diabetes [type 1 diabetes mellitus (T1DM), latent autoimmune diabetes in adults (LADA) and part of malnutrition-related diabetes] has been shown to have genetic predisposition. Studies in IDDM 5 have lead to the discovery of a novel polymorphism 163 A,G, of SUMO4 (small ubiquitin-related modifier) gene, associated with risk to T1DM in Asians, but not in Caucasians. We studied patients with T1DM (n = 134), patients with LADA (n = 101), patients with malnutrition-modulated diabetes mellitus (n = 66) and patients with fibrocalculous pancreatic diabetes (n = 43) and healthy controls subjects (n = 114) from Cuttack, India. Polymerase chain reaction,sequence-specific primer (PCR-SSP) was used to amplify the 163 A,G sequences. Restriction fragment length polymorphism (RFLP) was performed using restriction enzyme Taq I (PCR-RFLP). Differences in the allelic frequencies of the A and the G alleles were tested statistically using Fisher's exact test or chi-squared test wherever appropriate. P -values were considered significant when equal to or less than 0.05. No significant association was detected between SUMO4 M55V and T1DM susceptibility in Asian-Indians. Comparison of the A and G alleles with HLA DR3-DR4 did not result in any significant P -values. No significant association was found between SUMO4 M55V and LADA or malnutrition-related diabetes mellitus (MRDM). Our results show that Asian-Indians with T1DM are different from other Asian populations. Asian-Indians show more similarity to Caucasians with respect to the association of SUMO4 M55V variant in T1DM. Association studies on Asian-Indian patients with LADA and MRDM showed no significant difference in the presence of the A and the G alleles when compared to healthy controls. [source] Association of MHC class I chain related gene-A microsatellite polymorphism with the susceptibility to T1DM and LADA in Czech adult patientsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 5 2005P. Novota Summary The results in this study suggest that microsatellite polymorphism within the transmembrane region of MIC-A gene is associated with genetic susceptibility to adult-onset of type 1 diabetes mellitus (T1DM), MIC-A5.1 allele, corrected P = 0.001, whereas it is not associated with latent autoimmune diabetes in adults (LADA) in Czech population. According to our findings, we can hypothesize that adult-onset T1DM and LADA may have partly different immunogenetic aetiopathogenesis. [source] Prevention of diabetes: effect of mycophenolate mofetil and anti-CD25 on onset of diabetes in the DRBB ratPEDIATRIC DIABETES, Issue 6 2008Figen Ugrasbul Background:, Anti-CD25 and mycophenolate mofetil (MMF) treatment of patients with new-onset diabetes is currently being tested as one of the trials in TrialNet. We tested the effectiveness of MMF and anti-CD25 in preventing autoimmune diabetes in the diabetes-resistant biobreeding (DRBB) rat. Methods:, Autoimmune diabetes in the DRBB rat was induced with a Treg cell depletion regimen starting at 24,26 d of age. Treatment was started on the first day of the depletion regimen in the following groups: (i) control (vehicle); (ii) MMF 25 mg/kg/d intramuscularly daily for 8 wk; (iii) anti-CD25 0.8 mg/kg/d intraperitoneally 5 d/wk for 3 wk; and (iv) combination of MMF and anti-CD25. In a second set of experiments, treatments were started on day 5 of the depletion regimen (delayed treatment) with groups 1, 3, and 4. Rats that had diabetes-free survival for at least 30 d after the treatment was stopped underwent a second Treg depletion (redepletion). Results:, In each of the three treatment groups (n = 10/group), onset of diabetes was delayed or prevented in 20, 40 and 80% in groups 2, 3, and 4, respectively. After redepletion, diabetes-free survival was unchanged in group 2 and decreased to 10 and 30% in groups 3 and 4, respectively. With delayed treatment, groups 3 and 4 had 33 and 50% diabetes-free survival that decreased to 0 and 33% after redepletion. Summary:, MMF and anti-CD25 alone or in combination are effective in delaying and preventing diabetes in the DRBB rat especially if treatment is started before stimulation and expansion of the autoreactive T cells. [source] The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding ratPEDIATRIC DIABETES, Issue 1 2004Jadranka Popovic Abstract:, Background:, Autoimmune diabetes of the diabetes-resistant biobreeding (DRBB) rat shares similarities with diabetes in humans and has stages of diabetes that can be controlled and compared. FTY720 is an immunomodulator that has been efficacious in transplant and autoimmune models without inducing an immunosuppressed state. We determined the stages of diabetes that are affected by FTY720 in the DRBB rat. Methods:, Autoimmune diabetes was induced with RT6.1 T-cell-depleting antibody and polyIC starting at 4 weeks of age. FTY720 (1 mg/kg/d) was started at day 0, 5, 7, and 14 following the start of depletion. The rats that did not develop diabetes were maintained for 60 d following the last dose of FTY720 before undergoing a second course of depletion. Results:, FTY720 starting at day 0, 5, 7, and 14 of depletion prevented diabetes in 100, 100, 50, and 20% of the DRBB rats compared to 0% of the control rats. The surviving rats in the 5-, 7-, and 14-d groups developed diabetes after FTY720 treatment was stopped. Histological examination indicated insulitis in the control rats between day 7 and 11 of depletion and end-stage insulitis by day 18 of depletion compared to negligible insulitis in rats without diabetes. Redepletion in the surviving day 0 rats resulted in development of diabetes in 25% of these rats compared to none of the age-matched controls. Summary:, FTY720 can prevent autoimmune diabetes, if administered before and/or during stimulation and expansion of the autoreactive T cells or in the early stages of insulitis. The effectiveness diminishes with each successive stage of diabetes. [source] Preventative effects of the flowers of Inula britannica on autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocinPHYTOTHERAPY RESEARCH, Issue 4 2002Takao Kobayashi Abstract We have reported that an aqueous extract from the flowers of Inula britannica L. subsp. japonica Kitam. (IB) prevented immunologically induced experimental hepatitis in mice and suggested that the antihepatitic effect of IB is due to inhibition of IFN-, production. We then investigated the effects of IB on diabetes in mice induced by multiple low doses of streptozotocin (MLDSTZ), which is a mouse model for IFN-,-dependent autoimmune diabetes. C57BL/KsJ mice (male, 7 weeks) were provided with IB extract (500,mg/,kg/ day) in drinking water ad libitum, starting 7 days before the first STZ injection. Autoimmune diabetes was induced by MLDSTZ (40,mg/kg/day for 5 daily doses, i.p.). The IB treatment significantly suppressed the increase of blood glucose levels. Histological analysis of the pancreas showed that the degree of insulitis and destruction of ,-cells were reduced by IB treatment. The IFN-, production from stimulated splenic T lymphocytes was inhibited by the IB treatment. Moreover, the proportion of IFN-,-producing cells in the CD4+ population, which was increased by MLDSTZ, was significantly decreased by the IB treatment. These results suggest that IB has a preventative effect on autoimmune diabetes by regulating cytokine production. Copyright © 2002 John Wiley & Sons, Ltd. [source] Production of a recombinant cholera toxin B subunit-insulin B chain peptide hybrid protein by Brevibacillus choshinensis expression system as a nasal vaccine against autoimmune diabetesBIOTECHNOLOGY & BIOENGINEERING, Issue 7 2005Yoshikazu Yuki Abstract Mucosally induced tolerance is an attractive strategy for preventing or reducing autoimmune diseases. Here, we produced a recombinant CTB fusion protein linked with autoantigen T cell epitope of insulin B chain peptide 9,23 (C19S) at levels up to 200 mg/L culture media in Brevibacillus choshinensis secretion-expression system. Receptor-competitive assay showed that the CTB-insulin peptide binds to GM1 receptor almost equivalent degree as the native form of CTB. Non-obese diabetes (NOD) mice that spontaneously develop an insulin-dependent diabetes were nasally immunized with CTB-insulin peptide (5 µg) for three times. The nasal treatment significantly reduced the development of insulin-dependent diabetes and peptide specific DTH responses after systemic immunization with the insulin peptide B 9,23(C19S) in CFA. Nasal administration of as high as 50 µg of the peptide alone demonstrated a similar level of the disease inhibition. In contrast, all mice given 5 µg of the insulin peptide alone or 5 µg of insulin peptide with 25 µg of the free form of CTB did not lead to the suppression of diabetes development and DTH responses. Because molecular weight of the insulin peptide is about one tenth of that of the CTB-insulin peptide, the results demonstrate that the recombinant hybrid of autoantigen and CTB increased its tolerogenic potential for nasal administration by up 100-fold on molar base of autoantigen peptide. Taken together, nasally-induced tolerance by administration of the recombinant B.choshinensis -derived hybrid protein of CTB and autoantigen T cell-epitope peptide could be useful mucosal immunetherapy for the control of T cell-mediated autoimmune diseases. © 2005 Wiley Periodicals, Inc. [source] | ||||||||||||||||||||||