Plasmapheresis in the initial treatment of insulin-dependent diabetes mellitus in children.

Ludvigsson, Johnny; Heding, L. G.; Liedén, Gudrun; Marner, B.; Lernmark, Åke

doi:10.1136/bmj.286.6360.176

Cited by 141 publications

(59 citation statements)

References 14 publications

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“…The study serves as an illustration of the benefit of T-cell studies in unravelling the aetio-pathogenesis of autoimmune disease. Although this recent finding should not be interpreted as proof that autoantibodies are not relevant in the disease process, it is in line with earlier observations showing lack of efficacy of immunotherapy directed against the humoral immune response, such as plasmapheresis or intravenous immunoglobulin therapy [26].…”

supporting

confidence: 82%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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supporting

confidence: 82%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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“…Residual insulin secretion facilitates metabolic control and decreases the risk of keto-acidosis [3], and even modest beta cell function, with stimulated C-peptide above 0.2 nmol/l, may reduce long-term complications [4]. Type 1 diabetes is an autoimmune disease [5]; however, most attempts to use immune intervention to preserve residual beta cell function have achieved limited benefits or have been associated with adverse effects [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Treatment with anti-CD3 monoclonal antibodies appears to be the most promising treatment to date, but several patients treated in this way, as well as with anti-CD20 monoclonal antibodies, have experienced treatment-related adverse events [20,21].…”

Section: Introductionmentioning

confidence: 99%

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

et al. 2010

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Aims/hypothesis The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD 65 (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Methods Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 μg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. Results One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GADalum group fasting C-peptide was 0.332±0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354± 0.039 and 0.184±0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GADalum group than in the placebo-treated group after 4 years.

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“…Serum #673 is the World Health Organization (WHO) standard 97/550 [16] and serum sample #622 was derived from a set of ten well characterized sera from T1D patients [17,18]. The monoclonal antibodies included and N-GAD65mAb [20], and recognized epitopes located at the C-and the N-terminus, respectively.…”

Section: Gad65 Radioligand Binding Competition Assaymentioning

confidence: 99%

Antigen presentation of detergent-free glutamate decarboxylase (GAD65) is affected by human serum albumin as carrier protein

Steed

Gilliam

Harris³

et al. 2008

Journal of Immunological Methods

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SummaryThe smaller isoform of glutamate decarboxylase (GAD65) is a major autoantigen in type 1 diabetes (TID). Its hydrophobic character requires detergent to keep the protein in solution, which complicates studies of antigen processing and presentation. In this study an attempt was made to replace detergent with human serum albumin (HSA) for in vitro antigen presentation. Different preparations of recombinant human GAD65 complexed with HSA were incubated with Priess B cells (HLA DRB1*0401) and antigen presentation was tested with HLA DRB1*0401-restricted and epitopespecific T33.1 (GAD65 epitope 274-286) and T35 (GAD65 epitope 115-127) T cell hybridomas. Specific epitope recognition by T33.1 (274-286) and T35 (115-127) cells varied between the different GAD65/HSA preparations, and a reverse pattern of antigen presentation were detected by the two hybridoma. The HSA-specific T-cell hybridoma 17.9 response to the different GAD65/HSA preparations followed the same pattern as that observed for the T33.1 cells. The content of immunoreactive GAD65 measured with four GAD65 antibodies indicated that the lowest GAD65 concentration resulted in the highest 274-286, but the lowest 115-127 presentation. This suggests that HSA-GAD65 complexes qualitatively affect the epitope specificity of GAD65 presentation. HSA may enhance the 274-286 epitope presentation, while suppressing the 115-127 epitope.Keywords antigen presentation; GAD65; Human serum albumin; T cell assay; Type 1 diabetes; T cells; Diabetes; Autoimmunity; Antigen Presentation/Processing IntroductionType 1 diabetes mellitus (TID) is an autoimmune disease that results in the specific destruction of the pancreatic islet beta cells. The smaller isoform of glutamate decarboxylase (GAD65) is implicated as a major contributing autoantigen in the pathogenesis of beta cell destruction [1,2]. Autoantibodies directed to GAD65 (GAD65Ab) are present in the majority of new onset T1D patients [3,4] and GAD65-specific T cells have been identified in T1D patients and in spontaneously diabetic NOD mice and BB rats (for review see [5,6] [9]. The establishment of a standard T cell assay remains critical for the understanding of GAD65 antigen uptake, processing and presentation.GAD65, which catalyzes the generation of the neurotransmitter GABA, is associated with intracellular membranes [10,11]. In vitro, the highly hydrophobic GAD65 requires detergents to remain in solution [12]. However, because detergents are extremely cytotoxic, it is critical that the detergent is removed prior to incubation with antigen-presenting cells (APC) and responder T cells.In the present study, we tested the well known property of human serum albumin (HSA) to maintain proteins of hydrophobic character in solution (for review see [13,14]). The aim of our study was to test whether GAD65 complexed with HSA affected antigen presentation by human Priess B cells to two GAD65-and one HSA-specific specific HLA-matched T cell hybridoma as readouts of antigen presentation. The specific epitope response of the two ...

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Plasmapheresis in the initial treatment of insulin-dependent diabetes mellitus in children.

Cited by 141 publications

References 14 publications

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

Antigen presentation of detergent-free glutamate decarboxylase (GAD65) is affected by human serum albumin as carrier protein

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