GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Chéramy, Mikael; Skoglund, Camilla; Johansson, I.; Ludvigsson, Johnny; Hampe, Christiane S.; Casas, Rosaura

doi:10.1016/j.clim.2010.06.001

Cited by 36 publications

(44 citation statements)

References 36 publications

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“…Further analysis of the collected samples revealed an early (one month after treatment) and sustained (9 months after treatment) increase in GAD-specific IL-5 and IL-13 responses (Axelsson et al 2010). GAD-alum treatment also led to increases in IgG3/IgG4 and decreases in IgG1 (Cheramy et al 2010), as well as increases in GAD65-specific CD4 þ CD25 hi Foxp3 þ T cells . Patients who had been treated with GAD-alum within 6 months of diagnosis had better preservation of fasting Cpeptide levels than those that were treated later , although these beneficial effects did not translate into reduced insulin requirement.…”

Section: Protein/peptide-based Immunotherapies Gadmentioning

confidence: 99%

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Clemente-Casares

Tsai²,

Huang³

et al. 2011

Cold Spring Harbor Perspectives in Medicine

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Development of strategies capable of specifically curbing pathogenic autoimmune responses in a disease-and organ-specific manner without impairing foreign or tumor antigen-specific immune responses represents a long sought-after goal in autoimmune disease research. Unfortunately, our current understanding of the intricate details of the different autoimmune diseases that affect mankind, including type 1 diabetes, is rudimentary. As a result, progress in the development of the so-called "antigen-specific" therapies for autoimmunity has been slow and fraught with limitations that interfere with bench-tobedside translation. Absent or incomplete understanding of mechanisms of action and lack of adequate immunological biomarkers, for example, preclude the rational design of effective drug development programs. Here, we provide an overview of antigen-specific approaches that have been tested in preclinical models of T1D and, in some cases, human subjects. The evidence suggests that effective translation of these approaches through clinical trials and into patients will continue to meet with failure unless detailed mechanisms of action at the level of the organism are defined.C urrent approaches toward a potential cure for Type I diabetes (T1D) have focused on three main targets: (1) ablation of the b-cell-specific autoimmune response; (2) b-cell replacement therapy using islet transplantation; and (3) potentiation of b-cell mass and function using pharmacologic agents capable of promoting b-cell proliferation, regeneration and/or repair.Pancreasandislet-transplantationin thecontext of systemic immunosuppression are the only approaches that have afforded patients complete independence from exogenous insulin. However, they have also highlighted the fact that, in the absence of immunosuppression, transplantation invariably meets with failure. For example, although 70% of islet-grafted patients remain insulin independent 1 year after transplantation, a significant fraction of them revert to insulindependency within 5 years, albeit with significantly lower insulin needs (Shapiro et al. 2000Merani and Shapiro 2006;Robertson 2010). Because disease recurrence is typically associated with an anamnestic autoimmune response against the grafted tissue (Laughlin et al.

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Section: Protein/peptide-based Immunotherapies Gadmentioning

confidence: 99%

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Clemente-Casares

Tsai²,

Huang³

et al. 2011

Cold Spring Harbor Perspectives in Medicine

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“…Despite the low rate of complications reported, there is a potential risk for more serious effects related to immunosuppression. (107,110). Mesenchymal stem cell therapies and combination of multiple immunomodulatory drugs are currently under study.…”

Section: Methods Of Preserving Pancreatic Functionmentioning

confidence: 99%

“…Immunosuppressive therapy, such as cyclosporine, azathioprine, prednisone, and antithymocyte globulin, aiming for depletion and inactivation of cells, were used in newly diagnosed patients, but with limited efficacy and temporary effects due to its toxicity (104). Immunomodulators, such as anti-CD3 monoclonal antibodies, used in newly diagnosed T1DM also allowed the maintenance of the secretion of CP for one to two years with low toxicity, and benefits in glycemic control (105)(106)(107). After 48 months of follow up, patients who received the monoclonal antibodies anti-CD3 had lower daily insulin requirements, with improved A1C and glycemic variations smaller than the control.…”

Section: Methods Of Preserving Pancreatic Functionmentioning

confidence: 99%

Understanding Pancreatic Secretion in Type 1 Diabetes

Almeida¹,

Matheus²,

Lima³

2011

Type 1 Diabetes Complications

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“…[234]. Additionally, high titers of GAD autoantibodies (GADA) at baseline were related to a better clinical outcome in terms of C-peptide preservation [244]. Analysis of in vitro stimulated cytokine secretion and FOXP3 mRNA revealed secretion of IL-5 and IL-13 by peripheral blood mononuclear cells (PBMC), as well as increased expression of FOXP3 mRNA one month after the first injection.…”

Section: Phase II Trial In Childrenmentioning

confidence: 99%

Regin in Blood Immune Regulation in Type 1 Diabetes

Pihl¹

2013

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Type 1 Diabetes (T1D) is an autoimmune disease resulting in insulin deficiency as a result of autoimmune destruction of pancreatic β-cells. Preserving β-cell function in patients with T1D would be of great benefit since patients with sustained endogenous insulin secretion are known to suffer less from secondary complications due to hyperglycemia. Glutamic acid decarboxylase 65 (GAD 65 ) is a major autoantigen targeted by self-reactive lymphocytes in T1D, and has been used in several attempts at treating T1D by inducing tolerance to β-cell antigens. We showed positive clinical effects of GAD 65 formulated with aluminium hydroxide (GAD-alum) on preservation of C-peptide secretion in a phase II clinical trial. Unfortunately, a phase III clinical trial in a larger population failed to confirm this finding. Regulatory T cells (Treg) are instrumental in maintaining peripheral tolerance to self-antigens. Deficiencies in Treg function are thought to influence the pathogenesis of autoimmune diseases, including T1D. One proposed mechanism of achieving tolerance to β-cell antigens in T1D is the induction of antigen-specific Treg through immunomodulation. The general aim of this thesis was to study immune regulation in T1D, the role of Treg and immunomodulatory effects of GAD-alum treatment in particular. Our hypothesis was that Treg biology is altered in T1D and pre-diabetes, and that an induction of GAD 65 -specific Treg contributes to the clinical efficacy of GAD-alum treatment. We demonstrated that T cells expressing Treg-associated markers were increased in number in patients with recent-onset T1D, as well as in children with high risk of developing T1D. We found that antigen recall 4 years after GAD-alum treatment induced cells with both regulatory and effector phenotypes in GAD-alum treated patients. Furthermore there was no effect on Treg-mediated suppression in GAD-alum treated patients, while patients with T1D, regardless of treatment, exhibited deficient Treg-mediated suppression of Teff that was intrinsic to the Treg population. We followed patients participating in a phase III trial of GAD-alum, and using an extended antibody panel we risk, but found no effects of variant alleles on the risk of developing T1D, or on the efficacy of GAD-alum treatment. We show small effects on C-peptide secretion and autoantibody positivity in patients with T1D. In conclusion, we find that while Treg are deficient in patients with T1D, induction of Treg is an unlikely mechanism of action of GAD-alum treatment. SUPERVISOR

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GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Cited by 36 publications

References 36 publications

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

Understanding Pancreatic Secretion in Type 1 Diabetes

Regin in Blood Immune Regulation in Type 1 Diabetes

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