GAD Autoantibody Affinity in Adult Patients With Latent Autoimmune Diabetes, the Study Participants of a GAD65 Vaccination Trial

Krause, Stephanie; Landherr, Ulrike; Agardh, Carl‐David; Hausmann, Simone; Link, Katarina; Hansen, Jesse M; Lynch, Kristian; Powell, Michael J.; Furmaniak, Jadwiga; Rees-Smith, Bernard; Bonifacio, Ezio; Ziegler, Anette G.; Lernmark, Åke; Achenbach, Peter

doi:10.2337/dc13-1719

Cited by 43 publications

(47 citation statements)

References 20 publications

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“…In addition, high titer GADA tended to remain positive with high GADA titer in contrast to low titer GADA and was less evanescent. These results mirror previous smaller European studies, which showed the more aggressive nature of the disease, allied to GADA persistence, in those with "high levels" of GADA (28) and "high autoantibody affinity" (29). In this latter study, GADA affinity correlated strongly with GADA titer, and low affinity GADA was associated with prolonged preservation of FCP, as was low titer GADA in our present study.…”

Section: Discussionsupporting

confidence: 79%

“…A recent small, but detailed, European study of b-cell function and insulin sensitivity also found no differences between LADA and type 2 diabetes (30). Also, in our present study, 74.4% of low-GADA titer patients became GADA negative versus only 8.3% for high-GADA titer patients, so low GADA titer is an unstable state that reflects a limited degree of autoimmunemediated destruction, unrelated to progression to type 1 diabetes (29) or, indeed, only reflects the systemic inflammation characteristic of type 2 diabetes (31,32). It was reported that GADA could result from distinct immunization events, in which those children with high-affinity GADA and/or epitope specificity are at high risk of type 1 diabetes (33).…”

Section: Discussionmentioning

confidence: 47%

“…In LADA there is a broad range of progression in b-cell function, GADA titer, and GADA affinity. These three features have been shown to be positively associated both now in Chinese as well as previously in Europeans (29). It follows that there is an association between GADA and the destructive autoimmune effect.…”

Section: Discussionmentioning

confidence: 74%

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Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes

Liu

Xiang

et al. 2014

Diabetes Care

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OBJECTIVEThis study investigated the relationship between GAD autoantibody (GADA) titers and changing of b-cell function in patients with latent autoimmune diabetes in adults (LADA). RESEARCH DESIGN AND METHODSThis 3-year prospective study enrolled 95 subjects from 15 Chinese cities including 25 high-titer (GADA ‡180 units/mL) LADA patients, 42 low-titer (GADA <180 units/mL) LADA patients, and 28 type 2 diabetic patients, the latter two groups as controls of similar age, sex, and BMI. Clinical characteristics were determined annually, including glycosylated hemoglobin (HbA 1c ), fasting C-peptide (FCP), and 2-h postprandial C-peptide (PCP). RESULTSDespite similar initial FCP and PCP, FCP and PCP both decreased more in subjects with high GADA titer (FCP from mean 0.49 nmol/L at entry to 0.13 nmol/L at the third year; P < 0.05) than with low GADA titer (FCP from mean 0.48 to 0.38 nmol/L) and type 2 diabetes (FCP from mean 0.47 to 0.36 nmol/L); the latter two groups being similar. After 3 years, residual b-cell function (FCP >0.2 nmol/L) was detected in only 42% with an initial high GADA titer compared with 90% with a low GADA titer and 97% with type 2 diabetes (P < 0.01 for both). GADA positivity at the third year persisted more in subjects with initially high GADA (92%) than with low GADA (26%) titers (P < 0.01). CONCLUSIONSIn selected LADA patients, initial GADA titers identified subjects with different degrees of persistent autoimmunity and disease progression. LADA patients with a low GADA titer had metabolic phenotypes and loss of b-cell function similar to type 2 diabetic patients.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 47%

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Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes

Liu

Xiang

et al. 2014

Diabetes Care

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“…Second, the manner in which antigens have been delivered may not induce a protective response. In a recent trial of alumGAD65, high titers of anti-GAD65 antibodies were induced but the therapy did not alter the progression of disease(99, 100). Strategies that have been successful in allergic diseases, such as early oral administration of antigen have not been tested.…”

Section: Can Better Trials Deliver Better Results?mentioning

confidence: 99%

Progress and challenges for treating Type 1 diabetes

Garyu

Meffre

Cotsapas

et al. 2016

Journal of Autoimmunity

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It has been more than 30 years since the initial trials of Cyclosporin A to treat patients with new onset Type 1 diabetes (T1D). Since that time, there have been insights into genetic predisposition to the disease, the failures of immune tolerance, and mechanisms that cause the immune mediated β cell destruction. The genetic loci associated affect lymphocyte development and tolerance mechanisms. Discoveries related to the roles of specific immune responses gene such as the major histocompatibility complex, PTPN22, CTLA-4, IL-2RA, as well as the mechanisms of antigen presentation in the thymus have suggested ways in which autoreactivity may follow changes in the functions of these genes that are associated with risk. Antigens that are recognized by the immune system in patients with T1D have been identified. With this information, insights into the novel cellular mechanisms leading to the initiation and orchestration of β cell killing have been developed such as the presentation of unique antigens within the islets. Clinical trials have been performed, some of which have shown efficacy in improving β cell function but none have been able to permanently prevent loss of insulin secretion. The reasons for the lack of long term success are not clear but may include the heterogeneity of the immune response and in individual responses to immune therapies, recurrence of autoimmunity after the initial effects of the therapies, or even intrinsic mechanisms of β cell death that proceeds independently of immune attack after initiation of the disease. In this review, we cover developments that have led to new therapeutics and characteristics of patients who may show the most benefits from therapies. We also identify areas of incomplete understanding that might be addressed to develop more effective therapeutic strategies.

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“…In the model, quiescent autoreactive T cells (including memory clones) are re-exposed to β-cell antigens (islet graft) [46] and metabolic inhibition could be envisaged as an induction therapy in this clinical setting. With respect to the natural history of T1D, however, one possibility would be to associate metabolic blockade to antigen specific vaccination with β-cell associated antigens [47] such as GAD65 [48]. The duration of the treatment is an important issue.…”

Section: Targeting T-cell Metabolism In Type 1 Diabetesmentioning

confidence: 99%

T-cell Metabolism as a Target to Control Autoreactive T Cells in β-Cell Autoimmunity

et al. 2017

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Purpose of reviewAn increasing body of evidence indicates that bio-energetic metabolism of activated T cells is a potential target to control the autoimmune response in type 1 diabetes (T1D).Recent findingsT-cell activation and proliferation is linked to the cell capacity to provide sufficient energy and biosynthesis molecules to support T-cell growth and division. This makes T cells susceptible to metabolic inhibition for the control of the T-cell response. There is a wide therapeutic arsenal of metabolic inhibitors, including novel classes of drugs that have become recently available.SummaryWith the current knowledge and availability of metabolic inhibitors, we are now in the position to design a metabolic inhibition strategy to determine whether targeting of autoreactive T cells is an effective strategy to control the process of β-cell destruction in T1D.

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GAD Autoantibody Affinity in Adult Patients With Latent Autoimmune Diabetes, the Study Participants of a GAD65 Vaccination Trial

Abstract: Intervention with GAD-alum in LADA patients had no effect on GADA affinity. Our data suggest that patients with low GADA affinity have a prolonged preservation of residual β-cell function.

Cited by 43 publications

References 20 publications

Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes

Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes

Progress and challenges for treating Type 1 diabetes

T-cell Metabolism as a Target to Control Autoreactive T Cells in β-Cell Autoimmunity

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