GAD Autoantibody Epitope Pattern After GAD-alum Treatment in Children and Adolescents with Type 1 Diabetes

Overview

Journal Pediatr Diabetes

Publisher Wiley

Specialties Endocrinology
Pediatrics

Date 2011 Aug 19

PMID 21848927

Citations 2

Authors

Camilla Skoglund

Mikael Cheramy

Rosaura Casas

Johnny Ludvigsson

Christiane S Hampe

Affiliations

Soon will be listed here.

Abstract

Aims: We have previously shown that two injections of glutamic acid decarboxylase formulated in alum (GAD-alum) preserved residual insulin secretion in children and adolescents with recent onset type 1 diabetes (T1D), and was accompanied by increased GAD autoantibody (GADA) titers. The aim of this study was to investigate whether GAD-alum treatment affected the GADA epitope pattern.

Methods: Serum samples from patients treated with GAD-alum (n = 33) or placebo (n = 27), at baseline, 1, 3, 9, and 15 months after the initial injection, were tested for their binding capacity to specific GADA epitopes in an epitope-specific radioligand binding assay with six recombinant Fab (rFab) (b96.11, DPA, DPD, MICA3, b78, and N-GAD(65) mAb).

Results: No significant differences in variability of binding to any of the tested rFab were observed from baseline to 15 months. There was a sustained low binding of GADA to the b78- and N-GAD(65) mAb-defined epitopes, often recognized by GADA in patients with stiff person syndrome (SPS) and seldom in T1D patients. However, binding of GADA to the T1D-associated b96.11-defined epitope increased between baseline and 3 months in GAD-alum (-8.1%, min -72.4%, max 39.6%) compared to placebo patients (1.5%, min -28.3%, max 28.6%) (p = 0.02). Subsequently, the b96.11-defined epitope recognition returned to levels similar to that observed at baseline.

Conclusions: GAD-alum injections did not affect binding of GADA to SPS-related epitopes, further supporting the safety of the treatment. There were no changes in GADA epitope specificity to the T1D-related epitopes, except for a temporarily increased binding to one of the tested epitopes.

Citing Articles

GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Hampe C, Shojaie A, Brooks-Worrell B, Dibay S, Utzschneider K, Kahn S J Endocr Soc. 2024; 8(3):bvad179.

PMID: 38333889 PMC: 10853002. DOI: 10.1210/jendso/bvad179.

Characteristics of in-vitro phenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals.

Cheramy M, Hampe C, Ludvigsson J, Casas R Clin Exp Immunol. 2013; 171(3):247-54.

PMID: 23379430 PMC: 3569531. DOI: 10.1111/cei.12026.

References

Agardh C, Cilio C, Lethagen A, Lynch K, Leslie R, Palmer M . Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications. 2005; 19(4):238-46. DOI: 10.1016/j.jdiacomp.2004.12.003. View

Skyler J, Krischer J, Wolfsdorf J, Cowie C, Palmer J, Greenbaum C . Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1. Diabetes Care. 2005; 28(5):1068-76. DOI: 10.2337/diacare.28.5.1068. View

Padoa C, Crowther N, Thomas J, Hall T, Bekris L, Torn C . Epitope analysis of insulin autoantibodies using recombinant Fab. Clin Exp Immunol. 2005; 140(3):564-71. PMC: 1809383. DOI: 10.1111/j.1365-2249.2005.02802.x. View

Tisch R, Yang X, Liblau R, McDevitt H . Administering glutamic acid decarboxylase to NOD mice prevents diabetes. J Autoimmun. 1994; 7(6):845-50. DOI: 10.1006/jaut.1994.1067. View

Raju R, Foote J, Banga J, Hall T, Padoa C, Dalakas M . Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients. J Immunol. 2005; 175(11):7755-62. DOI: 10.4049/jimmunol.175.11.7755. View

Richter W, Endl J, Eiermann T, Brandt M, Kientsch-Engel R, Thivolet C . Human monoclonal islet cell antibodies from a patient with insulin-dependent diabetes mellitus reveal glutamate decarboxylase as the target antigen. Proc Natl Acad Sci U S A. 1992; 89(18):8467-71. PMC: 49941. DOI: 10.1073/pnas.89.18.8467. View

Orban T, Farkas K, Jalahej H, Kis J, Treszl A, Falk B . Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy. J Autoimmun. 2009; 34(4):408-15. PMC: 2860016. DOI: 10.1016/j.jaut.2009.10.005. View

Eldor R, Kassem S, Raz I . Immune modulation in type 1 diabetes mellitus using DiaPep277: a short review and update of recent clinical trial results. Diabetes Metab Res Rev. 2009; 25(4):316-20. DOI: 10.1002/dmrr.942. View

Mire-Sluis A, Das R, Lernmark A . Standardization of antibody preparations for use in immunogenicity studies: a case study using the World Health Organization International Collaborative Study for Islet Cell Antibodies. Dev Biol (Basel). 2003; 112:153-63. View

10.

Fenalti G, Hampe C, Arafat Y, Law R, Banga J, Mackay I . COOH-terminal clustering of autoantibody and T-cell determinants on the structure of GAD65 provide insights into the molecular basis of autoreactivity. Diabetes. 2008; 57(5):1293-301. DOI: 10.2337/db07-1461. View

11.

Baekkeskov S, Aanstoot H, Christgau S, Reetz A, Solimena M, Cascalho M . Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990; 347(6289):151-6. DOI: 10.1038/347151a0. View

12.

Ronkainen M, Hoppu S, Korhonen S, Simell S, Veijola R, Ilonen J . Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes. Eur J Endocrinol. 2006; 155(4):633-42. DOI: 10.1530/eje.1.02271. View

13.

Padoa C, Banga J, Madec A, Ziegler M, Schlosser M, Ortqvist E . Recombinant Fabs of human monoclonal antibodies specific to the middle epitope of GAD65 inhibit type 1 diabetes-specific GAD65Abs. Diabetes. 2003; 52(11):2689-95. DOI: 10.2337/diabetes.52.11.2689. View

14.

Ronkainen M, Savola K, Knip M . Antibodies to GAD65 epitopes at diagnosis and over the first 10 years of clinical type 1 diabetes mellitus. Scand J Immunol. 2004; 59(3):334-40. DOI: 10.1111/j.0300-9475.2004.01402.x. View

15.

Muir A, Peck A, Clare-Salzler M, Song Y, Cornelius J, Luchetta R . Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest. 1995; 95(2):628-34. PMC: 295528. DOI: 10.1172/JCI117707. View

16.

Hjorth M, Axelsson S, Ryden A, Faresjo M, Ludvigsson J, Casas R . GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells in type 1 diabetic patients. Clin Immunol. 2010; 138(1):117-26. DOI: 10.1016/j.clim.2010.10.004. View

17.

Baekkeskov S, Kanaani J, Jaume J, Kash S . Does GAD have a unique role in triggering IDDM?. J Autoimmun. 2000; 15(3):279-86. DOI: 10.1006/jaut.2000.0443. View

18.

Kaufman D, Clare-Salzler M, Tian J, Forsthuber T, Ting G, Robinson P . Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993; 366(6450):69-72. PMC: 8216222. DOI: 10.1038/366069a0. View

19.

Bekris L, Jensen R, Lagerquist E, Hall T, Agardh C, Cilio C . GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccination. Diabet Med. 2007; 24(5):521-6. DOI: 10.1111/j.1464-5491.2007.02091.x. View

20.

Tisch R, McDevitt H . Antigen-specific immunotherapy: is it a real possibility to combat T-cell-mediated autoimmunity?. Proc Natl Acad Sci U S A. 1994; 91(2):437-8. PMC: 42963. DOI: 10.1073/pnas.91.2.437. View