The goal of this application is a) to investigate anti-idiotypic antibodies (anti-Id) directed to the four major autoantibodies in human Type 1 Diabetes (T1D), and b) to develop anti-Id to selectively deplete autoantigen-reactive B lymphocytes as a novel therapy to prevent T1D. Anti-Id to a major autoantibody in T1D (GAD65Ab) are found in the majority of healthy individuals. These anti-Id specifically target the antigen-binding site of GAD65Ab and thus block antigen recognition. Anti- Id to another major autoantibody (IAA) have been described previously in both T1D patients and the BB rat - an animal model for T1D- indicating that these idiotypic networks may be of relevance for T1D pathogenesis. At clinical diagnosis patients with T1D have significantly lower GAD65Ab-specific anti-Id titers as compared to healthy individuals. Moreover, anti-Id activity correlates with beta cell function, as observed in a longitudinal analysis of children with new onset T1D, who experienced a transitional increase in c-peptide levels. These data strongly suggest that GAD65Ab-specific anti-Id are part of the regulatory immune response to GAD65 and may therefore protect against T1D. Recent findings that injections of NOD mice with a monoclonal anti-Id prevented T1D support this hypothesis of protective anti-Id. This application will determine when anti-Id activiy is lost during development of T1D. Longitudinal samples from progressors and non-progressors will be analyzed for anti-Id to establish whether loss of anti-Id activity in progressors precedes T1D development. Another aim is to determine whether known high-risk and protective HLA genotypes are associated with low and high anti-Id activity, respectively. Such an association would support the hypothesis that HLA risk/protection is mediated in part by anti-Id activity. Anti Id are described to have regulatory immune functions. They neutralize autoantibodies, downregulate autoantibody secretion, and induce depletion of antigen-specific B lymphocytes. These characteristics are already employed in the treatment of other autoimmune diseases. A role of B lymphocytes in T1D has been suggested in animal studies, and the recent Rituximab trial demonstrated that global B lymphocyte depletion has a beneficial effect on the preservation of beta cell function. However global B lymphocyte depletion also eliminates beneficial B lymphocytes and is not a realistic option for the prevention of T1D. To avoid the global depletion of B lymphocytes, autoantigen-Fc fusion proteins will be used as mimetics of anti-Id. These fusion proteins will deplete B lymphocytes that are reactive to all epitopes of the autoantigen, while anti-Id will only target B lymphocytes of a single antibody epitope specificity. Autoantigen-Fc fusion proteins of all four major autoantigens (insulin, GAD65, IA-2, and ZnT8) will be used in this approach. The results from this project will be crucial for the further development of a novel preventative therapy.

Public Health Relevance

To date no cure for Type 1 diabetes is available and new directions are necessary to identify pathogenic pathways to design prevention and intervention therapies. We identified a novel immune factor in the pathogenesis of Type 1 diabetes. While a protective role for similar factors has been described in other autoimmune diseases, this is a novel concept in Type 1 diabetes research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK026190-27
Application #
8868978
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
1980-01-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
27
Fiscal Year
2015
Total Cost
$367,981
Indirect Cost
$125,147
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Liimatainen, Suvi; Honnorat, Jerome; Pittock, Sean J et al. (2018) GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies. Orphanet J Rare Dis 13:55
Hampe, C S; Radtke, J R; Wester, A et al. (2018) Reduced display of conformational epitopes in the N-terminal truncated GAD65 isoform: relevance for people with stiff person syndrome or DQ8/8-positive Type 1 diabetes mellitus. Diabet Med :
Manto, Mario; Hampe, Christiane S (2018) Endocrine disorders and the cerebellum: from neurodevelopmental injury to late-onset ataxia. Handb Clin Neurol 155:353-368
Mulukutla, Surya N; Tersey, Sarah A; Hampe, Christiane S et al. (2018) Elevated unmethylated and methylated insulin DNA are unique markers of A+?+ ketosis prone diabetes. J Diabetes Complications 32:193-195
Mitoma, Hiroshi; Manto, Mario; Hampe, Christiane S (2018) Time Is Cerebellum. Cerebellum 17:387-391
Mitoma, Hiroshi; Manto, Mario; Hampe, Christiane S (2018) Immune-mediated cerebellar ataxias: Practical guidelines and therapeutic challenges. Curr Neuropharmacol :
Mitoma, Hiroshi; Manto, Mario; Hampe, Christiane S (2017) Immune-mediated cerebellar ataxias: from bench to bedside. Cerebellum Ataxias 4:16
Bansal, N; Hampe, C S; Rodriguez, L et al. (2017) DPD epitope-specific glutamic acid decarboxylase (GAD)65 autoantibodies in children with Type 1 diabetes. Diabet Med 34:641-646
Mitoma, Hiroshi; Manto, Mario; Hampe, Christiane S (2017) Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias. J Immunol Res 2017:2913297

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