2015 Poll Visiting Scientist Lecture
Kevan C. Herold, MD
Professor of Immunology and of Medicine (Endocrinology)
Director, Yale Diabetes Center
Deputy Director for Translational Science, YCCI
Yale School of Medicine
Chris Hampe, Ph.D.
Research Associate Professor
Metabolism, Endocrinology, & Nutrition
Islet Cell Membrane Antibodies in Diabetes
"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 activity 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."