George S. Eisenbarth

Barbara Davis Center for Childhood Diabetes, University of Colorado, USA

Title: Trimolecular complex and endocrine autoimmunity

Abstract:

The principal genetic determinants of multiple endocrine autoimmune disorders are genes with the major histocompatibility complex, and different from many complex genetic disorders clinically useful disease prediction is possible for Type 1 diabetes and Addison’s disease.  From HLA typing of more than 30,000 newborns in Denver Colorado in the DAISY study headed by Dr. Marian Rewers, subsets with extreme risk can be identified.  General population children with the highest risk DR/DQ/DP genotype have a risk of 1/5 of developing islet autoimmunity while siblings of patients with diabetes with DR3/4-DQ2/8 highest risk genotype who inherited their HLA haplotypes identical by descent with sibling proband, have a risk exceeding 80% when followed from birth, and similar risk for progression to diabetes.  The exact mechanism determining such risk is unknown, but from studies of the NOD mouse model we believe it will relate to recognition of specific peptide presented by high risk class II alleles and recognized by specific non-stringent T cell receptor chains.  For the NOD mutating a single amino acid of the B:9-23 peptide prevents all diabetes.  This peptide is presented by I-Ag7 and recognized primarily by T cell receptors having the TRAV5D-4*04 TCRα variable region segment, despite multiple different N region sequences, Jα, and T cell receptor β chains.  Alpha chain only retrogenic mice (utilizing endogenous TCR β chains) with multiple different TRAV5D-4*04 alpha chains develop anti-insulin autoimmunity.  We hypothesize that a central substrate for loss of tolerance of the NOD mouse and potentially man are germline encoded components of the trimolecular complex.

Biography:

George S. Eisenbarth, MD, PhD, is currently the Executive Director of the Barbara Davis Center for Childhood Diabetes and Professor of Pediatrics, Medicine, and Immunology at the University of Colorado at Denver and Health Sciences Center and president of the Clinical Immunology Society.  After undergraduate training at Columbia University, Dr. Eisenbarth received his MD and PhD from Duke University Medical School in 1975, completed medical house staff and endocrine fellowship at Duke where we was first author for a NEJM manuscript describing that the Autoimmune Polyendocrine Type II Syndrome was HLA associated and screening of relatives of probands for multiple autoimmune disorders was of importance.  He pursued a postdoctoral fellowship in the Laboratory of Biochemical Genetics headed by Marshall Nirenberg at the NIH where he produced the first monoclonal anti-islet antibodies (A2B5) and, in collaboration with Barton Haynes and Anthony Fauci, some of the first anti-T cell monoclonals (CD-7 and anti-transferrin receptor).  Following his fellowship at the NIH he returned to Duke University to head a laboratory devoted to diabetes research which discovered the severe T cell lymphopenia of the BB rat and expression of class II positive T cells associated with Graves’ disease and type 1 diabetes.

In 1982 he moved to the Joslin Diabetes Center and Harvard Medical School where he founded its Immunology Section.  Dr. Eisenbarth's laboratory at Joslin discovered the linkage of diabetes of the NOD mouse to the MHC.  In 1986 he proposed the model that type I diabetes was a chronic autoimmune disorder with multiple Stages (based on discovery of progressive loss of first phase insulin secretion of prediabetic twins in the presence of islet autoantibodies) and that, with a combination of immunologic assays and progressive loss of insulin secretion, diabetes could be predicted. He instituted some of the first immunotherapy trials for type 1 diabetes, and in particular trials of anti-thymocyte globulin, with evidence of temporary disease remission, and, collaborating with Howard Weiner, described the ability of oral insulin to delay diabetes in the NOD mouse under the rubric of “oral tolerance”.   The prediction of type I diabetes advanced to the stage that trials for the prevention of type I diabetes were initiated.  In particular “Combinatorial Autoantibody Prediction” utilizing the presence of ≥2 biochemically determined autoantibodies is becoming the standard for disease prediction for type 1 diabetes and recently applied to multiple autoimmune disorders. With prediction possible, international consortia DPT-1 and Trialnet (and its predecessor DPT-1) have been pursuing prevention strategies with initial trials unable to delay disease, except potentially for a subset of individuals with high levels of insulin autoantibodies treated with oral insulin. 

After a decade at the Joslin Diabetes Center, Dr. Eisenbarth moved to the Barbara Davis Center, a Research Institute and Clinical Center devoted to type 1 diabetes, autoimmunity, and transplantation research.  Dr. Eisenbarth’s laboratory created the ancillary study of DPT with the measurement of “biochemical” autoantibodies, including the newly discovered ICA512bdc autoantigen, for the 100,000 relatives of DPT.  At the Barbara Davis Center, with colleague Marian Rewers (epidemiologist), the DAISY study was created which has applied immunogenetic and immunologic prediction of type 1 diabetes to infants from the general population, followed from birth with the discovery of extremely high risk groups and environmental factors influencing activation of both diabetes and celiac related autoimmunity and the initial description of the LYP(PTPN22) gene polymorphism in type 1 diabetes. A major focus of Dr. Eisenbarth’s laboratory has been autoimmunity directed at insulin and in particular the insulin peptide B:9-23.  His laboratory developed the high-throughput filtration insulin autoantibody assay that has become a standard and is applicable to both man and the NOD mouse.  In recent studies his laboratory has created an experimental autoimmune diabetes model in Balb/c mice using immunization with insulin peptide B:9-23, produced the first T cell transgenic mice targeting this peptide, and discovered that knocking out both the insulin 1 and insulin 2 gene with a mutated transgenic  preproinsulin (B16 alanine) gene in NOD mice prevents diabetes.  This has resulted in NOD mice with no diabetes, supporting the hypothesis that insulin may be the essential autoantigen for this very well studied model.  His laboratory has recently demonstrated a remarkable dependence of targeting of the B:9-23 peptide and autoimmunity based on a shared alpha chain of the T cell receptor.  This has led to the hypothesis that a primary autoantigen peptide, B:9-23, and a non-stringent T cell receptor recognition of such a peptide can underlie organ specific autoimmunity.  Insulin and its peptides can be used to prevent type 1 diabetes in animal models and the use of insulin and its peptides is an area of active study in man. 

Dr. Eisenbarth is the founder of the Immunology Section of the Joslin Diabetes Center, a founding member and past president of the Immunology of Diabetes Workshop/Society, and currently serves on the Editorial Boards of the journal Diabetes and the Journal of Clinical Endocrinology Metabolism.  Among many other awards he received the 1986 Outstanding Scientific Achievement Award by the American Diabetes Association, the 1997 David Rumbough Scientific Award by the  Juvenile Diabetes Foundation, the  2006 Laureate Pasteur-Weizmann/Servier International Prize and Tribute, and the 2009 Banting Prize for Outstanding Lifetime Scientific Achievement by the American Diabetes Association. Dr. Eisenbarth serves on the steering committees of TrialNet, TEDDY and the Immune Tolerance Network and is a founding member of the Brehm Coalition.