Check GAD antibody positivity with the Diamyd anti-GAD RIA plate*

GAD Back to the Future…Åke LernmarkÅke Lernmark, MD, Ph.D., is R.H.Williams Professor of Medicine atthe University of Washington inSeattle. Lernmark focused hisattention on diabetes and theantigen that later proved to beGAD at an early stage. Lernmarkwas first to demonstrate the presenceof antibodies against GADin patients with insulin-dependentdiabetes, and to use molecularmethods to define HLA genes thatare necessary, but not sufficient todevelop the disorder.The beta cell specific loss associated withthe clinical onset of Type 1 diabetesmellitus (T1DM) is a remarkable phenomenon.The ablation of the insulinproducingcells does not seem to affectneighboring cells producing glucagon,somatostatin or pancreas polypeptide. The eradication of thebeta cells is a testimony to the laser knife-like precision ofthe immune system to recognize and attack antigen. Theimmune mediated loss of beta cells is well documented inpancreas specimens from T1DM patients of short diseaseduration. The degree and character of the inflammatory cellinfiltration vary from patient to patient and would not predictclinical onset. The loss of beta cells appears more predictiveand the major question that we and others try to answeris whether the immune attack on the beta cells can bereversed by controlling the autoimmune reaction againstglutamic acid decarboxylase (GAD65) either before or afteronset. While autoantibodies to insulin and IA-2 are predictiveof T1DM primarily in the young, the predictive value ofGAD65 autoantibodies appears less age-dependent. It is thereforeoften argued that GAD65 is the major autoantigen inT1DM, which is consistent with GAD65 autoantibodiesbeing most prevalent (more than 80% of new onset patients)at onset. Although recent follow up studies suggestthat GAD65 autoantibodies are not necessarily the firstautoantibody to appear before the clinical diagnosis is made,appearance of all three autoantibodies to GAD65, IA-2 andinsulin is the best predictor of disease. Recognition ofGAD65 by helper CD4 and killer CD8 positive cells are likelyto precede the autoantibody appearance. At present,there is a lack of reliable and standardized tests that detectT cell reactivity against islet autoantigens (1). This is in contrastto GAD65 and IA-2 autoantibodies, which can be reliablymeasured against a WHO standard (2). At least therewill be one reliable way to monitor whether SpecificImmune Therapy (SIT) with GAD65 might alter the courseof T1DM disease associated autoimmunity.Following the molecular cloning of the human (3) androdent GAD proteins (4) it was possible to carry out experimentswith recombinant GAD65 to demonstrate that spontaneousdiabetes in the NOD mouse (5, 6) was preventable.Of equal importance was the observation that diabetes wasnot inducible by GAD65 in rats (7) and mice (8). T1D thereforedid not immediately seem to mimic other autoimmunediseases, which have animal models that are based on theactual immunization of an autoantigen. About 10 yearsafter the demonstration that NOD mouse diabetes was preventable,Phase I (toxicity) and Phase II (safety) clinical trialsof GAD65 have been completed. In the absence of adverseevents among the GAD65 autoantibody positive Type 2 diabetespatients (so-called LADA patients or LatentAutoimmune Diabetes in the Adult) it may now be possibleto move into Phase III clinical trials to test whetherGAD65 SIT is efficacious.The future approach to determine whether GAD65 SIT1994Researchers showthat transplantedislets survivelonger if they arepretreated withGAD1998Researcherstransfer diabetesbetween animalswith GAD-reactiveT cellsStart ofPhase Iclinical trialDiamyd Phase Iclinical trial in 24healthyindividualscompletedDiamyd Medicalinitiatesdevelopment of aGAD baseddiabetes vaccine1996Researchers showthat progressionto T1DM isassociated with achange in GADAisotypes1999Researchers showthat ß-cellexpression of GADis required fordevelopment ofT1DM in the NODmouse2000Start of Phase IIclinical trial