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

is truly inducing immune tolerance, deviation, or both, is tocarefully move from adult patients who already have diabetessuch as LADA patients to new onset adult T1DM patientsand then possibly to triple autoantibody positive firstdegree relatives since our ability to predict disease in suchsubjects is now well documented thanks to the DPT-1study with parenteral insulin administration (9). Theattempts to approach prevention in the fashion modeled inanimals will by necessity require a carefully staked outpathway. Novel observations are particularly tantalizing asto the possibility to use GAD65 SIT and cause no harm inhealthy subjects.The beta cell expression of GAD65 in human beta cells iswell established. There is a lack of qualitative and quantitativestudies on GAD65 in the non-insulin producing endocrineislet cells. Also, we still do not fully understand the roleof GABA for normal beta cell function. Recent observationssuggest that increased body mass index (BMI) is associatedwith GAD65 autoantibodies in subjects not developing diabetes(10, 11). It will be critical to find out if subclinicalGAD65 autoimmunity is related to obesity phenotypes arisingbecause of altered beta cell function, insulin resistance,or both. Future studies will also require detailed studies ofGAD65 gene expression in CNS areas controlling food intakesince GAD65 gene polymorphisms affecting GABA productionmay be related to morbid obesity (P. Boutin and P.Frougel, personal communication). The role of GAD65 genepolymorphism in food intake regulation, obesity developmentand beta cell function may therefore need to be furtherstudied before we can embark on large scale GAD65SIT.The relationship between Stiff Man Syndrome and GADautoimmunity was critical to the demonstration that T1DMsera immunoprecipitated 64K protein with GAD enzymeactivity (12). We have now learned that the immune responseto GAD65 in SMS is qualitatively and quantitatively diffferentfrom T1DM and the approach to prevent either SMS,T1DM, or both may require differentGAD65 SIT. One approach may be tobase the SIT on the HLA associationwith the disease. In the InsulinAutoimmune Syndrome the autoantibodyformation is strongly associatedwith HLA DRB1*0401. This haplotypeis insufficient for the association withinsulin autoantibodies in T1DM, whichis rather associated with HLADQA1*0501-B1*0201. Hence insulin aswell as GAD65 is the autoantigen ofmore than one disorder of autoimmunecharacter. Future studies will needto take these similarities and differencesinto account to design interventiontrials that may lead to the identificationof novel approaches to prevent orreverse autoantigen-specific autoimmunity.Don’t sit around, GAD back tothe future…References1. Peakman M, et al,Characterization of preparations of GAD65, proinsulin, and the islet tyrosinephosphatase IA-2 for use in detection of autoreactive T cells in Type 1 diabetes:report of phase II of the Second International Immunology of Diabetes SocietyWorkshop for Standardization of T cell assays in Type 1 diabetes.Diabetes 50:1749-1754, 2001.2. Mire-Sluis AR, et al,The World Health Organization International Collaborative Study for Islet CellAntibodies.Diabetologia 43:1282-1292., 2003. Karlsen AE, et al,Cloning and primary structure of a human islet isoform of glutamic acid decarboxylasefrom chromosome 10.Proc Natl Acad Sci US 88:8337-8341, 1991.4. Kaufman DJ, et al,Autoimmunity to two forms of glutamate decarboxylase in Insulin-dependentdiabetes mellitus.J. Clin. Invest. 89:283-292, 19925. Kaufman DL, et al,Spontaneous loss of T cell tolerance to glutamic acid decarboxylase in murineinsulin-dependent diabetes.Nature 366:69-72, 1993.6. Tisch R, et al,Immune response to glutamic acid decarboxylase correlates with insulitis in nonobesediabetic mice.Nature 366:72-75, 1993.7. Bieg S, et al,GAD65 and insulin B chain peptide (9-23) are not primary autoantigens in theType 1 diabetes syndrome of the BB rat.Autoimmunity 31:15-24, 1999.8. Plesner A, et al,Immunization of diabetes-prone or non-diabetes-prone mice with GAD65 doesnot induce diabetes or islet cell pathology.J Autoimmun 11:335-341, 1998.9. DPT-1: Effects of insulin in relatives of patients with Type 1 diabetes mellitus. NEngl J Med 346:1685-1691, 2002.10. Rolandsson O, et al,Levels of glutamate decarboxylase (GAD65) and tyrosine phosphatase-like protein(IA-2) autoantibodies in the general population are related to glucose intoleranceand body mass index.Diabetologia 42:555-559, 1999.11. Weets I, et al,Male-to-female excess in diabetes diagnosed in early adulthood is not specific forthe immune-mediated form nor is it HLA-DQ restricted: possible relation toincreased body mass index.Diabetologia 44:40-47, 2001.12. Baekkeskov S, et al,Identification of the 64K autoantigen in insulin-dependent diabetes as the GABAsynthesizingenzyme glutamic acid decarboxylase.Nature 347:151-156, 1990.Researchers preventT1DM in theNOD mouse byvaccination withGAD-plasmid DNAScientists prevent T1DM inthe NOD mouse with GADgenemodified Vaccinia virusResearchers report thatGAD gene polymorphismmay be associated withobesity200120022003ADA says in its Clinical PracticeRecommendations for 2002 that“autoantibody tests may be of value toidentify which newly diagnosedpatients have immune-mediated Type 1-diabetes in circumstances where it is notobvious".Resarchers successfullyuse GAD gene therapy fortreatment of Parkinson’sdisease in an animalmodelDiamyd Phase IIclinical trial in47 LADApatientscompleted