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

References1. Quinn A, et al,MHC class I-restricted determinants on the glutamicacid decarboxylase 65 molecule induce spontaneousCTL activity.J Immunol. 2001;167:1748-57.2. Bowie L, et al,Generation and maintenance of autoantigen-specificCD8+ T cell clones isolated from NOD mice.J. Immunol. Methods. 1999;228:87-95.3. Gauvrit A, et al,Identification of a relevant GAD65 H-2Kd-restrictedepitope recognized by CD8+ T cells in NOD mice.2003. Unpublished data.4. Bach J-M, et al,High affinity presentation of an autoantigenic peptidein Type I diabetes by an HLA class II protein encodedin a haplotype protecting from disease.J. Autoimmun. 19975. Bach JM, et al,Identification of mimicry peptides based on structuralmotifs of epitopes derived from 65-kDa glutamic aciddecarboxylase.Eur. J. Immunol. 1998;28:1902-1910.6. Endl J, et al,Identification of naturally processed T cell epitopesfrom glutamic acid decarboxylase presented in the contextof HLA-Dr. alleles by T lymphocytes of recentonset IDDM patients.J. Clin. Invest. 1997;99:2405-2415.J.-M. Bach, Ph.D., D.V.M., is AssistantProfessor in Endocrinology and Director ofthe ImmunoendocrinologyUnit of Nantes, France. Doctor Bach hasspecialized in the study of the cellularimmune response to GAD in Type 1 diabetes(mouse, dog and human).GAD Peptide Vaccines forT1DM:Not Just a Blueprint?TJ.-M. Bachype 1 diabetes is an autoimmunedisease resulting in thedestruction of pancreatic islet ß-cells, which secrete insulin, byautoreactive T lymphocytes.One of the major challenges ofthe new century will be the treatment of organspecificautoimmune disease. For Type 1 diabetes, itmeans disease prevention before the completedestruction of the ß-cell mass, or replacement ofinsulin-secretive cells after their disappearance.Pancreas and isletcell transplantation are effectiveß-cell replacement therapy for diabetes, but theshortage of human donor pancreata has led tosearch for potential alternative sources of isleT cells(pig islets, in vitro generation of ß-cells from pancreaticduct cells or from stem cells). Beside replacementapproaches, diabetes prevention implicatesthe development of immunotherapies, especiallyspecific immunomodulations of auto-antigensinvolved in Type 1 diabetes pathogenesis.Immunotherapies are also necessary for extensive ß-cell replacement approaches, to block the autoimmmuneprocess and to avoid strong immunosuppressortreatments. To be attractive, immunotherapiesof Type 1 diabetes have to produce a long-lastingprotective response specific for self-antigens.On one hand, specific modulations and tolerancecould be obtained in rodent models withwhole self-proteins or DNA encoding auto-antigens.On a second hand, synthetic peptide-basedvaccines could be a very attractive approach forspecific immunomodulations, permitting to targetclonal elimination or unresponsiveness of aggressiveT cells. Peptides can be produced in largequantities with high purity at low cost, and aresafer than recombinant proteins. To allow thedesign of antigen-specific immune therapies targetingpathogenic autoreactive T cells, we need tocharacterize peptide specificities of autoreactive Tcells, which should also provide fabulous markersof isleT cell damage, useful for therapeutic trialsand diagnosis of individuals with increased riskfor disease, and could help to unravel the pathophysiologyof autoimmune diabetes.Several self-antigens have been identified in Type1 diabetes. Among them, GAD (Glutamic AcidDecarboxylase) is a crucial early target involved indiabetes in human and non-obese diabetic (NOD)mouse. Its role is considered presently as decisive inautoimmunity initiation as well as in progression toovert disease. A majority of studies of diabetes autoimmunityprocess and prevention are focused onthis autoantigen. In rodent models, the role of apeculiar set of T lymphocytes, expressing the CD8marker, in ß-cell aggression is not clearly understood.CD8 + T cells could be implicated not only in diabetesinduction, but also in progression to destructiveinsulitis and overt diabetes. Teams of E. Sercarz (1)and A. Cooke (2) have identified two peptides derivedfrom GAD and recognized by CD8 + T lymphocytesin NOD mouse (peptide 546 and 515,respectively). CD8 + T cells specific for these peptidesare detected early in young NOD mouse. Oursquad have very recently specific another GADderivedpeptide (peptide 90), which may be crucialin diabetes progression in mice [3]. For the firsttime, we showed that CD8 + T cells specific for aGAD-derived peptide are implicated in diabetesaggravation. Specific cytotoxic CD8 + T cells wereactivated and could play an important role in progressionof insulitis to overt disease. We presentlytest immunoprevention of spontaneous diabetes inNOD mice using CD8 + T cell-inducing peptides.And in humans? In humans, while autoantibodyresponses have been extensively characterized,very little is known of the natural history of Tcell autoreactivities, neither for CD8 + T cells (probablythe first T lymphocytes to colonize pancreaticislets), nor for T lymphocytes expressing CD4antigen. We and others have already identifiedGAD-derived peptides presented to CD4 + T lymphocytesof recent-onset diabetic patients[4-6]. Inhumans, we need also to identify relevant CD8 + Tcell-inducing peptides of GAD. In the future, discoveryof GAD-peptides recognized by self-reactiveaggressive CD8 + T lymphocytes and elucidationof key immunological events leading to diabetesinitiation or aggravation in humans may permit todefine efficient peptide-vaccine strategies.page 22 dmccad june 2003