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

GAD in GraphsGAD65 Specific RegulatoryT Cells May ProvideProtection from DiabetesNAnthony Quinnumerous studies haveshown that T cells of theCD8 + and CD4 + subsetsare both involved in theimmunopathogenesis ofType 1 diabetes (T1D) inhumans. Likewise, both these cell types are alsonecessary for T1D in NOD mice, the murine modelfor spontaneous autoimmune diabetes. We havebeen studying the cellular immune responses toself-antigens in NOD mice to determine significancein the initiation of islet-specific damage. Thefocus has been on two very relevant issues regardingthe initiation of autoimmune disease: the identificationof host-derived factors that influence susceptibilityto autoimmune disease and the role ofinfectious agents in the induction and persistenceof autoimmunity. Although both issues are broadgeneralized topics – particularly the study of susceptibilityfactors – there are very specific issuesthat can be readily addressed and that provide valuableinformation for our understanding of the pathogenicprocesses in autoimmune disease.First, does the quality of the autoimmuneresponse to self-antigens influence the susceptibilityto autoimmune disease? Recently, we have beenseeking to determine if CD8 + T cell responses toglutamic acid decarboxylase (GAD65) are clinicalllyrelevant in the NOD mouse model of T1D.GAD65 is one of the first beta cell antigens toprime autoimmune responses that are detectablein the spleens of naive prediabetic NOD mice.Our preliminary data demonstrates that GAD65-reactive CD8 + T cells can be found in prediabeticNOD mice, while others have shown that suchcells are present in the peripheral blood of humanpatients recently diagnosed with diabetes.Currently, we are investigating the nature ofGAD65-specific regulatory T cells which may provideprotection from diabetes in individuals whoare considered to be at-risk but remain diabetesfree.Such mechanisms may provide protection tosiblings/relatives of diabetic individuals and maybe represented in male NOD mice and F1 mice,both of which display a reduced susceptibility todiabetes compared to female NOD mice.Secondly, can islet proteins, or fragments fromthem, be used to prevent diabetes in young NODmice or humans? Autoimmune diseases such as diabetesare likely the result of immunological dysregulationsuch that the balance between the antagonisticforces of regulation and pathogenesis tilts in favor ofthe pathogenic mechanisms. One of our objectives isto initiate GAD65-specific mechanisms that are capableof restoring the immunological balance in diabetes-pronemice. Hopefully, the clues gained in themurine models can also provide insights into applicationsto humandisease.Tony Quinn, Ph.D., isAssociate Professor inBiological Sciences atthe University ofToledo, and AdjunctProfessor inMicrobiology andImmunology at theMedical College of Ohio, Toledo, Ohio. Quinnis an immunologist with a long-standinginterest in the regulation of immunity, as itrelates to the control of autoimmune disease,and the enhancement of targeted immuneresponses. Quinn is currently studying thecellular immune responses to self-antigens inautoimmune diabetes and their roles in theinitiation of pancreas-specific damage.Relative amount of GAD65immunoprecipitated (% of PAS)(%) Diabetes10080604020Clinical onset of IDDM is associatedwith a decreased Th2 GAD response2520151050IgMGAD65-GMCSFPre. IDDM -IDDM -IDDM(High)Petersen et al (1999). Progression to Type 1 diabetesis associated with a change in the immunoglobulinisotype profile of autoantibodies toglutamic acid decarboxylase (GAD65). ChildhoodDiabetes in Finland Study Group. Clin Immunol90:2 276-81• Isotype-specific IgE and IgMGAD65 autoantibodies in firstdegree relatives before clinical onset(Pre), IDDM at onset (IDDM), lowrisk IDDM relatives (-IDDM) andhigh risk relatives (-IDDM High).• Individuals with a low risk forType 1 diabetes have a higher Th2response to GAD65 than do individualsat high risk or already withdiseaseAdoptive transfer of GAD-reactiveCD4 + Th1 cells induces diabetes inNOD/SCID mice5A injeced miceOVA3E3 injected miceSALINE injected mice00 2 4 6 8 10 12Time (wk)Zekzer et al. (1998) GAD-reactive CD4 + Th1 cellsinduce diabetes in NOD/SCID miceJ Clin Invest 101:68-73• Adoptive transfer of the GADspecificCD4 + T cell line 5A inducesdiabetes In NOD/SCID mice, buttransfer of an OVA-specific controlT cell line (OVA3E3) does not• GAD-specific T cells cause diabetes**dmccad june 2003page 29