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

theory, the immune system mistakenlyattacks GAD in the beta cells aswell.GAD Provokes an Immune AttackIn 1992, a number of studies showedthat some of the ICAs, the antibodiesdescribed back in 1974 that werevery predictive for diabetes, targetedGAD. One study from Bottazzo’sresearch group in London found thatICAs from the blood serum samplesof pre-diabetic individuals seemed toattack GAD. Likewise Dr. GeorgeEisenbarth and Dr. Robert Gianiniand colleagues at Joslin DiabetesCenter in Boston studied ICAs fromHugh McDevitt, at Stanford University suggested in 1993that diabetes could be prevented in its earliest stages by relatives of people with diabetes.preventing the T cell attack against GAD.They found that GAD was one targetof ICAs, but there might be otherantigens as well.These reports showed an attack on GAD by the humoralimmune system – that is antibodies. But these antibodiesare probably not what destroys the beta cells. Morelikely, they are destroyed by the cellular immune responsein the form of T cells, white blood cells that infiltrate thepancreatic islets.The same year, Drs. Atkinson and Maclaren, working inconjunction with the UCLA research team, took T cellsfrom people with newly diagnosed diabetes, relatives ofpeople with diabetes, and nondiabetic individuals, andexposed them all to GAD65. The T cells that reacted andmultiplied in the presence of GAD65 tended to be thosefrom people with diabetes and their relatives who hadICAs and would later develop diabetes. This showed thatGAD provokes a T cell attack, which may be whatdestroys the beta cell in diabetes.In 1993, two studies published in Nature helped confirmGAD as the first known target of the T cells andsuggested that diabetes could be prevented in its earlieststages by preventing the T cell attack against GAD. Onestudy was from Kaufman and colleagues at UCLA in conjunctionwith Dr. Atkinson, and the other was from Dr.Hugh McDevitt, Dr. Roland Tisch and their colleagues atStanford University. In each case, the researchers testedNOD mice for reactivity to some known antigens in diabetes,including the two forms of GAD. They found thatthe attack on GAD by T cells coincided with the developmentof insulitis – infiltration of the beta cells with whiteblood cells. Only later did the T cells attack other knownantigens in the beta cells.This suggested that GAD is the first antigen to beattacked by T cells, and that this attack then diversifies toinclude other antigens, and that these were recognizedand attacked by the immune system. Was this actually thecause, or was there some other antigen, as yet unknown,that provoked the first attack?To help answer these questions, both groups of researcherstried deactivating the T cell response in their NODmice. The UCLA group injected NOD mice with GAD atthree weeks of age, a treatment already shown to inactivateT lymphocytes against GAD. Most of the mice treatedwith GAD showed no T cell response against GAD, indicatingcomplete immune system tolerance to GAD. TheGAD tolerant mice showed no reaction to the other betacell antigens, and never developed any degree of insulitisor diabetes. This suggested that GAD – and not any ofthe other known antigens – provoked diabetes. On theother hand, mice treated with other antigens did developa T cell attack to the other beta cell to antigens, did developinsulitis, and went on to develop diabetes.The Stanford researchers likewise tried inactivatingGAD-reactive T cells – but in this case by injecting NODmice with GAD65 into their thymus (a major site ofimmune system programming). The 70 percent of NODmice who actually became tolerant of GAD had markedlyreduced T lymphocyte responses to the other beta cellantigens, reduced insulitis, and no development of diabetes.“I think this is an important step toward understandingthe disease process,” Dr. Tisch explained. “It appears thatthe disease occurs in specific stages, and now we may beable to categorize the antigens with regard to reactivitywithin those stages.”The Prediction and Prevention Pay-OffNow that GAD has been identified, cloned, and shown tobe important in the development of diabetes, it can playan important role in diabetes treatment, to predict whowill get diabetes – probably years before they develop anysymptoms of the disease. Now we have a very specificassay to show whether a healthy person has GAD antibody.But the ultimate implications of GAD go far beyondpredicting who will get diabetes. The recent studies inNOD mice show that GAD, too, might play a role in preventingdiabetes.Unfortunately, testing oral GAD in humans won’t befeasible until researchers have access to recombinantGAD in industrial-sized quantities and at an affordablecost. “We’ve actually discovered a direction for potentiallypreventing diabetes in human beings. Using treatmentssuch as with GAD we should be able to prevent diabetesin all individuals who are at risk of developing it,” concludedDr. Clare-Salzler.page 10 dmccad june 2003