forewordResearch Scientists throughout <strong>the</strong> world are currently faced<strong>with</strong> a time-old challenge – to define and understand <strong>the</strong>mechanisms leading to development of autoimmune diseases,and <strong>the</strong>n to determine and develop efficient means oftreating or preventing <strong>the</strong>m. While <strong>the</strong>se might sound like two distinctchallenges, <strong>the</strong> definition of <strong>the</strong> molecules targeted in an autoimmune diseaseprocess also provides <strong>the</strong> candidates for <strong>the</strong>rapeutic targeting.To date, <strong>the</strong>re is no vaccine for any of <strong>the</strong> many autoimmune diseases thataffect millions of people throughout <strong>the</strong> world. A number of candidate moleculeshave been identified and targeted, such as insulin in Type 1 diabetesand myelin basic protein in Multiple Sclerosis, but clinical vaccination trialsusing <strong>the</strong>se molecules have not yet been successful. Given <strong>the</strong> recent advancesin gene technology and knowledge of <strong>the</strong> genetic codes comprising bothMan and experimental animals, <strong>the</strong> potential for discovery of new candidatemolecules is great. However, one candidate molecule identified manyyears ago still stands <strong>the</strong> test of time.Glutamic acid decarboxylase 65 (<strong>GAD</strong>65) is a candidate auto<strong>anti</strong>genimplicated in development of <strong>the</strong> autoimmune disease Type 1 diabetes. Inautumn 1994, ‘The Story of <strong>GAD</strong>’ by Robert Dinsmoor appeared in <strong>the</strong>Countdown magazine, a publication of <strong>the</strong> Juvenile Diabetes ResearchFoundation International. This article described <strong>the</strong> series of research discoveriesencompassing <strong>the</strong> period 1982-1993 that led to definition of<strong>GAD</strong>65 as a prime candidate auto<strong>anti</strong>gen in Type 1 diabetes. The articleended <strong>with</strong> two pertinent statements – that access to recombinant <strong>GAD</strong>in industrial-sized qu<strong>anti</strong>ties would be required for testing of <strong>GAD</strong> <strong>the</strong>rapiesin humans, and that <strong>GAD</strong>-based <strong>the</strong>rapies should provide a meansof preventing diabetes.During <strong>the</strong> last 10 years, intensive efforts have led to development ofhigh quality recombinant <strong>GAD</strong>65 proteins, which have been tested inPhase I and Phase II clinical trials.Additionally, recent research efforts havealso identified <strong>GAD</strong> as an important elementin Parkinson’s and o<strong>the</strong>r neurologicaldiseases, indicating that <strong>the</strong> candidate moleculehas not only remained a potential keyto prevention of diabetes, but also import<strong>anti</strong>n treatment of o<strong>the</strong>r diseases as well. Thereis obviously still more to learn about thisfascinating protein.This issue is dedicated to <strong>GAD</strong>65 <strong>with</strong> anumber of contributions made by several prominent <strong>GAD</strong> researchers. Aswell as personal reflections of <strong>the</strong>ir own past experiences of <strong>GAD</strong>, <strong>the</strong>current status and proposals for future applications of <strong>GAD</strong> are presented.We hope you find <strong>the</strong>se articles interesting.Assoc. Prof. Robert A. HarrisintroductionIntroduction byLars KlareskogIn 1999 diamyd medical initiated a unique cooperation<strong>with</strong> <strong>the</strong> Karolinska Hospital whensetting up its Competence Center forAutoimmune Diabetes (DMCCAD) at <strong>the</strong>Center for Molecular Medicine (CMM) atKarolinska. Since its inception, <strong>with</strong> Robert Harris at<strong>the</strong> helm, DMCCAD has become an interesting pointfor cross-fertilization of ideas related to various autoimmunediseases including Type 1 diabetes, MS andRheumatoid Arthritis.It is generally agreed that Glutamic AcidDecarboxylase 65 (<strong>GAD</strong>) is an important <strong>anti</strong>gen inType 1 diabetes. As in o<strong>the</strong>r autoimmune diseases,recent research is focused on induction of tolerance todisease specific <strong>anti</strong>gens. This may protect self structuresunder attack <strong>with</strong>out interfering <strong>with</strong> <strong>the</strong> immunesystem’s capabilities in o<strong>the</strong>r areas, such as combattingviral infections or cancer.While it is already generally accepted that <strong>GAD</strong><strong>anti</strong>bodies (<strong>GAD</strong>A) is a major diagnostic marker forType 1 diabetes and predicting <strong>the</strong> course of developmentof Type 2 diabetes (LADA-patients), toleranceinduction to <strong>GAD</strong> may become a way to prevent <strong>the</strong>development of insulin dependency in LADA patients.I have had <strong>the</strong> pleasure of being able to follow <strong>the</strong>development of <strong>Diamyd</strong> Medical’s <strong>GAD</strong>-based vaccinefor LADA patients. The outcome of <strong>the</strong> Phase IIstudy in LADA patients is important, not only becauseit may lead to a new drug for diabetes <strong>the</strong>rapy, butits results may also be of importance when designingfuture clinical trials in o<strong>the</strong>r diseases such as MS.page 4 dmccad june 2003
Lars Klareskog, MD, Ph.D., is Professor of Rheumatology and Head of<strong>the</strong> Rheumatology Research group at <strong>the</strong> Karolinska Hospital inStockholm and formerly Professor of Medical Immunology and Headof Clinical Immunology at <strong>the</strong> Uppsala Teaching Hospital. Klareskog'sresearch is specifically aimed at <strong>the</strong> causes and treatment of autoimmunedisorders. Klareskog is a member of <strong>the</strong> Nobel Foundation.Comments on <strong>Diamyd</strong> Diabetes Vaccineby Hans WigzellThat <strong>the</strong> human immune system can react against selfstructures is well known. Most such reactions do notcause disease – but some do.In <strong>the</strong> efforts to fight autoimmune disease such as Type1 diabetes, one <strong>the</strong>rapeutic approach is to modify <strong>the</strong> immune reactionand induce functional tolerance to potentially relevant moleculessuch as <strong>GAD</strong> by administration of <strong>the</strong> autologous <strong>anti</strong>gen itself.Similar approaches have been successful before. For exampleadministration of auto<strong>anti</strong>gens have alleviated autoimmune diseasein animal models. Hyposensitization (where increasing doses of allergenare used to treat allergies) is ano<strong>the</strong>r example.How should <strong>GAD</strong> be used to induce functional tolerance?Using our knowledge from conventional as well as from autologousvaccines it seems logical to use doses from a few micrograms to 500Hans Wigzell, MD, D.Sc, is Professor of Immunology, Dean of <strong>the</strong>Karolinska Institute and Chief Scientific Advisor to <strong>the</strong> SwedishGovernment. Wigzell is one of Sweden´s most prominent and internationallyrenowned scientists in <strong>the</strong> field of Immunology. Wigzellwas Director General of <strong>the</strong> National Bacteriological Laboratory1988-1993; Director General of <strong>the</strong> Swedish Institute for InfectiousDiseases 1993-1994; Wigzell is since 1990 Chairman of <strong>the</strong> ECConcerted Research Programme: European Vaccine against AIDS(EVA). Wigzell was Chairman of <strong>the</strong> Nobel Committee 1990-1992and is Chairman of <strong>the</strong> Nobel Foundation.micrograms.To use alum as adjuvant seems highly recommendable. It is conventionaland it is biased to <strong>the</strong> humoral ra<strong>the</strong>r than <strong>the</strong> cellularimmune response which is logical when <strong>the</strong> cellular response is to bereduced.Subcutaneous administration is recommendable and conventional.Intravenous administration is much more problematic and intramuscularis less efficient in terms of immunogenicity.The <strong>GAD</strong>-vaccine differs from a conventional vaccine in that <strong>the</strong>administered <strong>anti</strong>gen is already present naturally in <strong>the</strong> body. Thisprobably means that <strong>the</strong> vaccine needs to be injected a couple oftimes. Therefore a prime and boost strategy seems logical.In summary, <strong>the</strong> diamyd approach to induce functional tolerance to<strong>GAD</strong> seems logical.dmccad june 2003page 5
- Page 6 and 7: The Story ofGADRobert Dinsmoor1975R
- Page 8 and 9: Åke Lernmark, MD, Ph.D., and his c
- Page 10 and 11: theory, the immune system mistakenl
- Page 12 and 13: GAD Back to the Future…Åke Lernm
- Page 14 and 15: 100GAD in GraphsGAD65 DNA vaccinati
- Page 16 and 17: In Nature, Anything that CanHappen
- Page 18 and 19: References1. Baekkeskov, S., et al,
- Page 20 and 21: GAD in GraphsIncidence of diabetes
- Page 22 and 23: References1. Quinn A, et al,MHC cla
- Page 24 and 25: References1. Tisch, R., et al,Induc
- Page 26 and 27: Vaccination with GAD PlasmidSuppres
- Page 28 and 29: GADGAD in GraphsGAD ELISPOT outperf
- Page 30 and 31: GAD in GraphsA1004 wks of age% Inci
- Page 32 and 33: Mark Atkinson, Ph.D.,is an American
- Page 34 and 35: GAD in GraphsIL-4 (pg/ml)2501007550
- Page 36 and 37: References1. Kobayashi T, et al,Isl
- Page 38 and 39: References1. A.Falorni, et al,Radio
- Page 40 and 41: References1. Chattopadhyay, S., et
- Page 42 and 43: Diamyd’s Commercial Development o
- Page 44: T cell GAD65For use of GAD in immun