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Immunology and Immunogenetics


 
 
Richard A Jackson, MD
Investigator
Joslin Diabetes Center
 
1/1/2001 -  
 
 

The long-term focus of Dr. Richard Jackson's laboratory is to develop strategies to prevent type 1 diabetes. One necessary step toward that goal is to be able to better identify people who are at risk of developing the disease before it appears. Presently, high-risk relatives can be identified using a combination of antibody tests - islet cell antibodies (ICA) and insulin autoantibodies (IAA) - and sensitive metabolic testing. An important part of Dr. Jackson's work as Director of the Hood Center for the Prevention of Childhood Diabetes is to find the most accurate and most widely applicable testing that can be used to screen the broadest number of individuals for signs that they will develop the disease.

Currently, testing focuses on first and second-degree relatives of someone with type 1 diabetes. High-risk relatives identified through testing have a 70-90 percent chance of developing diabetes within the next four years. In some cases, testing will fail to detect someone who is going to develop the disease, and in others those who test positive have a different clinical course. The addition of tests for two new autoantigens - GAD and IA2-ic - should add more precision to present calculations. For example, people with very high levels of anti-GAD antibodies are less likely to develop diabetes than those with lower levels.

Examining high risk relatives for the presence of diabetes-susceptibility genes has proven to be effective in improving the precision by which one can determine who will develop diabetes. Patients who are positive for islet cell antibodies and GAD, but who have the HLA gene DQB0602 are at very low risk, while those who have the DQB0302/0201 gene are likely to develop diabetes faster than relatives with similar antibody levels.

Screening for other diabetes susceptibility genes, IDDM2 (in the region of the insulin promoter) and IDDM4, and information on a new series of autoantigens may refine the lab's ability to identify high-risk relatives. Only 15 percent of new cases of type 1 diabetes occur in people who have a relative with diabetes, and thus, screening methods have to be adapted to the general population, where 85 percent of the diabetes will develop. If the current ongoing trials to prevent diabetes in relatives of patients with diabetes are as successful as some suspect they will be, there will be a powerful motivation to extend screening to the general population. But to do this more successfully, more portable laboratory measurement tools, like those being developed in the Immunology and Immunogenet-ics labs, must be available so that testing can be performed without a visit to a doctor's office to have blood drawn.

In collaboration with the Massachusetts Department of Public Health (DPH), Dr. Jackson's group has devised techniques for performing genetic screening, as well as auto-antibody analysis, that may be useful for screening the general population. These tests focus on newborn infants. Currently the Massachusetts DPH does screening in infants for certain childhood diseases, such as phenylketonuria, thyroid disease, sickle cell anemia, and others. Joslin investigators have developed methods for measuring antibodies and genetic markers on newborn filter papers blood samples. These methods use recombinant human proteins and forensic molecular biology techniques. They can be more easily standardized, are more portable, and can be performed without a doctor's visit, which make them useful when screening large populations. The next steps in this area are to establish the efficacy of the filter paper screening technique and to assess the impact of immunologic parameters on disease progression in those children who develop diabetes before the age of eight. Joslin investigators hope to identify specific susceptibility markers indicating an accelerated autoimmune process.

The emphasis on screening for "pre-diabetes" has become even more urgent in recent years due to results from Joslin showing that diabetes has been delayed or prevented in some high-risk relatives by treating with small daily doses of injected insulin. Currently, high risk relatives are being entered into the first, large-scale nationwide Diabetes Prevention Trial, the DPT-1, which is being funded by the National Institutes of Health. The goal of this nationwide study, which is being conducted at Joslin and nine other centers nationwide, will be to assess the effects of injected or oral insulin in delaying or preventing diabetes. Dr. Jackson is the principal investigator for this study at Joslin and one of the leaders of the study nationwide.

While this human trial is ongoing, Dr. Jackson and colleagues are testing other possible therapies in the NOD mouse model to prevent diabetes. In the past, evaluation of potential therapies in the NOD mouse have taken a year of follow-up to determine whether they are effective. With the help of section researcher Myra Lipes, M.D., a new mouse model, the NOD-SCID mouse, is being used in studies testing potential prevention strategies. These can be completed within 40 days, greatly speeding up the evaluation process so that if a promising treatment is identified, it can be moved into clinical trials sooner.

Selected References:

Keller, R.J., Eisenbarth, G.S., and Jackson, R.A., Insulin Prophylaxis in Individuals at High Risk of Type I Diabetes, Lancet, 1993, 341: 927-28.

Pugliese, A., Bugawan, T., Moromisato, R., Awdeh, Z., Alper, C., Jackson, R.A., Erlich, H., and Eisenbarth, G.S., Two Subsets of HLA-DQA1 Alleles Mark Phenotypic Variation in Levels of Insulin Autoantibodies in First Degree Relatives at Risk for Insulin-dependent Diabetes., J Clin Invest., 1994, 93: 2447-52.

Verge, C.F., Gianani, R., Yu, L., Pietropaolo, M., Smith, T., Jackson, R.A., et. al., Late Progression to Diabetes and Evidence for Chronic Beta-cell Autoimmunity in Identical Twins of Patients with Type I Diabetes, Diabetes, 1995, 44: 1176-1179.

Biographical Sketch:

Dr. Jackson is Acting Head of the Section on Immunology and Immunogenetics at Joslin, Director of the Hood Center for the Prevention of Childhood Diabetes at Joslin, Senior Physician at the Center and Assistant Professor of Medicine at Harvard Medical School. He received his medical degree from Ohio State University School of Medicine and completed residency training at Worcester Memorial Hospital and a fellowship training in endocrinology at Duke. He is a former Mary K. Iacocca Fellow and recipient of the Cookie Pierce Research Award from JDF.