Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1995-06-06
2001-10-09
Wortman, Donna C. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S068100, C435S811000, C436S506000
Reexamination Certificate
active
06300089
ABSTRACT:
BACKGROUND OF THE INVENTION
Diabetes is a major public health problem. As reported by the 1987 report of The National Long-Range Plan to Combat Diabetes of the National Diabetes Advisory Board, six million persons in the United States are known to have diabetes, and an additional 5 million have the disease which has not yet been diagnosed; each year, more than 500,000 new cases of diabetes are identified. In 1984, diabetes was directly causal in 35,000 American deaths and was a contributing factor in another 95,000.
Ocular complications of diabetes are the leading cause of new cases of legal blindness in people ages 20 to 74 in the United States. The risk for lower extremity amputation is 15 times greater in individuals with diabetes than in individuals without it. Estimates suggest that persons with diabetes undergo over one-half of the approximately 125,000 amputations performed annually in the United States.
Kidney disease is a frequent and serious complication of diabetes. Approximately 30 percent of all new patients in the United States being treated for end-stage renal disease have diabetes. This percentage is increasing at a rate of approximately 2 percent annually; therefore, within the next decade, diabetes-related kidney disease will account for more than one-half of all enrollees in the End-Stage Renal Disease Program.
Individuals with diabetes are also at increased risk for periodontal disease. Periodontal infections advance rapidly and lead not only to loss of teeth but also to compromised metabolic control. Women with diabetes risk serious complications of pregnancy. Current statistics suggest that the mortality rates of infants of mothers with diabetes is approximately 7 percent.
The economic burden of diabetes is enormous. Each year, patients with diabetes or its complications spend 24 million patient-days in hospitals. A conservative estimate of total annual costs attributable to diabetes is at least $24 billion (American Diabetes Association est., 1988); the full economic impact of this disease is even greater because additional medical expenses often are attributed to the specific complications of diabetes rather than to diabetes itself. Diabetes is a chronic, complex metabolic disease that results in the inability of the body to properly maintain and use carbohydrates, fats, and proteins. It results from the interaction of various hereditary and environmental factors and is characterized by high blood glucose levels caused by a deficiency in insulin production or an impairment of its utilization. Most cases of diabetes fall into two clinical types: insulin-dependent diabetes mellitus (IDDM or IDD) and non-insulin-dependent diabetes mellitus (NIDDM or NIDD). Each type has a different prognosis, treatment, and cause.
Approximately 5 to 10 percent of diabetes patients have IDD, formerly known as juvenile diabetes because of its frequent appearance early in life, usually in childhood or adolescence. IDD is characterized by a partial or complete inability to produce insulin. Patients with IDD would die without daily insulin injections to control their disease.
Few advancements in resolving the pathogenesis of diabetes were made until the mid-1970s when evidence began to accumulate to suggest that IDD had an autoimmune etiopathogenesis. It is now generally accepted that IDD results from the chronic autoimmune destruction of the insulin producing pancreatic &bgr;-cells. Lymphocytes and other inflammatory cells have been observed within the islets of Langerhans in newly diagnosed IDD patients and have been found preferentially in regenerating islets composed of &bgr;-cells rather than those of other cell types. This active immunological process is associated with a variety of autoantibodies to &bgr;-cell cytoplasmic and membrane antigens, insulin, and insulin receptors.
Thus, IDD is a disease which is replete with autoantibodies. These include islet cell autoantibodies of the cytoplasmic type (ICA) (Bottazzo, G. F., A. Florin-Christensen, and D. Doniach [1974
] Lance.
2:1279-1283); islet cell surface autoantibodies (ICSA) (Maclaren, N., S. W. Huang, and J. Føgh [1975
] Lancet
. i:997-1000); insulin autoantibodies (IAA) (Palmer, J. P., C. M. Asplin, and P. Clemons [1983
]Science
222:1337-1339) and the possible antiidiotypic insulin receptor autoantibodies (Ins.R. A.) (Maron, R., D. Elias, M. de J. Bartelt, G. J. Bruining, J. J. Van Rood, Y. Shechter, and I. R. Cohen [1983
] Nature
303:817-818). In 1982 it was reported that antibodies to a 64,000 M
r
islet cell antigen were detected in IDD patients (Bækkeskov, S. et al. [1982
] Nature
298:167-169). In a subsequent publication, Bækkeskov et al. reported the 64,000 M
r
antibodies associated with the IDD in the BB rat model (Bækkeskov, S. et al. [1984
] Science
224:1348-1350). Later, a follow-up study investigated patients who were related to individuals with IDD and, thus, were known to be at risk for developing the disease (Bækkeskov, S. et al. [1987
] J. Clin. Invest.
79:926-934). The results of this later study suggested that the 64,000 M
r
antibodies may be present in some IDD patients before the manifestation of clinical symptoms. However, in that same study, Bækkeskov et al. reported that the function of the 64,000 M
r
protein was unknown and that the data was inconclusive as to whether or not 64,000 M
r
antibodies were present before a decrease in &bgr;-cell function commenced.
Other antibodies to various non-&bgr;-cell specific molecules have been reported with an increased prevalence in IDD patients. These include antibodies to tubulin, single stranded and double stranded DNA, gastric parietal cells, intrinsic factor adrenocortical cells, thyroid peroxidase enzymes, and thyroglobulin. IDD patients have signs of polyclonal activation of B-lymphocytes, and the increased antibody titers to various antigens may be the result.
Furthermore, studies during the past decade have shown that patients with IDD have genetic markers, called histocompatibility antigens, that are associated with susceptibility to IDD. Because these genetic susceptibility markers are necessary but not sufficient for the development of IDD, it appears that some additional, as yet unknown, environmental factors could be required to initiate the destruction of the &bgr;-cells and the development of diabetes. Environmental factors, either viruses or chemical agents, may initiate an immune response against the &bgr;-cells to permit their immunologic destruction in genetically susceptible individuals (Atkinson, M. A., and N. K. Maclaren. [1990
] Scientific American
7:62-67). Therefore, identification of the prediabetic state in diabetes is essential in efforts to prevent the development of the disease. Perhaps the single most important advance of the past two decades in diabetes research has been recognition that autoimmune destruction of &bgr;-cells takes months or years to reach completion. Whereas currently the clinical diagnosis of diabetes is almost never made until the destructive process is nearly complete and insulin injections are required to prevent death, intervention before the insulin-producing cells have been irreversibly destroyed can provide a strategy to prevent progression of diabetes and its complications.
It is crucial, therefore, to find a means of accurately predicting the onset of IDD before the disease has progressed to the clinical stage.
Although many biological markers have been associated with IDD, until now, none of these markers have been shown to be uniformly present before the onset of the clinical symptoms of the disease (Maclaren, N. K. [1988
] Diabetes
37:1591-1594). Such early presence is essential for a compound to qualify as a useful predictive test for the disease. However, early presence alone is not sufficient for an accurate early detection method; a predictive test based on the presence or absence of a particular marker is valuable only if the predictive marker is present only in those who will get IDD, a
Atkinson Mark A.
Maclaren Noel K.
Saliwanchik Lloyd & Saliwanchik
University of Florida Research Foundation Inc.
Wortman Donna C.
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