Chemistry: analytical and immunological testing – For preexisting immune complex or auto-immune disease
Reexamination Certificate
1995-08-11
2002-05-21
Nolan, Patrick J. (Department: 1644)
Chemistry: analytical and immunological testing
For preexisting immune complex or auto-immune disease
C424S094100, C424S185100, C435S007210, C435S007910, C435S069300, C530S352000, C530S387100, C530S399000, C530S845000
Reexamination Certificate
active
06391651
ABSTRACT:
BACKGROUND OF THE INVENTION
Diabetes is a term that refers to a collection of diseases resulting in disordered energy metabolism and varying degrees of blood glucose elevations or hyperglycemia. One of the best characterized forms of the disease is that resulting in immunologically mediated destruction of the insulin secreting pancreatic beta cells. This severe form of the disease is termed Insulin Dependent Diabetes (IDD) since it is associated with progressive insulin deficiency and coincident symptoms such as weight loss, glycosuria and polyuria, and increased thirst or polydipsia. Other terms for this form of diabetes are Type 1 Diabetes (cf. Type 2 Diabetes which results from an inherent resistance to insulin action); Ketosis Prone Diabetes because there is abnormal generation of ketone bodies as a result of excessive breakdown of body fats due to the severe insulin deficiency, or Juvenile Diabetes, since virtually all diabetes that appears in childhood and adolescence is of this type (see Atkinson and Maclaren, N Engl J Med 1994:331:1428-1436).
Diabetes is a major public health problem, especially in Western countries. The incidence rates vary greatly worldwide, from as high as 40 per 100,000 persons in Finland to as low as 1-2 per 100,000 among Japanese, with the US in between. The peak incidence is during the pubertal years associated with increasing bodily demands for insulin associated with muscle growth. The prevalence rates in the US population under age 20 years is 0.25% and it approaches 0.4% over a lifetime, albeit an estimated 10-20% of patients with Non Insulin Dependent Diabetes (NIDD) or Type 2 or Maturity Onset Diabetes also have, in reality, slowly progressive IDD. Thus, it is estimated that there should be at least 1 million Americans affected by IDD.
Diabetes results in progressive damage to the blood vessels of the body, to a degree that depends upon the severity of hyperglycemia and its duration. The incident mortality rate for IDD has been calculated to be 7 fold higher than for age matched non diabetic controls. Whereas the decade long Diabetes Control and Complications Trial (DCCI) concluded in 1994 by the National Institutes of Health in the US showed that meticulous insulin replacement therapy would slow the appearance of damaged arteries, it was not able to prevent this since blood glucose levels were never kept within normal limits. Ocular complications of diabetes are the leading cause of new blindness in persons of 20-74 years of age. The risk of lower extremity amputation is 15 fold higher in those with diabetes, while more than half of the approximately 125,000 persons undergoing lower limb amputation do so as a direct consequence of diabetes. Approximately 40% of persons undergoing renal transplantations have kidney failure because of their diabetes, and the proportion due to diabetes continues to rise each year. Women with diabetes produce newborn infants with a 7% newborn mortality rate, albeit this outcome can be greatly improved with tight glycemic control during the gestation period. Other complications of diabetes include increased heart disease and stroke, loss of nerve cells or neurones innervating the limbs and intestine, impotence and infertility, cataract formation in the lens of the eyes, increased periodontal disease, and predisposition to infectious diseases especially from bacteria and yeast. Of all patients with diabetes, those with IDD have a disproportionate share of these complications because of its severity and usual early age of onset In the US, the direct health care costs attributable to diabetes in 1994 have been estimated to exceed $120 billion. Thus it is important that the pathogenesis of IDD be understood and strategies be developed to prevent it as a fully expressed clinical disease.
Patients with IDD are unusually prone to other diseases that have become recognized to have autoimmune origins. These diseases include thyroiditis or Hashimoto disease, Graves disease, Addison disease, atrophic gastritis and pernicious anemia, celiac disease and vitiligo (Maclaren, Diabetes Care 1985:8 suppl:3438). Evidence that IDD itself has an autoimmune nature began with histological studies of patients that succumbed at diagnosis which indicated that the islets were infiltrated with a chronic inflammatory (lymphocytic) infiltrate termed insulitis. This was supported in the early 1970's by reports of islet cell autoantibodies reactive to antigens within the cytoplasm (ICA) (Lendrum et al. Lancet 1975:1:880-882) or confined to the islet cell surfaces (ICSA) (Maclaren et al. Lancet 1975:1:977-1000) as detectable by indirect immunofluorescence. Later it was recognized that many patients also develop autoantibes to insulin (IAA) before their diagnosis (Pahner et al., Science 1983:222:1337-1339) as well as to insulin receptors (Maron et al., Nature 1983:303:817-818). Autoantibodies were also reported to an islet cell protein composition of 64,000 M.Wt. in man (Baekkeskov et al., Nature 1982:298:167-169), in the Biobreeding (BB) rat model (Baekkeskov et al., Science 1984:224:1348-1350) and in the Non Obese Diabetic (NOD) mouse model (Atkinson and Maclaren, Diabetes 1988:37:1587-1590). This 64 KDa antigen has subsequently been reported to be the lower molecular weight isoform of glutamic acid decarboxylase (GAD
65
) (Baekkeskov et al., Nature 1990:347:151-156) (Kauffman et al., J Clin Invest 1992: 283-292). GAD is an enzyme that converts glutamate into the membrane stabilizing neurotransiitter called gamma amino butyric acid or GABA. In addition to autoantibodies to GAD, peripheral blood mononuclear cells were shown to be autoreactive in patients developing IDD (Atkinson and Maclaren et al., Lancet 1992:339: 458-459, and Harrison et al. Lancet 1993:341: 1365-1369). Indeed a leading possible cause for IDD is that immunity to enteroviral proteins (developed through infection by Coxsackie or closely related viruses) that have structural homologies to GAD, may in the genetically predisposed individual, trigger an autoimmune response to islet cells because of this molecular mimicry (Atkinson and Maclaren, Scientific American 1990:262:61-71; Kauffman et al. J Clin Invest 1992:89: 283-292; Atkinson, Maclaren et al., J Clin Invest 1994:94: 2125-2129).
Since the above immunological markers predate the clinical onset of IDD often by many years, their possible value in disease prediction became increasingly realized (Maclaren, Diabetes 1988:37:1591-1594), permitting in turn options for therapeutically induced delays in diabetes onset to be considered (Muir and Maclaren, J Autoimmunity 1993:16:301-310). Indeed by 1994, multicenter trials attempting to prevent IDD through prophylactic parenteral insulin or oral insulin therapies had been initiated in the US (the DPT-1 trial), as well as in Europe using prophylactic nicotinamide (the ENDIT trial). Among relatives, the appearance of LAA was shown to predate onset of IDD (Atkinson and Maclaren, Diabetes 1985:35: 894-898) while ICA proved to be valuable to the prediction of IDD in relatives (Riley, Maclaren et al., N Engl J Med 1990:323: 1167-1172) as well as in the general population (Schatz, Maclaren et al., J Clin Invest 1994:93: 2403-2407), as modifiable on the basis of coincident IAA (Krischer, Maclaren et al., J Clin Endo Metab 1993:77: 743-749). While not ideal the predictability of IDD based upon the ICA test provided the basis for the DPT-1 and ENDIT trials mentioned above. Furthermore, autoantibodies to the 64KDa islet cell protein also proved to have utility in IDD prediction (Atkinson, Maclaren et al., Lancet 1990:335: 1357-1360), as eventually realized by the chemical assay for autoantibodies to GAD
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. (Schott, Maclaren et al., J Autoimmunity 1994:7:865-872). These studies made it important to resolve the nature of all of the islet cell autoantigens involved in the pathogenesis of IDD (Atkinson and Maclaren, J Clin Invest 1993;92:1608-1616). Whereas ICA, as determined by indirect immunofluorescence of human cryocut pancreatic sections, was likely to represent multiple autoantigens
Lan Michael S.
Maclaren Noel K.
Notkins Abner L.
Needle & Rosenberg P.C.
Nolan Patrick J.
The United States of America as represented by the Secretary of
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