Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Anti-idiotypic
Reexamination Certificate
2000-01-20
2004-02-10
Chan, Christina (Department: 1604)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Anti-idiotypic
C530S388220, C530S388700, C530S388750, C530S389600, C530S387200, C530S391100
Reexamination Certificate
active
06689359
ABSTRACT:
FIELD OF INVENTION
This invention describes the development of unique autoantibodies which are the cause of several autoimmune and other diseases. It provides diagnostic and prophylactic uses for such antibodies in monoclonal and polyclonal form and also for the molecules recognised by the antibodies. More specifically, the invention provides for the use of these antibodies and the molecules they recognise as specific inhibitors of the development of autoantibodies with the same specificity in children and adults. These antibodies and target molecules are claimed to be of diagnostic, prophylactic and treatment use in a wide variety of autoimmune and other diseases. However, most of the background to the invention will focus on diabetes, not by way of limitation but by way of illustration or example.
The Spectrum of Human Autoimmune Diseases
Diseases associated with autoimmune phenomena can be classified within a spectrum ranging from conditions involving destructive lesions of a single organ or those in which organ or tissue damage is widely disseminated.
At the organ-specific end of the spectrum, the organs most commonly affected are the thyroid, adrenal glands, stomach and islets of Langerhans (which contain the insulin producing cells) in the pancreas, while at the non-organ specific pole, rheumatological or systemic (e.g. systemic lupus erythematosus) disorders predominate. Autoimmune diseases are, in rare cases, connected with fulminant viral infections which can also result in organ destruction. In autoimmunity, the damaging process is slow and sometimes it takes years before the disease becomes manifest. The following are organ-specific autoimmune diseases which result from autoimmune phenomena involving breakdown in immunological tolerance to self antigens.
Thyroid. Thyroid autoimmune disease involves a variety of clinical conditions which result in a common histopathological picture. There is diffuse infiltration of the gland by mononuclear lymphoid cells. The constituent diseases are primary myxoedema, Hashimoto's thyroiditis and Graves' disease. Progression from one to another is not uncommon. Primary myxoedema is the most common form of spontaneous hypothyroidism and is the last stage of the chronic inflammatory process. There is no goitre formation and the gland is almost completely atrophied.
Hashimoto's thyroiditis is also linked to hypothyroidism but is associated with goitre. In its various clinical forms, levels of thyroid hormone can either be compensated by increased levels of thyroid stimulating hormone (TSH) produced by the pituitary, or there can be clinical hypothyroidism in spite of raised TSH levels. In both autoimmune destructive conditions, women are affected five times more frequently than men.
The most common form of thyrotoxicosis is Graves' disease with or without goitre or exophthalmus. It is characterised by remissions and exacerbations. Despite that, the autoimmune process leads to hyperstimulation of the gland, due to the production of thyroid stimulating antibodies, final destruction of the thyroid often occurs. There is a female to male preponderance of 5:1.
In all thyroid autoimmune diseases, the demonstration of various autoantibodies to the gland confirms clinical diagnosis. Autoantibodies can be directed against thyroid cytoplasmic antigens, such as thyroglobulin, cell surface components, such as thyroid peroxidase, and thyrocyte surface expressed TSH receptors (i.e. Graves' disease).
Stomach. Autoimmune diseases of the stomach involve either the fundus or the antrum, leading to various degrees of inflammation affecting these two regions of the gland. In general, this process is named gastritis. In fundal gastritis, there is marked atrophy of the mucosa with consequent loss of intrinsic factor (IF) production leading to malabsorption of vitamin B12 and the subsequent development of pernicious anaemia. In these conditions, antibodies to IF and parietal cells are produced and are present in 90% of affected patients. Parietal cells are destroyed, but chief cells and mucus cells are also destroyed, despite the absence of circulating antibodies to the latter two cell types. There is a female to male preponderance of 3:1. Autoantibodies to gastrin-producing cells in the antrum have been demonstrated in some patients with antral gastritis. This type of gastritis is associated with gastric ulceration and in a proportion of patients, antibodies stimulating gastric cells have also been demonstrated.
Adrenals, Gonads and Placenta. Autoimmune disease of the adrenal (Addison's disease) is characterised by heavy mononuclear cell infiltration of the gland, adrenalitis, and the presence of autoantibodies to adrenal antigens. The symptoms are hyperpigmentation, weakness, fatigue, hypotension, gastro-intestinal symptoms and hypoglycaemia due to adrenal failure. Here again, the disease occurs mainly in women. By immunofluorescence the autoantibodies stain the three layers of the adrenal cortex, but a sub-type can also cross-react with analogous steroid-producing cells in the ovary, testis and placenta. When these latter specificities are present, they correlate with pre-clinical or clinically overt gonadal failure.
Pituitary. Lymphocytic hypophysitis is a rare autoimmune condition, resulting in hypopituitarism requiring hormone replacement therapy. There is a prevalence in females and the disease presents with a variety of other organ-specific autoimmune phenomena or associated disorders. Autoantibodies to prolactin-secreting cells can be detected, as well as other organ-specific antibodies in most cases.
Polyendocrine autoimmunity. Patients with organ-specific autoimmune disease may present with symptoms associated with failure of endocrine or other target organs (e.g. stomach). However, syndromes of multiple affected organs are not uncommon and autoantibodies to unaffected organs are also detectable in patients suffering with only one organ-specific disease. Thyroid and gastric autoimmunity are often seen in the same individual. Pernicious anaemia, resulting from fundal gastritis, is five times more frequent in patients with thyroid disorders and 30-50% of patients with pernicious anaemia also have a history of thyroid disease.
Associations also exist between adrenalitis and thyroiditis and adrenalitis and insulin dependent diabetes mellitus (IDDM). Often cases start with thyrotoxicosis and Addison's disease simultaneously and many patients with Addison's disease have at least one other autoimmune disease. Although hypophysitis and vitiligo (a condition which leads to patchy depigmentation of the skin, most likely due to autoimmune destruction of resident melanocytes) are rare, they often coexist with other overt organ specific conditions. The serological features, (i.e. the presence of circulating autoantibodies) which overlap among these autoimmune disorders is far more common than the co-existence of overt disease. For example, parietal cell antibodies are present in 50% of patients with thyroid disorders and 30% of patients with IDDM.
Current Knowledge Regarding the Pathology of IDDM
The current state of knowledge regarding the aetiology of IDDM (type I diabetes) focuses on the autoimmune destruction of islet &bgr; cells in an environment of a variety of circulating autoantibodies, autoreactive T cells in the circulation and in pancreatic islets (insulitis) and a variety of cytokines. A pathogenic role for autoantibodies has thus far not been demonstrated but their presence has been shown to be of predictive value for the identification of preclinical diabetes particularly in first degree relatives of IDDM patients. Consequently the immunological attack resulting in IDDM is considered to be a T cell dependent &bgr; cell destruction (Tisch and McDevitt; 1996). The evidence which lends support to this view is the presence of mononuclear cell infiltrates (insulitis) in the islets at disease onset (Gepts, 1965; Roep, and DeVries, 1992), the effect of immunosuppressive drugs in delaying disease onset (Bougneres e
Chan Christina
Haddad Maher
Wenderoth , Lind & Ponack, L.L.P.
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