Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-25
2002-04-02
Criares, Theofore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S398000
Reexamination Certificate
active
06365616
ABSTRACT:
TECHNICAL FIELD
This invention relates to the treatment of autoimmune diseases and transplantation rejection in mammals. More specifically, the present invention relates to the use of a narrowly-defined group of methimazole derivatives and tautomeric cyclic thiones for the purposes described herein.
BACKGROUND OF THE INVENTION
A primary function of immune response in mammals is to discriminate self from non-self antigens and to eliminate the latter. The immune response involves complex cell to cell interactions and depends primarily on three major types of immune cells: thymus derived (T) lymphocytes, bone marrow derived (B) lymphocytes, and macrophages. Immune response is mediated by molecules encoded by the major histocompatibility complex (MHC). The two principal classes of MHC molecules, Class I and Class II, each comprise a set of cell surface glycoproteins (see Stites, D. P. and Terr, A. I. (eds), “Basic and Clinical Immunology”, Appelton and Lange, Norwalk, Conn./San Mateo, Calif., 1991). MHC Class I molecules are found on virtually all somatic cell types, although at different levels in different cell types. By contrast, MHC Class II molecules are normally expressed only on a few cell types, such as lymphocytes, macrophages and dendritic cells.
Antigens are presented to the immune system by antigen presenting cells in the context of Class I or Class II cell surface molecules, for example, CD4
+
helper T-lymphocytes recognize antigens in association with Class II MHC molecules, and CD8
+
cytotoxic lymphocytes (CTL) recognize antigens in association with Class I gene products. It is currently believed that MHC Class I molecules function primarily as the targets of the cellular immune response, while Class II molecules regulate both the humoral and cellular immune response (Klein, J. and Gutze, E., “Major Histocompatibility Complex”, Springer Verlag, New York, 1977; Unanue, E. R.,
Ann. Rev. Immunology,
2:295-428, (1984)). MHC Class I and Class II molecules have been the focus of much study with respect to research in autoimmune diseases because of their roles as mediators or initiators of immune response. MHC Class II antigens have been the primary focus of research in the etiology of autoimmune diseases, whereas MHC Class I antigens have historically been the focus of research in transplantation rejection.
Numerous experimental animal models for human disease have linked aberrant expression and/or function of MHC Class I and MHC Class II antigens to the autoimmune disease process, for example, insulin-dependent diabetes mellitus (IDDM) (Tisch and McDevitt, Cell 85: 291-297 (1996)), systemic lupus erythematosus (SLE) (Kotzin, Cell 85: 303-306 (1996)), and uveoretinitis (Prendergast et al., Invest. Opthalmol. Vis. Sci. 39: 754-762 (1998)).
The pathological link between MHC Class I and/or Class II expression and disease has been examined in many of these model systems using a variety of biochemical and genetic approaches. However, the strongest evidence for aberrant MHC gene function as a mediator of autoimmune disease stems from transgenic animal models in which the MHC genes have been inactivated. Using MHC Class I deficient animals resistance to the autoimmune disease process—and hence the dependence of autoimmunity upon MHC gene expression—can be directly demonstrated in animal models for IDDM (Serreze et al., Diabetes 43: 505-509 (1994)), and SLE (Mozes et al., Science 261: 91-93 (1993)).
Moreover, the dependence of the progressive multifocal inflammatory autoimmune disease phenotype exhibited by TGF-betal deficient transgenic mice (Shull et al., Nature 359: 693-699 (1992); Kulkarni et al., Proc. Natl. Acad. Sci. 90: 770-774 (1993); Boivin et al., Am. J. Pathol. 146: 276-288 (1995)) on MHC Class II expression has recently been demonstrated using MHC Class II deficient animals. Specifically, TGF-betal deficient animals lacking MHC Class II expression are without evidence of inflammatory infiltrates, circulating antibodies, or glomerular immune complex deposits (Letterio et al., J. Clin. Invest. 98: 2109-2119 (1996)).
In addition to the information supportive of MHC Class I and Class II antigens as critical for the development of autoimmunity in animal models there is equally strong evidence linking autoimmune processes with expression of MHC Class I and MCH Class II antigens in humans.
Graves' disease is a relatively common autoimmune disorder of the thyroid. In Graves' disease, autoantibodies against thyroid antigens, particularly the thyrotropin receptor (TSHR), alter thyroid function and result in hyperthyroidism (Stites, D. P. and Terr, A. I. (eds), “Basic and Clinical Immunology”, Appleton and Lang, Norwalk, Conn./San Mateo, Calif., 1991, pp. 469-470)). Thyrocytes from patients with Graves' disease have aberrant MHC Class II expression and elevated MHC Class I expression (Hanafusa et al., Lancet 2:1111-1115 (1983); Bottazzo et al., Lancet 2:1115-1119 (1983); Kohn, et al., in “International Reviews of Immunology,” Vol. 912, pp. 135-165, (1992)). Aberrant expression of MHC Class II and TSHR on fibroblasts, but not either alone, has recently been shown to induce Graves' disease in mice, i.e., aberrant expression of Class II on target tissue can yield autoimmune disease in animals with normal immune systems. Thionamide therapy has historically been used to treat Graves' disease. The most commonly used thionamides are methimazole, carbimazole and propylthiouracil. These thionamides contain a thiourea group; the most potent are thioureylenes (W. L. Green, in Werner and Ingbar's “
The Thyroid
”: A Fundamental Clinical Text, 6
th
Edition, L. Braverman and R. Utiger (eds), J. B. Lippincott Co., 1991, p. 324). The basis for thionamide therapy has, however, not focused on immune suppression. Rather, the basis has been suppression of thyroid hormone formation. Experiments suggesting an effect on immune cells, to inhibit antigen presentation or antibody formation, are largely discounted as nonphysiologic in vitro artifacts of high MMI concentration. MMI activity under those circumstances is suggested to be based on free-radical scavenger activity. See D. S. Cooper, in Werner E. Ingbar's “
The Thyroid
”, op. cit., pp. 712-734.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that, like Graves' disease, has a relatively high rate of occurrence. SLE affects predominantly women, the incidence being 1 in 700 among women between the ages of 20 and 60 (Abbus, A. K., Lichtman, A. H., Pober, J. S. (eds), “Cellular and Molecular Immunology”, W.B. Saunders Company, Philadelphia, 1991, pp. 360-370). SLE is characterized by the formation of a variety of autoantibodies and by 20 multiple organ system involvement (Stites and Terr, ibid, pp. 438-443). Current therapies for treating SLE involve the use of corticosteroids and cytotoxic drugs, such as cyclophosphamide. Immunosuppressive drugs, such as cyclosporin, FK506 or rapamycin suppress the immune system by reducing T cell numbers and function (Morris, P. J., Curr. Opin. in Immun., 3:748-751 (1991)). While these immunosuppressive therapies alleviate the symptoms of SLE and other autoimmune diseases, they have numerous severe side effects. In fact, extended therapy with these agents may cause greater morbidity than the underlying disease. A link between MHC Class I expression and SLE in animal models has been established. Thus, Class I deficient mice do not develop SLE in the 16/6 ID model (Mozes, et al., Science 261: 91-93 (1993)).
Women suffering from SLE who have breast cancer face particular difficulties. These individuals are immunosuppressed as a result of corticosteroid and cytotoxic drug treatment for SLE; radiation therapy for the treatment of the cancer, a current treatment of choice, would additionally exacerbate the immunosuppressed state. Further, radiation therapy can exacerbate disease expression or induce severe radiation complications. For these individuals, alternative therapies that would allow for simultaneous treatment of SLE and cancer are greatly
Curley Robert W.
Kohn Leonard D.
Rice John M.
Criares Theofore J.
Frost Brown Todd LLC
Sentron Medical, Inc.
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