1. Field of the Invention
This invention pertains to the administration of polycyclic aromatic compounds for the treatment of T cell-mediated diseases in mammals and compositions useful for treating T cell-mediated diseases.
2. Description of the Background Art
T cell-mediated diseases have been characterized by the induction of cytotoxic T-lymphocytes expressing the CD8 antigen on their cell surface and/or helper T cells expressing the CD4 antigen on their cell surface. These diseases, non-limiting examples being graft-versus-host diseaser graft rejection, and autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis, Graves diseases Addison's diseases polymyositis, insulin dependent diabetes, primary biliary cirrhosis, systemic Lupus erythematosus, psoriasis, scleroderma, represent a large number of host immune system disorders.
Graft-versus-host disease may occur when cells of the immune system such as stem cells or lymphocytes are transplanted into an allogeneic host, such as one genetically different at the major histocompatibility complex, which encodes cell surface antigens that give rise to strong immunological reactions. Transplants of cells of the immune system are made for treating certain forms of leukemia, aplastic anemia, and various immunodeficiency diseases. In order to prevent rejection of the foreign cells, the host is typically immunosuppressed, as with irradiation and/or immunosuppressive drugs. The transplanted immunocompetent cells recognize the host as foreign and mount an immune response directed against the host. In humans, the clinical manifestations of this graft-versus-host disease include fever, rash, anorexia, nausea, vomiting and watery or bloody diarrhea, weight loss and death.
It has also been reported that transfusion associated graft-versus-host disease can occur in immunocompetent transfusion recipients (Anderson, K. C., et al., New Eng. J. Med 323: 315-321, 1990).
Recipients of allogeneic (same species) solid tissue or organ grafts are usually treated with cytotoxic drugs such as cyclophosphamide, and other immunosuppressive drugs such as cyclosporin A (CsA), FK-506 (Metcalfe, S. et al., Transplantation 49:798-802, 1990), and more recently, 15-deoxyspergualin (Amemiya, H. et al., Transplantation 49:337-343, 1990). These drugs suppress the immune response against the transplanted tissue and thereby help prevent graft rejection. CsA is known to inhibit the activation of T cells by inhibiting the production and/or the secretion of cytokines such as interleukin-1 (L1), interleukin-2 (IL2), tumor necrosis factor (TNF) and interferon gamma, substances which are involved in the activation of cytotoxic T cells. Use of CsA, cyclophosphamide, 15-deoxyspergualin and FK-506 is limited not only because of the various toxic effects, but also due to the "global" induced immunosuppression which can lead to various infections and/or malignancyo Indeed, CsA therapy can result in the appearance of tumors, particularly lymphomas, in the treated host, necessitating discontinuance of therapy. CsA is also suspected to cause diabetes (Wahlstrom, M. E. et al., Transplantation 49:600-604, 1990). However CsA and FK-506 continue to be the most effective immunosuppressive therapy despite its dangerous side effects, due to a lack of other immunosuppressive agents that are as effective with less side effects.
Other approaches to treating allograft rejection involve the administration of monoclonal antibodies such as OKT3, which are specific for the T.sub.3 molecule associated with the T cell receptor on all T lymphocytes including cytotoxic T cells (New Engo J. Med. 313:338, 1986). OKT3 treatment eliminates the T-effector cells which mediate this reaction.
An autoimmune disease results from a malfunction or misdirection of the immune system. In a subject afflicted with an autoimmune disease, the immune system often does not distinguish between self and foreign antigens, resulting in recognition of autologous tissues or soluble molecules as if they were foreign, and subsequent immune responses to autologous cells or tissue cause autologous tissue distruction or inflammatory reactions normally reserved for foreign organisms, pathogens, cells or tissue.
Current treatments for autoimmune diseases also involve administration of drugs which non-specifically suppress the immune response. Examples of such drugs include methotrexate, cyclophosphamide, azathioprine, FK-506 and cyclosporin A. Glucocorticosteroids, such as prednisone and methylprednisolone are also commonly employed to treat autoimmunity. These drugs have limited efficacy against autoimmune diseases, have toxic side effects and tend to induce a "global" immunosuppression.
Another approach for treating autoimmune diseases involves induction of immunological tolerance or antigen-specific suppression by oral administration of the particular autoantigen involved in the disease. Examples include oral administration of collagen for collagen-induced arthritis (Nagler-Anderson et al. (Proc. Nat. Acad. Sci USA 83:7443-7446, 1986); oral administration of myelin basic protein to treat experimental allergic encephalomyelitis (Higgins, P. et al., J. Immunol. 140:1440-1445, 1988). However, this approach is limited due to the difficulty in identifying and purifying the antigen(s) responsible for the autoimmune disease.
Hypericin and related polycyclic aromatic compounds, generally of plant origin, are known to be useful in treating variety of diseases that are caused by viruses and retroviruses.
U.S. Pat. No. 4,898,891 (Feb. 6, 1990) discloses the antiviral activity of two aromatic polycyclic dione compounds, hypericin and pseudohypericin and related compounds.
The assignee's U.S. patent application Ser. No. 07/328,767, filed Mar. 20, 1989, as a continuation-in-part of U.S. patent application Ser. No. 07/084,008, filed Aug. 10, 1987 (now abandoned) expands upon the disclosure of U.S. Pat. No. 4,898, 891, which applications are entirely incorporated herein by reference, and disclose the use of hypericin and pseudohypericin as effective anti-retroviral agents.
The assignee's U.S. patent application Ser. No. 07/326,392, filed Mar. 28, 1989 as a continuation-in-part of U.S. patent application Ser. No. 07/172,065, filed Mar. 23, 1988 (now abandoned), which applications are entirely incorporated by reference herein, disclose antiretroviral compositions comprising effective amounts of hypericin and pseudohypericin in combination with nucleoside analogs such as azidothymidine (AZT), and describe methods for treating retroviral infections with such compositions.
The assignee's copending U.S. patent application Ser. No. 299,971, filed Jan. 19, 1989 and corresponding PCT Publication PCT/US90/00398 (Jul. 21, 1990), which applications are herein entirely incorporated by references disclose hypericin related compound containing compositions and methods for inactivating viruses and retroviruses present in bloods blood products and other body fluids and, more generally biological fluids, as well as articles useful for practicing such methods.
The assignee's U.S. patent application Ser. No. 07/417,163, filed Oct. 4, 1989 as a continuation-in-part of U.S. patent application Ser. No. 07/324,177, filed Mar. 19, 1989 (now abandoned) and corresponding PCT Publication PCT/US90/04163, which applications are herein entirely incorporated by reference, disclose compositions comprising aromatic polycyclic antiviral compounds and methods for treating viral infections. The disclosed polycyclic aromatic compounds include hypericin and related polycyclic diones as well as homologs, isomers, derivative, salts and analogs of such polycyclic dione compounds and mixtures thereof for treating viral and retroviral infections.
The assignee's copending U.S. patent application Ser. No. 07/552,889, filed May 14, 1990, which is entirely incorporated herein by referenced discloses aqueous pharmaceutical formulations and compositions comprising water-dispersed polycyclic aromatic compounds with improved biological and/or physical properties and methods of use thereof in treating viral and retroviral diseases.
Heretofore, there has been no disclosure or suggestion of the effects of the polycyclic aromatic compounds on T lymphocytes or their activities, nor on the function of the immune system.
At the present time there is a well-recognized need for effective agents and methods for treating T cell-mediated diseases, wherein the agents have no or low toxicity to the treated subject, but are effective in treating a broad spectrum of T-cell-mediated diseases. It is to such agents and methods that the present invention is directed.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents is considered material to the patentability of any of the claims of the present application, All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.