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  Carbon monoxide improves outcomes in tissue and organ transplants and suppresses apoptosisRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Animal Or Plant CellThe Patent Description & Claims data below is from USPTO Patent Application 20070202083. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. Provisional Application Nos. 60/300,289, filed Jun. 21, 2001; 60/334,340, filed Nov. 29, 2001; and 60/337,974, filed Dec. 7, 2001. TECHNICAL FIELD [0003] This invention relates to the field of enhancing cell survival. BACKGROUND [0004] Carbon monoxide (CO) gas is poisonous in high concentrations. However, it is now recognized as an important signaling molecule (Verma et al., Science 259:381-384, 1993). It has also been suggested that carbon monoxide acts as a neuronal messenger molecule in the brain (Id.) and as a neuro-endocrine modulator in the hypothalamus (Pozzoli et al., Endocrinology 735:2314-2317, 1994). Like nitric oxide (NO), carbon monoxide is a smooth muscle relaxant (Utz et al., Biochem Pharmacol. 47:195-201, 1991; Christodoulides et al., Circulation 97:2306-9, 1995) and inhibits platelet aggregation (Mansouri et al, Thromb Haemost. 48:286-8, 1982). Inhalation of low levels of CO has been shown to have anti-inflammatory effects in some models. [0005] Islet cell transplantation is a viable treatment for the amelioration of type I diabetes (Lacy et al., Annu. Rev. Immunol., 2:183-98, 1984; Weir et al., J. Am. Optom. Assoc. 69:727-32, 2000; Berney et al., Langenbechs Arch. Surg. 385: 378-8, 2000; Shapiro et al., N Engl. J. Med., 343:230-8, 2000). However, the processes of clinical islet transplantation are made difficult by a number of factors. One factor is primary nonfunction (PNF) of the graft. Another is the need for high numbers of donor islets needed for a successful reversal of diabetes (Shapiro et al., N Engl. J. Med., 343:230-8, 2000). Both situations reflect the same pathophysiology: the substantial cell loss in the graft within the first weeks after transplantation. After transplantation, islets suffer a variety of stress factors such as hypoxia before secondary vascularization (Carlsson et al., Diabetes 47:1027-32, 1998) and exposure to pro-inflammatory cytokines and free radicals released from macrophages in the microenvironment of the transplant (Rabinovitch et al., Diabetes 48:1223-9,1999; Kaufman et al., J Exp Med. 772:291-302, 1990; Corbett et al., Proc. Natl. Acad. Sci USA 90:1731-5, 1993) and from resident islet macrophages (Mandrup-Poulsen et al., J. Immunol. 739:4077-82, 1987; Arnush et al., J. Clin Invest. 702:516-26, 1998). The toxic effects of immunosuppressive drugs as well as rejection (Weir et al., Diabetes-46:1247-56, 1997) also contribute to islet cell loss. The existence of PNF after experimental syngeneic islet transplantation (Nagata et al., Transplant Proc. 22:855-6, 1990; Arita et al., Transplantation 65:1429-33, 1998) indicates that non-specific inflammation plays a major role in this scenario. [0006] Survival of a transplanted organ is thought to relate mainly to the success of immunosuppression, in terms of blocking the immune response that leads to graft rejection. However, it has previously been shown that transplanted organs can protect themselves from vascular injury leading to rejection through the expression of "protective genes" (see, e.g., Bach et al., Nature Med. 3:196-202 (1997); and Soares et al., Nat Med. 4:1073-1077, 1998). One such gene, heme oxygenase-1 (HO-1) catabolizes heme into biliverdin, free iron and CO (Tenhunen et al., Proc Natl Acad Sci USA 61:748-755, 1968). [0007] Endothelial cells (ECs) lining blood vessels maintain blood flow, allowing the continuous traffic of plasma and cellular constituents between blood and parenchymal tissues. To accomplish this function, ECs must promote a certain level of vasorelaxation and inhibit leukocyte adhesion as well as coagulation and thrombosis. However, when ECs are exposed to proinflammatory stimuli, they become "activated" and promote vasoconstriction, leukocyte adhesion and activation, and coagulation and thrombosis. These functional changes are due to the expression by activated ECs of a series of proinflammatory genes encoding adhesion molecules, cytokines/chemokines, and costimulatory and procoagulant molecules. Unfettered EC activation, as during acute and chronic inflammation, can lead to EC injury and apoptosis. EC apoptosis is a prominent feature associated with acute and/or chronic inflammation such as it occurs during hyperoxia, endotoxic shock, arteriosclerosis, ischemia reperfusion injury, and acute or chronic graft rejection. SUMMARY [0008] The present invention is based, in part, on the observations that CO promotes the survival and/or function of organ, tissue, and individual cell transplants. [0009] Accordingly, in one aspect, the present invention provides a method of administering to a transplant donor a pharmaceutical composition containing carbon monoxide, obtaining an organ, tissue or cells from the donor, and transplanting the organ, tissue or cells into a recipient, where the amount of carbon monoxide administered to the donor is sufficient to enhance survival or function of the organ or tissue after transplantation into the recipient. [0010] The pharmaceutical composition-can be administered to a live donor, to a brain-dead donor, or to the donor prior to and following brain death. [0011] Optionally, the organ can be treated in situ in the donor and/or ex vivo with a pharmaceutical composition comprising carbon monoxide. [0012] The method can also or alternatively include the step of administering to the recipient a second pharmaceutical composition that includes carbon monoxide, before and/or during and/or after the step of transplanting the organ or tissue into the recipient. [0013] In this or any of the methods described herein, the organ or tissue can be any organ which can be transplanted, e.g., a liver, a kidney, a heart, a pancreas, a lung, small intestine, and/or skin, and the donor can be of a species different from that of the recipient, or the donor and the recipient can be of the same species. The donor and the recipient can both be non-human animals or humans. Alternatively, the donor can be a non-human animal such as pig, and the recipient can be a-human. [0014] In another aspect, the invention provides a method of transplanting an organ, tissue or cells which includes providing an organ, tissue or cells of a donor, administering ex vivo or in situ to the organ, tissue or cells a pharmaceutical composition that includes carbon monoxide, and transplanting the organ or tissue into a recipient, wherein the amount of carbon monoxide is sufficient to enhance survival or function of the organ, tissue or cells in-the recipient. In one embodiment, the pharmaceutical composition is administered by perfusing the organ or tissue in situ while the organ or tissue is in the donor. [0015] Optionally, the method can include the step of administering to the recipient a second pharmaceutical composition containing carbon monoxide before and/or during and/or after transplantation of the organ or tissue into the recipient. [0016] In yet another aspect, the invention provides a method of transplanting an organ, tissue or cells that includes the steps of providing an organ, tissue or cells of a donor, transplanting the organ, tissue or cells into a recipient, and before, and/or during, and/or after the step of transplanting the organ, tissue or cells into the recipient, administering to the recipient an amount of a pharmaceutical composition containing carbon monoxide sufficient to enhance survival and/or function of the transplanted organ, tissue or cells in the recipient. [0017] In one embodiment, the pharmaceutical composition can be administered to the recipient within 0 to 20 days, e.g., within 1, 2, 4, 6, 8, 10, 12, 14, 18, or 20 days, after the organ has been transplanted into the recipient. In another embodiment, the pharmaceutical composition is administered to the recipient at least once, e.g., multiple times or continuously, from the time beginning 21 days after the step of transplanting the organ or tissue into the recipient for as long as needed to ensure survival of the graft. The pharmaceutical composition can be administered to the recipient upon determination that the transplanted organ or tissue-is undergoing or about to undergo rejection, e.g., chronic rejection or acute rejection. [0018] Optionally, the method can further include the step of administering to the donor a second pharmaceutical composition containing carbon monoxide prior to obtaining the organ or tissue from the donor. The second pharmaceutical composition can be administered to a live donor or to a brain-dead donor. [0019] The method can include the step of administering to the organ a second pharmaceutical composition containing carbon monoxide in situ in the donor and/or ex vivo. [0020] In another aspect, the invention provides a method of enhancing the survival and/or function of a donor organ, tissue or cell which includes providing an organ, tissue or cell of a marginal donor and exposing the organ, tissue or cell to an amount of a pharmaceutical composition containing carbon monoxide sufficient to enhance the survival and/or function of the donor organ, tissue or cell. [0021] In another aspect, the invention provides a method of maintaining an animal cell in vitro that includes providing a vessel containing a pressurized gas that includes carbon monoxide gas, providing an isolated cell in vitro, wherein the cell is a primary cell or stem cell, releasing the pressurized gas from the vessel to form an atmosphere that includes carbon monoxide gas, and maintaining the animal cell in vitro in the presence of the atmosphere that includes carbon monoxide gas. [0022] If desired, the cell can then be transplanted into a recipient. The cell may be obtained from a donor that is not the recipient, or it may be obtained from the recipient. Further, a carbon monoxide composition can be administered to the recipient prior to, and/or during, and/or after the transplantation step. This composition will typically be in the form of an inhaled gas. Continue reading... Full patent description for Carbon monoxide improves outcomes in tissue and organ transplants and suppresses apoptosis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Carbon monoxide improves outcomes in tissue and organ transplants and suppresses apoptosis patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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