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Immunologically privileged cells and uses thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.), Eukaryotic CellImmunologically privileged cells and uses thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060110377, Immunologically privileged cells and uses thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation of U.S. Ser. No. 09/770,601, filed Jan. 26, 2001, now U.S. Pat. No. N,NNN,NNN which is a division of U.S. Ser. No. 09/127,296, filed Jul. 30, 1998, now abandoned, and claims the benefit of U.S. Provisional Application Ser. No. 60/054,730, filed Aug. 5, 1997. The contents of all of the prior applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0003] The invention relates to immuno privileged cells and the use thereof in tissue transplant and cell-based therapies. [0004] Insulin dependent diabetes mellitus (IDDM) in humans and in non-obese diabetic (NOD) mice is an immune-mediated disorder in which mononuclear cells invade the pancreatic islets of Langerhans (insulitis) and effect the selective destruction of insulin-secreting pancreatic .beta. cells (Eisenbarth G. S. (1983) N. Engl. J. Med. 308, 322-27). Since the introduction of insulin therapy in 1922, the majority of acute deaths due to insulin deficiency have been prevented. However, current insulin treatment regimens are still suboptimal for blood glucose control and patients with IDDM are at significant risk for the development of serious long-term complications such as blindness and kidney disease. Although progress is being made in the field of allogeneic islet transplantation as an alternative approach to the treatment of IDDM, the clinical applicability of this approach has been severely limited by the scarce supply of available islets and the rapid and aggressive recurrence of autoimmune disease in transplanted islet grafts, which occurs despite treatment with systemic immunotherapy (Tyden et al., NEJM, 1996). [0005] Hepatocytes and the anterior pituitary tumor cell line, At T20, have been studied as potential insulin producing cells. Proinsulin, when transfected into hepatocytes which have only a constitutive pathway of protein secretion, is processed to insulin extremely inefficiently (Valera, A., Fillat, C., Costa, C., Sabater, J., Visa, J., Paujol, A. & Bosch, F. (1994) FASEB J. 8, 440-447; Kolodka, T. M., Finegold M., Moss L, Woo S. L. C. (1995) Proc. Natl. Acad. Sci. USA 92 3293-3297). At T20 cells have a regulated secretory pathway, with characteristic secretory granules containing the prohormone endopeptidases PC2 (Smeekens, S. P., Avruch, A. S., LaMendola, J., Chan, S. J. & Steiner, D. F. (1991) Proc. Natl. Acad. Sci. USA 88, 340-344), PC1/PC3 (Seidah, N. G., Marcinkiewicz, M. & Benjannet, S. (1991) Mol. Endocrinol. 5, 111-122), and carboxypeptidase H (Davidson, H. W. & Hutton, J. C. (1987) Biochem. J. 245,575-582) that identical in structure to native (i.e., .beta.-cell derived) insulin (Moore, H.-P., Walker, M. D., Lee, F., & Kelly R. B. (1983) Cell 35, 531-538; Ferber, S. Gross, D. J., Villa-Komaroff, L., Vollenweider, F., Meyer, K., Loeken, M., Kahn, C. R. & Halban, P. A. (1991) Mol. Endo. 5, 319-326). A major limitation of using transfected anterior pituitary cells for insulin gene delivery is that their major endogenous secretory product is ACTH, and, thus, implantation of these cells into diabetic recipients can result in a severe Cushings-like hypercortisolemic syndrome (BeltrandelRio, H., Schnedl, W. J., Ferber, S. & Newgard C. B. in Pancreatic Islet Transplantation, Vol 1, Lanza, R. P and Chick, W. L., Ed., R.G. Landes Company, Austin, pp 169-178, 1994). In addition, AtT20 cells, like many transformed .beta.-cell lines, have an active constitutive pathway, with proinsulin comprising up to 25% of the secreted immunoreactive insulin (Gross, D. J., Halban, P. A., Kahn, C. R., Weir, G. C., Villa-Komaroff, L. (1989) Proc. Natl. Acad. Sci. USA 86, 4107-4111). SUMMARY OF THE INVENTION [0006] The inventor has discovered that immunologically privileged cells, e.g., intermediate lobe pituitary cells, are particularly suited for delivering polypeptides, e.g., insulin, to a subject. These cells are highly resistant to the autoimmune attack characteristic of IDDM. [0007] Embodiments of the invention include implanting immunologically privileged cells (including, for example, intermediate lob pituitary cells and Sertoli cells) in order to deliver proteins which are not normally expressed in such cells to a subject. Such cells, even if non-autologous, do not trigger the normal immune response when introduced systemically. Therefore, they are resistant to damage or destruction in vivo. These cells are also resistant to autoimmune attack. This makes them well-suited for delivering insulin for treatment of IDDM because they will not be destroyed following introduction by the autoimmune response which normally depletes the insulin-producing .beta. cells in individuals with IDDM. [0008] In embodiments of the invention, the immunologically privileged cells are transfected with a heterologous nucleic acid sequence, e.g., a protein encoding sequence, prior to systemic introduction. They can be transfected with a control region which is active in the cell. Such control regions include intermediate lobe pituitary cell specific promoters, enhancers or other control elements; a POMC promoter, or a CMV promoter. In a preferred embodiment, the cells are animal-derived intermediate lobe pituitary cells and the control region is from the same species as the cell. [0009] In the embodiments preferred for human therapy, a heterologous nucleic acid sequence encoding a human therapeutic protein, for example, insulin, is transfected into an animal-derived immunologically privileged cell, and the cell is implanted systemically in a subject. If the protein expressed is insulin, its secretion from the cells must be controlled in a glucose stimulated manner in order to properly regulate insulin levels in vivo. This is accomplished by having the cells transfected to also express proteins necessary to exercise such control. These additional proteins can include one or more of and preferrably all of: glucose phosphorylating protein, e.g., glucokinase with a high Km for glucose, and preferably, the .beta.-cell isoform of glucokinase; a GLUT family member, e.g., GLUT-1,GLUT-3 or GLUT-5, and preferably GLUT-2 or another high Km glucose transporter; an ion channel which mediates glucose-stimulated insulin release, e.g., a K+/ATP ion channel, preferably, the sulfonylurea receptor/Kir 6.2 channel; and glucagon-like peptide-1 (GLP-1). [0010] Examples of other proteins which can be expressed in immunologically privileged cells include growth hormone, a hematopoietic hormone or growth factor, or a cytokine or lymphokine. The protein expressed would preferably be native to humans where intended for human treatment, but could also be native to animals if such protein was suitable for human-treatment of the cells where intended for veterinary use. [0011] The nucleotide sequences encoding any of the proteins to be expressed, or any of the control regions, can be inserted into the cell by standard transfection methods, e.g., adenoviral or retroviral gene delivery. These nucleotide sequences are preferably integrated into the chromosome of the cells. [0012] A number of variations of the invention described above are feasible and readily apparent to one skilled in the art. For example, the cells can be human or animal-derived, and include cells which are bovine, porcine, rodent (e.g., rat or mouse), or nonhuman primate derived. The protein expressed can be from the same or a different species from the cells, and can be autologous or non-autologous. The immunologically privileged cells can be cultured cells or cells derived from a transgenic animal. The cells can also be autologous cells which are transfected ex vivo with nucleotides coding for the protein(s) one wishes to express, and then introduced into the subject. The cells can also be allogenic, that is, a human cell from another human being not the subject, or xenogenic, from another species. One preferred intermediate lobe pituitary cell is a fetal or post natal cell. The cells may also be encapsulated in a non-antigenic coating, e.g., a hydrogel, an alginate compound, or a polymer (preferably a polymer which forms a semipermeable layer). [0013] As noted above, the immunologically privileged cells which express proteins can be introduced into humans or into non-human animals for veterinary uses. The therapy can be used in conjunction with immunosuppressants, for example, cyclosporine. Further, more than one therapeutic or beneficial protein can be expressed in a particular cell, if desired. [0014] In another embodiment, the invention includes using gene therapy techniques to transfect, in vivo, intermediate lobe pituitary cells with nucleotides which promote the expression of a protein. The nucleic acid can, by way of example, when integrated into the chromosome, stimulate the expression of an endogenous sequence. The nucleic acid can also encode a therapeutic or beneficial protein or proteins. Such proteins include growth hormone, a hematopoietic hormone or growth factor, or a cytokine or lymphokine, or insulin. Another embodiment of the invention includes using gene therapy techniques to transfect, in vivo, immunologically privileged cells (including intermediate lobe pituitary cells) with nucleotides which promote the expression of insulin and other proteins, in order to express insulin in a glucose stimulated insulin secreting manner. In yet another embodiment, the invention includes using gene therapy techniques to transfect, in vivo, other cell types to express insulin in a glucose stimulated insulin secreting manner. [0015] For any of these gene therapy embodiments, the transfection of the cells can be effected by conventional methods, including adenoviral or retroviral gene delivery. The nucleotide transfected encodes a protein not normally expressed by the target cell and operatively linked to a heterologous control region which supports expression of the nucleotide in the target cells. These techniques can be used in humans or non-human animals. Preferably, the subject is immunosuppressed by providing an immunosuppressant, e.g., cyclosporine before the transfection. [0016] The cell should also be transfected with a promoter, enhancer, or other control element, which is preferably active in the cells and included as part of the transfected nucleotide sequence, including POMC and a CMV promoter. For cells which are transfected to express insulin, they are preferably also transfected with oen or moare and preferrably all or: a glucose phosphorylating protein, e.g., glucokinase with a high Kmn for glucose and preferably, the .beta.-cell isoform of glucokinase; a GLUT family member, e.g., GLUT-1, GLUT-3 or GLUT-5, and preferably GLUT-2 or another high Km glucose transporter; an ion channel which mediates glucose-stimulated insulin release, e.g., a K+/ATP ion channel, preferably, the sulfonylurea receptor/Kir 6.2 channel; and glucagon-like peptide-1 (GLP-1). In such a case, the cells are also transfected with control regions for expression of such proteins. [0017] As another variation, in the case where insulin is expressed (whether the expressing cells are modified ex vivo or transfected in vivo), one can evaluate a parameter relating to glucose metabolism in connection with controlling insulin secretion. The parameter can include: the amount, distribution or structure of intracellular or extracellular insulin; glucose phosphorylating activity; or the amount, distribution, or structure of insulin encoding RNA; glucose utilization; glucose uptake; or insulin secretion [0018] The invention also includes immunologically privileged cells, or purified preparations thereof, discussed herein. As discussed herein, the cells have been engineered to express a protein they do not normally express. The cell can be an intermediate lobe pituitary cell, which expresses a human protein it does not otherwise express, e.g., human insulin. The cell can include one or more of and preferably all of: [0019] an insulin-encoding nucleic acid operatively linked to a control region other than the insulin control region, e.g., a control region which allows expression in intermediate lobe pituitary cells, e.g., a POMC promoter; [0020] a nucleic acid which encodes GLUT-2 operatively linked to a control region other than the GLUT-2 control region, e.g., a control region which allows expression in intermediate lobe pituitary cells, e.g., a POMC promoter; [0021] a nucleic acid which encodes a glucokinase, preferably the D cell isoform of glucokinase, operatively linked to a control region other than the glucokinase control region, e.g., a control region which allows expression in intermediate lobe pituitary cells, e.g., a POMC promoter; and [0022] a nucleic acid which encodes GLUT-2 operatively linked to a control region other than a GLUT-2 control region, e.g., a control region which allows expression in intermediate lobe pituitary cells, e.g., a POMC promoter; [0023] a nucleic acid which encodes a glucokinase, preferably the D cell isoform of glucokinase, operatively linked to a control region other than a glucokinase control region, e.g., a control region which allows expression in intermediate lobe pituitary cells, e.g., a POMC promoter; Continue reading about Immunologically privileged cells and uses thereof... 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