Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1998-06-02
2000-05-02
Priebe, Scott D.
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
4353201, 435325, 536 234, 424 932, 514 44, A61K 4800, C07H 2104, C12N 1563, C12N 1585
Patent
active
060569522
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to methods and compositions for the elimination of T cells that recognize specific preselected targets. In particular, the invention provides methods and compositions for the treatment of graft rejection and autoimmune diseases. In one embodiment, the invention provides modified killer cells that bear a preselected target molecule (e.g. an MHC molecule) attached to a signal transduction molecule (e.g. the zeta (.zeta.) chain of the T cell receptor or the low-affinity receptor for IgG, Fc.gamma.RIII (CD 16)). Recognition of the preselected molecule by a T cell activates the killer cell through the signal transduction molecule and the activated killer cell then kills or inhibits the T cell.
BACKGROUND OF THE INVENTION
Autoimmune diseases are pathological states mediated by an undesired immune response. More than 30 autoimmune diseases are presently known; these include many which have received much public attention, including myasthenia gravis (MG) and multiple sclerosis (MS). Characteristic of these diseases is the attack by the immune system on the tissues of the victim--these tissue antigens being non-immunogenic in non-diseased individuals because of the tolerance of the immune system to "self." In autoimmune diseases, this tolerance apparently is compromised, and the tissue of the afflicted subject is treated as an invader--i.e., the immune system sets about destroying this presumed foreign target.
Similarly in graft rejection the recipient of a graft or organ transplant mounts an immune response against the foreign (non-self) tissue. In this case the response is not a loss of tolerance, but rather a legitimate, although undesired, response directed against a foreign tissue.
A crude approach to treating graft or organ rejection or autoimmune disease is, of course, general immunosuppression. This has the obvious disadvantage of crippling the ability of the subject to respond to infectious organisms or tumors. An only slightly more sophisticated approach relies on the removal of antibodies or immune complexes involving the target tissue. This also has adverse side effects, is difficult to accomplish, and is not particularly effective.
Various approaches have been attempted to interdict the immune response to specific antigens. For example, the autoantigen thyroglobulin has been conjugated to ricin A and the conjugate was shown to suppress specifically the in vitro antibody response of lymphocytes which normally respond to this antigen. It was suggested that such immunotoxins would specifically delete autoantibody-secreting lymphocyte clones (Rennie, et al., Lancet (Dec. 10, 1983) 1338-1339).
Diener, et. al., Science 231: 148-150 (1986) suggested the construction of compounds which cause antigen-specific suppression of lymphocyte function by conjugating daunomycin to the hapten (in this case, of ovalbumin) using an acid-sensitive spacer. The conjugate caused hapten-specific inhibition of antibody secretion by B lymphocytes in vitro and in vivo. A conjugate of daunomycin (with an acid-sensitive spacer) to a monoclonal antibody-specific to T cells also eliminated the response by T-lymphocytes to concanavalin A.
Steerz et al., J. Immunol. 134: 841-846 (1985) utilized radiation as the toxic element in a toxin conjugate. Rats were administered a radioactively labeled, purified receptor from electric fish, prior to injection with cold receptor. Injection with this receptor is a standard procedure to induce experimental autoimmune myasthenia gravis (EAMG). Control rats that received preinjection only either of cold receptor or radiolabeled albumin, prior to administration of receptor to induce the disease develop the symptoms of EAMG; those pretreated with radioactively-labeled receptor showed reduced symptoms. It was surmised that the labeled, and therefore destructive, receptor selectively eliminated immunocompetent cells. Similar work utilizing a ricin/receptor conjugate for pretreatment was reported by Killen, et al., J. Immunol. 133: 2549-2553 (1984).
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REFERENCES:
Greenstein et al. (Mar. 1997) Nature Biotech., vol. 15, 235-238.
Fuchs et al. (1992) Science, vol. 258, 1156-1159.
Gilbert et al. (Jan. 1994) J. Exp. Med., vol. 179, 249-258.
Lanier, L. L. (Apr. 1997) Immunity, vol. 6, 371-378.
Leibson, P. J. (Jun. 1997) Immunity, vol. 6, 655-661.
Beckerleg Anne Marie S.
Priebe Scott D.
The United States of America as represented by the Department of
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