PEPTIDES AND METHODS OF TRANSPLANTATION AND RESTORATIVE ORGAN FUNCTION
This application describes compounds that are preimplantation factor (PIF) peptides, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof. This application also describes the use of those compounds for improving transplant tolerance, for restoring endocrine function, and for the treatment of transplant recipients of partial endocrine tissue grafts.
1 . A method of potentiating the effects of a steroid as a treatment in a subject in need thereof, the method comprising:
(i) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a PreImplantation Factor (PIF) peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or a combination thereof; and
(ii) administering a therapeutically effective amount of the steroid before, during or after step (i).
2 . The method of claim 1 , wherein the steroid is dexamethasone.
3 . The method of claim 1 , wherein the PIF peptide comprises one or a combination of an amino acid sequence comprising at least 86% sequence homology with: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO: 29.
4 . A method of restoring endocrine function in a subject comprising administering to the subject a therapeutically effective amount of a PIF peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof.
5 . The method of claim 4 , wherein the endocrine function is ovarian function.
6 . The method of claim 4 , wherein the therapeutically effective amount of a PIF peptide is the only therapeutic compound administered to the subject.
7 . The method of claim 4 , wherein the therapeutically effective amount is from about 0.1 mg/kg to about 5.0 mg/kg of subject.
8 . The method of claim 4 , wherein the method is free of administration of any immunomodulators.
9 . The method of claim 4 , wherein the method further comprises administration of one or a plurality of immunomodulators, analgesics, anti-inflammatory compounds, alpha-adrenergic agonists, antiarrhythmic compounds, anesthetic compounds, or combinations thereof.
10 . The method of claim 4 , wherein the method further comprises administration of one or a plurality of immunomodulators chosen from: azficel-T, etanercept, glatiramer acetate, lenalidomide, mifamurtide, pimecrolimus, thymalfasin, tinocordin, 6-mercaptopurine, anakinra, Cl esterase inhibitor recombinant, Cl esterase inhibitor human, dimethyl fumarate, ecallantide, fingolimod, glatiramer, icatibant, immunoglobulins, interferon alfa-n3, interferon alfacon-1, interferon beta-1a, interferon beta-1b, mercaptopurine, peginterferon beta-1a, rilonacept, siltuximab, and tocilizumab.
11 . The method of claim 4 , wherein the administering comprises one or more of the following modes of administration: intravenous, subcutaneous, intraperitoneal, intranasal, topical, intradermal, intramucosal, sublingual, oral, intravaginal, intramuscular, intracavernous, intraocular, intrarectal, into a sinus, gastrointestinal, intraductal, intrathecal, subdural, extradural, intraventricular, intrapulmonary, into an abscess, intraarticular, into a bursa, subpericardial, into an axilla, intrauterine, into the pleural space, transmucosal, and transdermal.
12 . The method of claim 4 , wherein the method is free of exposing the subject to x-rays or depletion of T-cell counts.
13 . The method of claim 4 , wherein endocrine function is restored for more than about 30, 40, 50, 60, 70, 80, 90 or 100 days.
14 . The method of claim 4 , wherein the step of administering to the subject a therapeutically effective amount of a PIF peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof is preceded by transplanting or engrafting endocrine tissue from a tissue donor into the subject.
15 . The method of claim 14 , wherein the endocrine tissue:
a) comprises an ovarian cell;
b) is ovarian tissue;
c) is free of pancreatic islet cells;
d) is free of adrenal cells; or
d) is an organ or part of an organ or a graft of an organ.
16 . A method of inducing transplant tolerance of one or a plurality of donor semi-allogeneic cells and/or cells derived from a species other than the transplant recipient in a recipient subject by increasing expression of HLA-Class I molecules in the subject or on the donor cells to an amount sufficient to increase the likelihood of transplant acceptance of the cells as compared to the levels of HLA Class I molecules on donor cells or in the subject untreated with a PIF peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof; the method comprising contacting the one or plurality of donor cells and/or the subject with a therapeutically effective amount of a PIF peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof.
17 . The method of claim 16 , wherein the method comprises contacting the one or plurality of donor cells with a therapeutically effective amount of a PIF peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof.
18 . The method of claim 16 , wherein the method comprises administering a therapeutically effective amount of a PIF peptide, compositions thereof, mimetics thereof, pharmaceutically acceptable salts thereof, or combinations thereof to the subject prior to or simultaneously with transplantation of the one or plurality of donor cells.
19 . The method of claim 16 , wherein the one or plurality of donor cells are embryo cells.