Reduction of graft-versus-host disease by modulation of SHIP activity

• US 8,163,710 B2
• Filed: 01/04/2010
• Issued: 04/24/2012
• Est. Priority Date: 09/19/2000
• Status: Active Grant

• Current Assignee: University of South Florida (State University System of Florida)
• Original Assignee: University of South Florida (State University System of Florida)
• Inventors: Kerr, William G.
• Primary Examiner(s): GIBBS, TERRA C
• Application Number:
  US12/651,809
• Publication Number:
  US 20100144841A1
• Time in Patent Office: 841 Days
• Field of Search: 435/6, 435/91.1, 435/91.31, 435/455, 514/1, 514/2, 514/44, 536/23.1, 536/24.5
• US Class Current: 514/44.R
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/025 Animal producing cells or organs for transplantation
• CPC Class Codes: A01K 2267/0325 Animal model for autoimmune diseases
• CPC Class Codes: A01K 2267/0387 Animal model for diseases of the immune system
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: C12N 2800/30 Vector systems comprising sequences for excision in presence of a recombinase, e.g. loxP or FRT
• CPC Class Codes: C12N 9/14 Hydrolases (3)
• CPC Class Codes: C12N 9/16 acting on ester bonds (3.1)
• CPC Class Codes: G01N 2333/916 acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)

Abstract

Inhibition of dendritic cell function in solid organ grafts or allogeneic bone marrow transplants prior to or during engraftment by blocking SH2-containing inositol phosphatase (SHIP) expression or function is taught as a method of abrogating immune rejection and thereby increasing the efficacy of engraftment of an allogeneic bone marrow transplant or solid organ allograft or xenograft. Also disclosed is a transgenic mouse having the genotype SHIP^−/− which exhibits enhanced survival following mismatched allogeneic marrow grafts.

Claims

1. A method for treating or reducing the probability of graft-versus-host disease (GvHD) in a human having or in need of a transplant, comprising administering to the human an efficacious amount of a substance that inhibits SH2-containing inositol-5-phosphatase (SHIP) expression in the human, wherein the substance comprises an interfering RNA specific for SHIP mRNA or an anti-sense polynucleotide specific for SHIP mRNA, and wherein the inhibition of SHIP expression treats or reduces the probability of GvHD.

2. The method of claim 1, wherein the transplant is a bone marrow allograft, a solid organ allograft or xenotransplant, or a major histocompatibility complex (MHC) disparate marrow graft having an MHC disparity of 1, 2, 3 or more allelic mismatches.

3. The method of claim 1, wherein the substance comprises the anti-sense polynucleotide.

4. The method of claim 1, wherein the human has cancer, autoimmune disease, HIV/AIDS, a genetic deficiency, or a combination thereof.

5. The method of claim 1, wherein the substance comprises the interfering RNA.

6. The method of claim 1, wherein the substance is administered prior to, or at the time of, the transplant.

7. The method of claim 1, wherein the substance is administered intravenously or intra-arterially.

15. The method of claim 1, wherein the human has GvHD and the substance is administered to treat the GvHD in the human.

16. The method of claim 1, wherein the human does not have GvHD, and wherein the substance is administered to reduce the probability of GvHD in the human.

8. A method for treating or reducing the probability of graft-versus-host disease (GvHD) in a human, comprising administering to the human:

a transplant; and

an efficacious amount of a substance that inhibits SH2-containing inositol-5-phosphatase (SHIP) expression in the human, wherein the substance comprises an interfering RNA specific for SHIP mRNA or an anti-sense polynucleotide specific for SHIP mRNA, and wherein the inhibition of SHIP expression treats or reduces the probability of GvHD.

9. The method of claim 8, wherein the substance comprises the interfering RNA.

10. The method of claim 8, wherein the substance comprises the anti-sense polynucleotide.

11. The method of claim 8, wherein the transplant is a bone marrow allograft, a solid organ allograft or xenotransplant, or a major histocompatibility complex (MHC) disparate marrow graft having an MHC disparity of 1, 2, 3 or more allelic mismatches.

12. The method of claim 8, wherein the human has cancer, autoimmune disease, HIV/AIDS, a genetic deficiency, or a combination thereof.

13. The method of claim 8, wherein the substance is administered prior to, or at the time of, administration of the transplant.

14. The method of claim 8, wherein the substance is administered intravenously or intra-arterially.

17. The method of claim 8, wherein the human has GvHD and the substance is administered to treat the GvHD in the human.

18. The method of claim 8, wherein the human does not have GvHD, and wherein the substance is administered to reduce the probability of GvHD in the human.