Control of NK cell function and survival by modulation of SHIP activity

• US 7,713,945 B2
• Filed: 04/13/2007
• Issued: 05/11/2010
• 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): WOLLENBERGER, LOUIS V
• Application Number:
  US11/787,064
• Publication Number:
  US 20080076731A1
• Time in Patent Office: 1,124 Days
• Field of Search: None
• US Class Current: 514/44.00R
• 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 reducing antigen presenting cell (APC) function in a human in need of allogeneic transplantation, comprising administering an efficacious amount of interfering RNA specific for SH2-containing inositol-5-phosphatase (SHIP) mRNA to the human, before or during allogeneic transplantation, wherein the interfering RNA reduces SHIP expression or function, and APC function, in the human.

2. The method of claim 1, wherein the allogeneic transplant is of a type selected from the group consisting of solid organ, and bone marrow.

3. A method for reducing antigen presenting cell (APC) function in a human in need of allogeneic transplantation, comprising administering an efficacious amount of a double-stranded RNA molecule to the human, before or during allogeneic transplantation, wherein the double-stranded RNA molecule reduces SH2-containing inositol-5-phosphatase (SHIP) expression or function and APC function in the human.

4. A method for inhibiting the expression of SH2-containing inositol-5-phosphatase (SHIP) protein in a human in need of allogeneic transplantation, comprising administering an efficacious amount of interfering RNA specific for SHIP mRNA to the human, before or during allogeneic transplantation, wherein the interfering RNA reduces SHIP protein expression in the human.

5. The method of claim 4, wherein the allogeneic transplant is of a type selected from the group consisting of solid organ, and bone marrow.

6. The method of claim 4, wherein the allogeneic transplant is a bone marrow transplant.

7. The method of claim 4, wherein the allogeneic transplantation is carried out after said administering of the interfering RNA.

8. The method of claim 7, wherein the allogeneic transplant is a bone marrow transplant.

9. The method of claim 8, wherein the allogeneic bone marrow transplantation is carried out for treatment of cancer, autoimmune disease, HIV/AIDS, or a genetic impairment.

10. The method of claim 4, wherein the interfering RNA is administered intravenously.