# US 2014/0154207 A1 · Kit containing stem cells and cytokines for use in attenuating immune responses

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- Number: US 2014/0154207 A1
- Document ID: US20140154207A1
- Status: Published application
- Kind: A1
- Application number: 14/174,557
- Filed: 2014-02-06
- Published: 2014-06-05
- Earliest claimed: 2008-01-31
- Assignees: Rutgers, The State University of New Jersey
- Applicants: Rutgers, The State University of New Jersey
- Inventors: Yufang Shi; Liying Zhang; Guangwen Ren
- Web page: https://patentgrep.com/patent/US20140154207A1

## CPC

- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 38/191: {Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta}
- A61K 38/2006: {IL-1}
- A61K 38/21: Interferons {[IFN]}
- A61K 38/217: {IFN-gamma}
- C12N 5/0663: {Bone marrow mesenchymal stem cells (BM-MSC)}
- A61K 35/12: Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells (vaccines or medicinal preparations containing antigens or antibodies A61K39/00)
- C07K 14/525: Tumour necrosis factor [TNF]
- C07K 14/545: IL-1
- C07K 14/57: IFN-gamma
- C12N 2501/23: Interleukins [IL]
- C12N 2501/24: Interferons [IFN]
- C12N 2501/25: Tumour necrosing factors [TNF]
- C12N 2502/11: blood or immune system cells
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to a composition and methods of treatment for inflammation comprising of adult stem cells and inflammatory cytokines. The invention further relates to the treatment of inflammation associated with autoimmune disorders, allergies, sepsis, cancer as well as to preventing, reducing or treating transplant rejection and/or graft-versus-host disease (GvHD).

## Claims

### Claim 1

A composition comprising:
(a) a population of isolated mesenchymal stem cells,
(b) isolated interferon gamma, and
(c) at least one cytokine selected from the croup consisting of isolated interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor alpha in admixture with a pharmaceutically acceptable carrier.

### Claim 2

(canceled)

### Claim 3

A method for attenuating an immune response comprising administering an effective amount of
(a) isolated mesenchymal stem cells,
(b) isolated interferon gamma, and
(c) isolated interleukin-1 alpha, interleukin-1 beta or tumor necrosis factor alpha to a subject in need of treatment thereby attenuating the subject's immune response.

### Claim 4

A Method for enhancing a local immune response comprising the steps:
(a) administering to a subject in need of treatment an effective amount of an inhibitor of inducible nitric oxide synthase, an inhibitor of indoleamine 2,3 dioxygenase, a population of inducible nitric oxide synthase-deficient mesenchymal stem cells, a population of indoleamine 2,3-dioxygenase-deficient mesenchymal stem cells or any combinations thereof; and
(b) inhibiting the production of one or more of nitrogen oxide (NO), indoleamine 2,3 dioxygenase (IDO), or prostaglandin E 2 (PGE2), thereby enhancing a local immune response.

### Claim at position 5

5-7. (canceled)

### Claim 8 (depends on 1)

The composition of claim 1, wherein said population of isolated mesenchymal stem cells is produced by a method comprising the steps of: (i) obtaining multipotent progenitor cells; (ii) culturing said multipotent cells in a suitable medium; (iii) separating mesenchymal stem cells from differentiated cells in said medium; (iv) activating at least a subset of said separated mesenchymal stem cells with interferon gamma (IFNγ) and at least one cytokine selected from the group consisting of interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα).

### Claim 9

A method for inducing immunosuppression in a patient in need thereof comprising administering to said patient an effective amount of
(a) a population of mesenchymal stem cells;
(b) isolated interferon gamma; and
(c) a cytokine selected from the group consisting of isolated interleukin-1 alpha, isolated interleukin-1 beta, tumor necrosis factor alpha, and a combination thereof.

### Claim 10 (depends on 9)

The method of claim 9, wherein said population of isolated mesenchymal stem cells, said isolated interferon gamma and said cytokine are administered individually or as a mixture.

### Claim 11 (depends on 10)

The method of claim 10, wherein said patient in need suffers from any one of the conditions selected from the group consisting of an autoimmune disorder, allergy, sepsis, cancer, and organ transplantation.

### Claim 12 (depends on 9)

The method of claim 9, wherein said population of mesenchymal stem cells is produced by a method comprising the steps of
(i) obtaining multipotent progenitor cells,
(ii) culturing said multipotent cells in a suitable medium
(iii) separating mesenchymal stem cells from differentiated cells in said medium
(iv) activating at least a subset of said separated mesenchymal stem cells with interferon gamma (IFNγ) and at least one cytokine selected from the group consisting, of interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα), for sufficient period of time.

### Claim 13 (depends on 12)

The method of claim 12, wherein said site of treatment is local to the site of said condition.

### Claim 14 (depends on 4)

The method of claim 4, wherein said inhibitors of iNOS or IDO and said population of mesenchymal stem cells are administered individually or as a mixture.

### Claim 15 (depends on 14)

The method of claim 14, wherein the mixture is a vaccine.

### Claim 16 (depends on 15)

The method of claim 15, wherein said condition is cancer.

### Claim 17 (depends on 16)

The method of claim 16, wherein said patient is post receiving a regimen of immune therapy.

### Claim 18 (depends on 16)

The method of claim 16, the immune therapy comprises administering an interferon.

### Claim 19

A method of producing activated mesenchymal stem cells comprising the steps of:
(i) obtaining multipotent progenitor cells,
(ii) culturing, said multipotent cells in a suitable medium,
(iii) separating clonal mesenchymal stem cells from differentiated cells in said medium,
(iv) activating at least a subset of said separated mesenchymal stem cells with interferon gamma (IFNγ) and at least one cytokine selected from the group consisting of interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL-1β)) and tumor necrosis factor alpha (TNFα).

### Claim 20 (depends on 4)

The method of claim 4, wherein the administration step is to a local tissue.

### Claim 21 (depends on 4)

The method of claim 4, wherein said inhibition of the production of one or more of nitrogen oxide (NO), indoleamine 2,3 dioxygenase (IDO), or prostaglandin E 2 (PGE2) is by at least a 50%, 60%, 70%, 80%, 90%, 95%, or 97% as compared to a subject not receiving the inhibitors.

### Claim 22 (depends on 4)

The method of claim 4, wherein said inhibitor of inducible nitric oxide synthase is a compound selected from the group consisting of 1400 W, GW 274150, aminoguanidine, (1-iminoethyl) lysine, and S-alkylated isothiourea.

### Claim 23 (depends on 4)

The method of claim 4, wherein said inhibitor of indoleamine 2,3 dioxygenase is a compound selected from the group consisting of 1-methyl-tryptophan (1-MT), and exiguamine A.