T cell balance gene expression, compositions of matters and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016377631-A1
Application number	US-201615245748-A
Country	US
Kind code	A1
Filing date	Aug 24, 2016
Priority date	Feb 27, 2014
Publication date	Dec 29, 2016
Grant date	—

Abstract

This invention relates generally to compositions and methods for identifying the regulatory network that modulates, controls or otherwise influences T cell balance, for example, Th17 cell differentiation, maintenance and/or function, as well compositions and methods for exploiting the regulatory network that modulates, controls or otherwise influences T cell balance in a variety of therapeutic and/or diagnostic indications. This invention also relates generally to identifying and exploiting target genes and/or target gene products that modulate, control or otherwise influence T cell balance in a variety of therapeutic and/or diagnostic indications.

First claim

What is claimed is:

1 . A method of diagnosing, prognosing and/or staging an immune response involving T cell balance, comprising detecting a first level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes selected from the genes of Table 1 or Table 2 and comparing the detected level to a control of level of signature gene or gene product expression, activity and/or function, wherein a difference in the detected level and the control level indicates that the presence of an immune response in the subject.

2 . A method of monitoring an immune response in a subject comprising detecting a level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 at a first time point, detecting a level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 at a second time point, and comparing the first detected level of expression, activity and/or function with the second detected level of expression, activity and/or function, wherein a change in the first and second detected levels indicates a change in the immune response in the subject.

3 . A method of identifying a patient population at risk or suffering from an immune response comprising detecting a level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 in the patient population and comparing the level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 in a patient population not at risk or suffering from an immune response, wherein a difference in the level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 in the patient populations identifies the patient population as at risk or suffering from an immune response.

4 . A method for monitoring subjects undergoing a treatment or therapy for an aberrant immune response to determine whether the patient is responsive to the treatment or therapy comprising detecting a level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 in the absence of the treatment or therapy and comparing the level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 in the presence of the treatment or therapy, wherein a difference in the level of expression, activity and/or function of one or more signature genes or one or more products of one or more signature genes of Table 1 or Table 2 in the presence of the treatment or therapy indicates whether the patient is responsive to the treatment or therapy.

5 . The method of any one of claims 1 to 4 wherein the immune response is an autoimmune response or an inflammatory response.

6 . The method of claim 5 wherein the inflammatory response is associated with an autoimmune response, an infectious disease and/or a pathogen-based disorder.

7 . The method of any one of claims 1 to 6 wherein the signature genes are Th17-associated genes.

8 . The method of any one of claims 4 to 7 , wherein the treatment or therapy is an antagonist for GPR65 in an amount sufficient to induce differentiation toward regulatory T cells (Tregs), Th1 cells, or a combination of Tregs and Th1 cells.

9 . The method of any one of claims 4 to 7 , wherein the treatment or therapy is an agonist that enhances or increases the expression of GPR65 in an amount sufficient to induce T cell differentiation toward Th17 cells.

10 . The method of any one of claims 4 to 7 , wherein the treatment or therapy is specific for a target gene selected from the group consisting of DEC1, PZLP, TCF4 and CD5L.

11 . The method of claim 10 , wherein the treatment or therapy is an antagonist of a target gene selected from the group consisting of DEC1, PZLP, TCF4 and CD5L in an amount sufficient to switch Th17 cells from a pathogenic to non-pathogenic signature.

12 . The method of claim 10 , wherein the treatment or therapy is an agonist that enhances or increases the expression of a target gene selected from the group consisting of DEC1, PZLP, TCF4 and CD5L in an amount sufficient to switch Th17 cells from a non-pathogenic to a pathogenic signature.

13 . The method according to any one of claims 8 to 12 , wherein the T cell modulating agent is an antibody, a soluble polypeptide, a polypeptide agent, a peptide agent, a nucleic acid agent, a nucleic acid ligand, or a small molecule agent.

14 . The method according to any one of claims 8 to 13 , wherein the T cells are naïve T cells, partially differentiated T cells, differentiated T cells, a combination of naïve T cells and partially differentiated T cells, a combination of naïve T cells and differentiated T cells, a combination of partially differentiated T cells and differentiated T cells, or a combination of naïve T cells, partially differentiated T cells and differentiated T cells.

15 . A method of modulating T cell balance, the method comprising contacting a T cell or a population of T cells with a T cell modulating agent in an amount sufficient to modify differentiation, maintenance and/or function of the T cell or population of T cells by altering balance between Th17 cells, regulatory T cells (Tregs) and other T cell subsets as compared to differentiation, maintenance and/or function of the T cell or population of T cells in the absence of the T cell modulating agent.

16 . The method of claim 15 , wherein the T cell modulating agent is an antagonist for GPR65 in an amount sufficient to induce differentiation toward regulatory T cells (Tregs), Th1 cells, or a combination of Tregs and Th1 cells.

17 . The method of claim 15 , wherein the T cell modulating agent is an agonist that enhances or increases the expression of GPR65 in an amount sufficient to induce T cell differentiation toward Th17 cells.

18 . The method of claim 15 , wherein the T cell modulating agent is specific for a target gene selected from the group consisting of DEC1, PZLP, TCF4 and CD5L.

19 . The method of claim 18 , wherein the T cell modulating agent is an antagonist of a target gene selected from the group consisting of DEC1, PZLP, TCF4 and CD5L in an amount sufficient to switch Th17 cells from a pathogenic to non-pathogenic signature.

20 . The method of claim 18 , wherein the T cell modulating agent is an agonist that enhances or increases the expression of a target gene selected from the group consisting of DEC1, PZLP, TCF4 and CD5L in an amount sufficient to switch Th17 cells from a non-pathogenic to a pathogenic signature.

21 . The method according to any one of claims 15 to 20 , wherein the T cell modulating agent is an antibody, a soluble polypeptide, a polypeptide agent, a peptide agent, a nucleic acid agent, a nucleic acid ligand, or a small molecule agent.

22 . The method according to any one of claims 15 to 21 , wherein the T cells are naïve T cells, partially differentiated T cells, differentiated T cells, a combination of naïve T cells and partially differentiated T cells, a combination of naïve T cells and differentiated T cel

Assignees

• Broad Inst Inc
• Brigham & Womens Hospital Inc
• Harvard College
• Massachusetts Inst Technology

Inventors

• Kuchroo Vijay
• Regev Aviv
• Gaublomme Jellert
• Lee Youjin
• Shalek Alexander K
• Wang Chao
• Yosef Nir
• Park Hongkun

Classifications

• A61P37/02

  Immunomodulators · CPC title

• C12Q2600/158

  Expression markers · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• C07K2317/75

  Agonist effect on antigen · CPC title

• C07K16/2896

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title