Methods for regulating T cell subsets by modulating transcription factor activity

Abstract

Methods for modulating production of a T helper type 2 (Th2)-associated cytokine, in particular interleukin-4, by modulating the activity of one or more transcription factors that cooperate with NF-AT family proteins to regulate expression of a Th2-associated cytokine gene are disclosed. In one embodiment, the activity of a maf family protein (e.g., c-Maf or a small maf protein, such as p18) is modulated. In another embodiment, the activity of a protein that interacts with an NF-AT family protein (e.g., NIP45) is modulated. Combination methods, for example wherein the activities of a maf family protein and an NF-AT protein are modulated or the activities of a maf protein and NF-AT-interacting protein are modulated, are also encompassed by the invention. Methods for modulating development of T helper type 1 (Th1) or T helper type 2 (Th2) subsets in a subject using agents that modulate transcription factor activity are also disclosed.

Description

RELATED APPLICATIONS [0001] This application is a continuation application of U.S. Ser. No. 10 / 236,629, entitled “Methods and Compositions for Regulating T cell Subsets by Modulating Transcription Factor Activity”, filed Sep. 5, 2002, which is a continuation application of U.S. Ser. No. 08 / 755,592, entitled “Methods and Compositions for Regulating T cell Subsets by Modulating Transcription Factor Activity”, filed Nov. 25, 1996, which is a continuation-in-part of U.S. Ser. No. 08 / 636,602, entitled “Methods and Compositions for Regulating T cell Subsets by Modulating Transcription Factor Activity”, filed Apr. 23, 1996, the entire contents of which are expressly incorporated herein by reference. This application is also related to U.S. Ser. No. 08 / 755,584, entitled “NF-AT Interacting Protein NIP45 and Methods of Use Therefor”, filed Nov. 25, 1996 (Attorney Docket No. HUI-026), the entire contents of which are expressly incorporated herein by reference.GOVERNMENT FUNDING [0002] Work des...

AI Technical Summary

Benefits of technology

[0010] The modulatory methods of the invention generally involve contacting a cell with an agent that modulates the expression or activity of a transcription factor(s) such that production of the Th2-associated cytokine by a cell is modulated. In particular, preferred agents of the invention act intracellularly to modulate the activity of the transcription factor. In one embodiment, the modulatory method of the invention stimulates production of a Th2-associated cytokine. For example, Th2-associated cytokine production can be stimulated in Th1 cells, B cells or non-lymphoid cells. In another embodiment, the modulatory method of the invention inhibits production of a Th2-associated cytokine. A Th2-associated cytokine modulated in the method preferably is interleukin-4.

[0011] A variety of agents can be used to stimulate the expression or activity of a transcription factor that regulates expression of a Th2-associated cytokine gene. For example, a stimulatory agent of the invention can be a nucleic acid molecule encoding the transcription factor that is introduced into and expressed in the cell. Alternatively, chemical agents that enhance the expression or activity of the transcription facto can be used as stimulatory agents.

[0012] A variety of agents can be used to inhibit the expression or activity of a transcription factor that regulates expression of a Th2-associated cytokine gene. Examples of suitable inhibitory agents include antisense nucleic acid molecules that are complementary to a gene encoding the transcription factor, intracellular antibodies that bind the transcription factor (e.g., in the cell nucleus), inhibitory forms of the transcription factor (e.g., dominant-negative forms) and chemical agents that inhibit the expression or activity of the transcription factor.

[0013] Combination methods, involving modulation of the expression or activity of two, three or more transcription factors that regulate Th2-associated cytokine gene expression, are also encompassed by the invention. Accordingly, in other embodiments of the invention, a cell is contacted with at least one additional agent that modulates the activity of at least one additional transcription factor that contributes to the regulation of the Th2-associated cytokine gene. Preferably, the at least one additional transcription factor whose expression or activity is modulated is selected from the group consisting of NF-AT family proteins, NF-AT-interacting proteins, maf family proteins and AP-1 family proteins.

[0014] Cytokine production by a cell can be modulated in vitro or in vivo in accordance with the methods of the invention. In one embodiment, a cell is contacted with a modulating agent(s) in vitro and then the cell is administered to a subject to thereby regulate the development of Th1 and / or Th2 subsets in the subject. Accordingly, in another aspect, the invention provides methods for regulating the development of Th1 or Th2 subsets in a subject. In addition to the embodiment wherein ex vivo modified cells are administered to the subject, in another embodiment, these methods involve direct administration to the subject of an agent that modulates the activity of one or more transcription factors that regulate expression of a Th2-associated cytokine gene such that development of Th1 or Th2 cells in the subject is modulated.

[0015] The modulatory methods of the invention can be used to manipulate Th1:Th2 ratios in a variety of clinical situations. For example, inhibition of Th2 formation may be useful in allergic diseases, malignancies and infectious diseases whereas enhancement of Th2 formation may be useful in autoimmune diseases and organ transplantation.

Problems solved by technology

However, as therapeutic options, systemic administration of cytokines or antibodies may have unwanted side effects and, accordingly, alternative approaches to manipulating Th1 / Th2 subsets are still needed.

However, none of these AP-1 proteins is expressed in a Th1- or Th2-specific manner and there is no evidence for the differential recruitment of AP-1 family members to the IL-2 or IL-4 composite sites (Rooney, J. et al.

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