Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1996-11-25
2003-03-25
Priebe, Scott D. (Department: 1632)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S069100, C435S455000
Reexamination Certificate
active
06537810
ABSTRACT:
BACKGROUND OF THE INVENTION
CD4+ T helper cells are not a homogeneous population but can be divided on the basis of cytokine secretion into at least two subsets termed T helper type 1 (Th1) and T helper type 2 (Th2) (see e.g., Mosmann, T. R. et al. (1986)
J. Immunol.
136:2348-2357; Paul, W. E. and Seder, R. A. (1994)
Cell
76:241-251; Seder, R. A. and Paul, W. E. (1994)
Ann. Rev. Immunol.
12:635-673). Th1 cells secrete interleukin-2 (IL-2) and interferon-&ggr; (IFN-&ggr;) while Th2 cells produce interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-10 (IL-10) and interleukin-13 (IL-13). Both subsets produce cytokines such as tumor necrosis factor (TNF) and granulocyte/macrophage-colony stimulating factor (GM-CSF). In addition to their different pattern of cytokine expression, Th1 and Th2 cells are thought to have differing functional activities. For example, Thl cells are involved in inducing delayed type hypersensitivity responses, whereas Th2 cells are involved in providing efficient “help” to B lymphocytes and stimulating production of IgG1 and IgE antibodies.
There is now abundant evidence that the ratio of Th1 to Th2 cells is highly relevant to the outcome of a wide array of immunologically-mediated clinical diseases including autoimmune, allergic and infectious diseases. For example, in experimental leishmania infections in mice, animals that are resistant to infection mount predominantly a Th1 response, whereas animals that are susceptible to progressive infection mount predominantly a Th2 response (Heinzel, F. P., et al. (1989)
J. Exp. Med.
169:59-72; Locksley, R. M. and Scott, P. (1992)
Immunoparasitology Today
1:A58-A61). In murine schistosomiasis, a Th1 to Th2 switch is observed coincident with the release of eggs into the tissues by female parasites and is associated with a worsening of the disease condition (Pearce, E. J., et al. (1991)
J. Exp. Med
173:159-166; Grzych, J-M., et al. (1991)
J. Immunol.
141:1322-1327; Kullberg, M. C., et al. (1992)
J. Immunol.
148:3264-3270). Many human diseases, including chronic infections (such as with human immunodeficiency virus (HIV) and tuberculosis) and certain metastatic carcinomas, also are characterized by a Th1 to Th2 switch (see e.g., Shearer, G. M. and Clerici, M. (1992)
Prog. Chem. Immunol.
54:21-43; Clerici, M and Shearer, G. M. (1993)
Immunology Today
14:107-111; Yamamura, M., et al. (1993)
J. Clin. Invest.
91:1005-1010; Pisa, P., et al. (1992)
Proc. Natl. Acad. Sci. USA
89:7708-7712; Fauci, A. S. (1988)
Science
239:617-623). Furthermore, certain autoimmune diseases have been shown to be associated with a predominant Th1 response. For example, patients with rheumatoid arthritis have predominantly Th1 cells in synovial tissue (Simon, A. K., et al. (1994)
Proc. Natl. Acad. Sci. USA
91:8562-8566) and experimental autoimmune encephalomyelitis (EAE) can be induced by autoreactive Th1 cells (Kuchroo, V. K., et al. (1993)
J. Immunol.
151:4371-4381).
The ability to alter or manipulate ratios of Th1 and Th2 subsets requires an understanding of the mechanisms by which the differentiation of CD4 T helper precursor cells (Thp), which secrete only IL-2, choose to become Th1 or Th2 effector cells. It is clear that the cytokines themselves are potent Th cell inducers and form an autoregulatory loop (see e.g., Paul, W. E. and Seder, R. A. (1994)
Cell
76:241-251; Seder, R. A. and Paul, W. E. (1994)
Ann. Rev. Immunol.
12:635-673). Thus, IL-4 promotes the differentiation of Th2 cells while preventing the differentiation of precursors into Th1 cells, while IL-12 and IFN-&ggr; have the opposite effect. One possible means therefore to alter Th1:Th2 ratios is to increase or decrease the level of selected cytokines. Direct administration of cytokines or antibodies to cytokines has been shown to have an effect on certain diseases mediated by either Th1 or Th2 cells. For example, administration of recombinant IL-4 or antibodies to IL-12 ameliorate EAE, a Th1-driven autoimmune disease (see Racke; M. K. et al. (1994)
J. Exp. Med
180:1961-1966; and Leonard, J. P. et al. (1995)
J. Exp. Med.
181:381-386), while anti-IL-4 antibodies cure the Th2-mediated parasitic disease,
Leishmania major
(Sadick, M. D. et al. (1990)
J. Exp. Med.
171:115-127). 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.
The molecular basis for the tissue-specific expression of IL-4 in Th2 cells, or any T cell cytokine, has remained elusive. One possibility is the presence of repressor proteins that selectively silence cytokines. Transcriptional silencing has been well documented for bacteria, yeast and mammalian genes. Examples include
E. coli
thermoregulation genes (Goransson, M. et al. (1990)
Nature
344:682-685), yeast &agr;2 mating type genes (Keleher, C. A. et al. (1988)
Cell
53:927-936) and mammalian MHC class I and TcR&agr; genes (Weisman, J. D. and Singer, D. S. (1991)
Mol. Cell. Biol.
11:4228-4234; Winoto, A. and Baltimore, D. (1989)
Cell
59:649-655). Indeed, early experiments involving injection of IL-2 genomic DNA into Xenopus oocytes suggested the existence of a repressor protein for IL-2 in resting versus activated T cell extracts (Mouzaki, A. et al. (1991)
EMBO J.
10:1399-1406). These studies suggested that the absence of IL-2 production in resting T cells was due to proteins that silenced the transcription of IL-2 by interacting with negative elements in the IL-2 promoter.
A second possibility is the existence of Th selective transactivators. A family of four related transcription factors called Nuclear Factor of Activated T cells (NF-AT), plays a key role in the regulation of cytokine gene expression (see e.g., Emmel, E. A. et al. (1989)
Science
246:1617-1620; Flanagan, W. M. et al. (1991)
Nature
352:803-807; Jain, J. et al. (1993)
Nature
365:352-355; McCaffrey, P. G. et al. (1993)
Science
262:750-754; Rao, A. (1994)
Immunol. Today
15:274-281; Northrop, J. P. et al. (1994)
Nature
369:497). However, NF-AT family members can bind to and transactivate the promoters of multiple cytokine genes including IL-2 and IL-4 (Rooney, J. et al. (1995)
Immunity
2:545-553; Szabo, S. J. et al. (1993)
Mol. Cell. Biol.
13:4793-4805; Flanagan, W. M. et al. (1991)
Nature
352:803-807; Northrop, J. P. et al. (1994)
Nature
369:497). Thus, they are not likely to be responsible for directing Th1- or Th2-specific cytokine transcription. Most, if not all, NF-AT binding sites in cytokine promoter regulatory regions are accompanied by nearby sites that bind auxiliary transcription factors, usually members of the AP-1 family. It has been shown that NF-AT and AP-1 proteins bind coordinately and cooperatively and are required for full activity of the IL-2 and IL-4 promoters. Different AP-1 proteins, specifically c-Jun, c-Fos, Fra-1, Fra-2, Jun B and Jun D, have been shown to bind to these sites (Rao, A. et al. (1994)
Immunol. Today
15:274-281; Jain, J. et al. (1993)
Nature
365:352-355; Boise, L. H. et al. (1993)
Mol. Cell. Biol.
13:1911-1919; Rooney, J. et al. (1995)
Immunity
2:545-553; Rooney, J. et al. (1995)
Mol. Cell. Biol.
15:6299-6310). 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. (1995)
Mol. Cell. Biol.
15:6299-6310). Thus, neither NF-AT proteins nor the AP-1 family members c-Jun, c-Fos, Fra-1, Fra-2, Jun B and Jun D can account for the tissue-specific transcription of IL-4 in Th2 cells.
SUMMARY OF THE INVENTION
This invention pertains to methods for regulating production of Th2-associated cytokines and for regulating Th1 or Th2 subsets by modulating the activity of one or more transcription factors that regulate expression of Th2-specific cytokine genes. As described further herein, it has now been discovered that the tissue-specific expression of IL-4 in Th2 cells is n
Glimcher Laurie H.
Ho I-Cheng
DeConti, Jr. Esq. Giulio A.
Kanik Cynthia L.
Lahive & Cockfield LLP
President and Fellows of Harvard College
Priebe Scott D.
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