Nucleic acid molecules encoding a 103 gene product and uses...

Details Nucleic acid molecules encoding a 103 gene product and uses... Nucleic acid molecules encoding a 103 gene product and uses...

2000-04-28

2001-11-27

Gambel, Phillip (Department: 1644)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C536S023500, C435S069100, C435S455000, C435S252300, C435S320100

Reexamination Certificate

active

06323334

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to methods and compositions for the treatment and diagnosis of immune disorders, especially T lymphocyte-related disorders, including, but not limited to, chronic inflammatory disease and disorders (e.g., Crohn's disease, reactive arthritis, and Lyme disease), insulin-dependent diabetes, organ specific autoinmmunity (including, e.g., multiple sclerosis, Hashimoto's thyroiditis and Grave's disease), contact dermatitis, psoriasis, graft rejection, graft versus host disease, sarcoidosis, atopic conditions (e.g., asthma and allergy including, but not limited to, allergic rhinitis and gastrointestinal allergies such as food allergies), eosinophilia, conjunctivitis, glomerular nephritis, systemic lupus erythematosus, scleroderma, certain pathogen susceptibilities such as helminthic (e.g., leishmaniasis) and certain viral infections (including HIV and bacterial infections such as tuberculosis and lepromatous leprosy).
In particular, the methods and compositions of the present invention relate to detection and/or modulation of expression and/or activity of a gene product referred to herein as the 103 gene, as well as to detection and/or modulation of expression and/or activity of gene products encoded by the 103 gene (i.e., a “103 gene product”).
2. BACKGROUND OF THE INVENTION
The majority of mature T lymphoeytcs can be divided into two distinct phenotypes: CD8
+
cytotoxic T lymphocytes (CTLs), which display the CD8 marker on their cell surface, and CD4
+
helper T lymphocytes (T helper or TH cells), which display the CD4 marker on their cell surface. This subdivision is also associated with functional differences between the two cell types. CTLs are, in general, involved in cell-mediated, or cellular, immune responses, and are activated by intracellular pathogens such as, for example, microbes and viruses. In particular, foreign antigens (e.g., viral antigens) are synthesized within infected cells and presented on the surfaces of such cells in association with class I major histocompatibility complex (MHC) molecules. CTL precursors display T cell receptors that recognize these antigens, triggering activation, maturation and proliferation of the precursor CTLs and resulting in CTL clones capable of destroying the cells exhibiting the antigens recognized as foreign.
T helper (TH) cells are involved in both humoral (i.e., antibody) and cell-mediated forms of immune response. With respect to the involvement of TH cells in humoral, or antibody, immune response, extracellular antigens are endocytosed by antigen presenting cells (APCs), processed and presented, preferentially in association with class II MHC molecules, to CD4
+
class II MHC-restricted TH cells. These TH cells in turn activate B lymphocytes, resulting in antibody production. With respect to the role of TH cells in cell-mediated forms of immune response, some agents, such as mycobacteria which cause tuberculosis and leprosy, are engulfed by macrophages and processed in vacuoles containing proteolytic enzymes and other toxic substances. While these macrophage components are capable of killing and digesting most microbes, agents such as mycobacteria survive and multiply. However, the agents' antigens are processed by the macrophages and presented in association with class II MHC molecules to CD4
+
class II MHC-restricted TH cells. These TH cells, in turn, become stimulated to secrete interferon-&ggr; (IFN-&ggr;) which activates macrophages. Such activation results in an increased bacteriocidal ability.
TH cells have been further categorized into two distinct subpopulations, termed TH1 and TH2 cell subpopulations. These two subpopulations of TH cells have been categorized on the basis of their restricted cytokine profiles and different functions. For example, TH1 cells are known to produce IL-2, tumor necrosis factor &bgr; (TNF-&bgr;) and IFN-&ggr;. TH2 cells are known to produce interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10) and interleukin 13 (IL-13). The different subpopulations are derived from a common precursor, or “naive” TH cell population (referred to as THP), and acquire their set pattern of cytokine production during a process referred to as “commitment.”
Genetic and environmental factors acting at the level of antigen presentation influence the commitment of a common naive T cell precursor to TH1 or TH2 differentiation. For example, the conditions of antigen stimulation (including both the nature and amount of antigen involved), the type of antigen-presenting cells and the type of hormone and cytokine molecules present all seem to represent determinants of the pattern of TH1 versus TH2 differentiation from a common naive T helper cell precursor. In particular, the decisive role appears to belong to the particular cytokines present in the cells environment. For example, IL-4, which is produced by TH2 and TH2-like cells, also appears to be an important factor in the commitment of naive THP cells to the TH2 subtype. Further, once TH1 and TH2 subpopulations are expanded, the two cell types tend to negatively regulate one another through the actions of cytokines unique to each subpopulation. For example, IFN-&ggr;, which is produced by TH1 cells, negatively regulates TH2 cells, while TH2-produced IL-10 negatively regulates TH1 cells. Moreover, cytokines produced by TH1 and TH2 antagonize the effector functions of one another (Mosmian, T. R. and Moore, 1991,
Immunol. Today
12:49). Although a full accounting of the exact factors important in driving TH1 and/or TH2 differentiation are, as yet, largely unknown, certain transcription factors activated in response to a given cytokine have been shown to be important in TH1 and/or TH2 differentiation. For example, the activation of signal transducer and activator of transcription (STAT)-6 by IL-4 has been shown to be important in TH2 differentiation, and the activation of STAT-4 has been shown to be important in TH1 differentiation (e.g., Romagnani, S., 1997,
Immunology Today
18:263-266; Ray, A. and Cohn, L., 1999,
The Journal of Clinical Investigation
104(8):985-993).
Although the TH1 and TH2 subtypes were originally identified in murine systems (see, for example, Mosmann, T. R. and Coffman, R. L., 1989,
Ann, Rev. Immunol.
7:145), the existence of TH1-like and TH2-like subpopulations has also been established in humans (see, e.g., Del Prete, A. F. et al., 1991,
J. Clin. Invest.
88:346; Wiemenga, E. A. et al., 1990,
J. Imm.
144:4651; Yamamura, M. et al., 1991,
Science
254:277; Robinson, D. et al., 1993,
J. Allergy Clin. Imm.
92:313; Anderson, G. P. and Coyle, A. J., 1994,
Trends in Pharmacological Sciences
15(9):324-32; Romagnani, S., 1997,
Immunology Today
18:263-266). Human TN1-like and TH2-like cells have similar cytokine profiles to the TH1 and TH2 cells originally identified in murine systems, and preferentially express activation markers (e.g., CD30 and LAG-1). CD30, a member of the tumor necrosis factor (TNF) receptor family, is primarily expressed by TH2-like cells, and lymphocyte activation gene 3 (LAG-3) is preferentially expressed by TH1-like cells.
TH cells having characteristics (e.g., cytokine production profiles) of both TH1 and TH2 cell subpopulations have been designated THO cells (see, e.g., Firestein, G. S. et al., 1999,
J. Imm.
143:518). CD8
+
T cytotoxic (Tc)-cell subpopulations have also been identified based on the cytokines they produce. In general, activated CD8
+
CTLs exhibit a TH1-like cytokine profile, but under some conditions CD8
+
CTLs exhibit a TH2-like cytokine profile (Seder, R. A. et al., 1995,
J. Exp. Med.
181:5-7; Manetti, R. et al., 1994,
J. Exp. Med.
180:2407-2411; Maggi, E. et al., 1994,
J. Exp. Med.
180:489-495). As noted above, TH1 and TH2 cell subpopulations appear to have great relevance to immune response against infectious agents such as viruses and intracellular parasites.
TH1-like and TH2-like cells appear to function as part of different effector functions of the immun

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