Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-08-31
2004-08-10
Kemmerer, Elizabeth (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S004000, C435S007100, C435S007200, C435S007240, C436S501000
Reexamination Certificate
active
06773895
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention belongs to the field of modulation of inflammatory processes, in particular of inflammatory airway diseases, in which macrophages play an important role. The inflammatory processes can be modulated according to the invention by influencing the function of receptors on macrophages, which receptors are identified to be involved in the inflammatory process.
Inflammatory processes involve a cascade of reactions. A wide variety of factors are involved in inflammatory processes leaving a single treatment to avoid said factors unsuccessful. This is in particular true for inflammatory processes of the airways, like the chronic inflammatory airway diseases.
Chronic inflammatory airway diseases include Chronic Bronchitis and Chronic Obstructive Pulmonary Disease (COPD). For example, COPD is a complex disease encompassing symptoms of several disorders: chronic bronchitis which is characterized by cough and mucus hypersecretion, small airway disease, including inflammation and peribronchial fibrosis, and emphysema. COPD is characterized by an accelerated and irreversible decline of lung function. The major risk factor for developing COPD is continuous cigarette smoking. Since only about 20% of all smokers are inflicted with COPD, a genetic predisposition is also likely to contribute to the disease.
The initial events in the early onset of COPD are inflammatory, affecting small and large airways. An irritation caused by cigarette smoking attracts macrophages and neutrophils the number of which is increased in the sputum of smokers. Perpetual smoking leads to an ongoing inflammatory response in the lung by releasing mediators from macrophages, neutrophils and epithelial cells that recruit inflammatory cells to sites of the injury. So far there is no therapy available to reverse the course of COPD. Smoking cessation may reduce the decline of lung function. Only a few drugs provide some relief for patients. Longlasting &bgr;2-agonists and anticholinergics are applied to achieve a transient bronchodilatation. A variety of antagonists for inflammatory events are under investigation like, LTB
4
-, IL-8-, TNF&agr;-inhibitors.
Chronic inflammatory airway diseases can be attributed to activated inflammatory immune cells, e.g. macrophages. There is a need for modulating the function of macrophages in order to eliminate a basis for inflammatory processes.
SUMMARY OF THE INVENTION
The present invention relates to substances which modulate receptors involved in inflammatory processes and whose modulated functions positively influence inflammatory diseases.
DESCRIPTION OF THE INVENTION
In the present invention it was found that macrophages involved in an inflammatory process, preferably in a chronic inflammatory airway disease, more preferably in chronic bronchitis or COPD, show a pattern of differentially expressed nucleic acid sequence and protein expression which differs from the pattern of gene expression of macrophages from healthy donors or donors in an irritated status, which latter do contain macrophages in an activated status. Therefore, macrophages show different activation levels under different inflammatory conditions, and it is shown in the present invention that macrophages in a hyperactive status are involved in an inflammatory process, preferably in a chronic inflammatory airway disease, more preferably in chronic bronchitis or COPD. The present invention provides for the inhibition of the hyperactivation or the reduction of the hyperactive status of a macrophage by allowing the identification of substances which modulate receptors involved in the hyperactivation or maintaining the hyperactive status.
The invention is based on the identification of a differentially expressed nucleic acid sequence or protein which is involved in causing the induction and/or maintenance of the hyperactive status of macrophages involved in an inflammatory process, preferably in a chronic inflammatory airway disease, more preferably in chronic bronchitis or COPD. Such differentially expressed nucleic acid sequence or protein is in the following named differentially expressed nucleic acid sequence or protein of the invention respectively. In particular, the present invention teaches a link between phenotypic changes in macrophages due to differentially expressed nucleic acid sequence and protein expression pattern and involvement of macrophages in inflammatory processes and, thus, provides a basis for a variety of applications. For example, the present invention provides a method and a test system for determining the expression level of a macrophage protein or differentially expressed nucleic acid sequence of the invention and thereby provides e.g. for methods for diagnosis or monitoring of inflammatory processes with involvement of hyperactivated macrophages in mammalian, preferably human beings, especially such beings suffering from an inflammatory process, preferably in a chronic inflammatory airway disease, more preferably in chronic bronchitis or COPD. The invention also relates to a method for identifying a substance by means of a differentially expressed nucleic acid sequence or protein of the invention processes, which substance modulates, i.e. acts as an inhibitor or activator on the said differentially expressed nucleic acid sequence or protein of the invention and thereby positively influences chronic inflammatory processes by inhibition of the hyperactivation or reduction of the hyperactive status of macrophages, and thereby allows treatment of mammals, preferably human beings, suffering from a said disease. The invention also relates to a method for selectively modulating such a differentially expressed nucleic acid sequence or protein of the invention in a macrophage comprising administering a substance determined to be a modulator of said protein or differentially expressed nucleic acid sequence. The present invention includes the use of said substances for treating beings in need of a treatment of an inflammatory process, preferably a chronic inflammatory airway disease, more preferably chronic bronchitis or COPD.
For the present invention in a first step differentially expressed nucleic acid sequences and proteins are identified which have a different expression pattern in a hyperactivated macrophage compared to a macrophage which is not hyperactivated. For the sake of conciseness this description deals particularly with investigation of macrophages involved in COPD, however, equivalent results may be observed with samples from patients suffering from other chronic inflammatory airway diseases, e.g. chronic bronchitis. The investigation of the different expression pattern leads to the identification of a series of differentially expressed nucleic acid sequences in macrophages, differentially expressed in dependency on the activation status of a macrophage involved in an inflammatory process, as exemplified in the Examples hereinbelow.
Briefly, such a differentially expressed nucleic acid sequence is identified by comparative expression profiling experiments using a cell or cellular extract from a hyperactivated macrophage, i.e. for example from the site of inflammation in a COPD and from the corresponding site of control being not suffering from said disease, however, suffering from an irritated condition like cigarette smoke exposure.
A differentially expressed nucleic acid sequence or protein of the invention can easily be detected by such a method because amongst the differentially expressed macrophage genes a class of differentially expressed nucleic acid sequences can be identified which encodes a class of macrophage surface receptors which is characterized in that it is expressed at a lower or higher level than the control level in a macrophage which is not hyperactivated. Such a macrophage surface receptor of the invention is hereinafter named ILM receptor. However, the invention does not only concern a naturally occurring ILM receptor, but also includes within the meaning of ILM receptor a receptor which is functionally equivalent to,
Jung Birgit
Kistler Barbara
Kraut Norbert
Mueller Stefan
Quast Karsten
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
Kemmerer Elizabeth
Pocchiari Susan K.
Raymond Robert P.
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