Method for inhibiting inflammatory responses

Details Method for inhibiting inflammatory responses Method for inhibiting inflammatory responses

2000-02-22

2003-10-28

Duffy, Patricia A. (Department: 1645)

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

Bacterium or component thereof or substance produced by said...

C424S190100, C424S192100

Reexamination Certificate

active

06638518

ABSTRACT:

BACKGROUND
Asthma has attracted a great deal of attention from both the public and from the medical community in the past few years. It has been termed an “epidemic,” and been the subject of cover stories in major newspapers and magazines. This is primarily due to the observation that the disease is worsening, particularly in Western, industrialized nations. In the past three decades, the prevalence, severity, and mortality of asthma have increased significantly. A recent study estimated the total annual cost in the United States at almost $6 billion. Once thought to be due to airway muscle spasm, asthma is now known to be an inflammatory disorder; during an asthma exacerbation, inflammation precedes bronchospasm. In acute asthma, eosinophils may form up to half of the cellular infiltrate, and bronchoalveolar eosinophilia invariably follows allergen inhalation in asthma attacks. Eosinophils cause inflammation and bronchial hyperreactivity through release of mediators such as leukotrienes, major basic protein, eosinophilic cationic protein, and eosinophilic peroxidase (Bruijnzeel, Ann
NY Acad Sci
725, 259-267, (1994)).
Numbers and activity of eosinophils are controlled by cytokines released from activated T cells, especially IL-4, IL-5, and IL-13. T-lymphocytes can be divided on the basis of cytokine production, into Th1 and Th2 (Mosmann, T. R. et al.,
J. Immunol.,
136, 2348-2357, (1986)). Th1 cells produce IL-2 and IFN-&ggr;, but no IL-4 or IL-5, and Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13 but no IL-2 or IFN-&ggr;. Th1 and Th2 cells interact in a counterregulatory fashion: IL-4 and IL-10 promote Th2 development (Parronchi et al.,
J. Immunol.,
149, 2977-2983 (1992), Swain et al.,
J. Immunol.,
145, 3796-3806 (1990)) and inhibit Th1 cell and cytokine production (Moore, K. W. et al.,
Science,
248, 1230-1234 (1990)), and IFN-&ggr; inhibits the proliferation of Th2 cells (Gajewski et al.,
J. Immunol.,
140, 4245-4252 (1988)) and promotes the development of Th1 cells (Parronchi et al.,
J. Immunol.,
149 2977-2983 (1992)). IL-12, mainly a product of activated macrophages, is also a strong promoter of Th1 responses (Bliss, et al.,
J. Immunol.,
156, 887-894 (1996)) and is often considered a Th1 cytokine; many of the activities ascribed to IL-12 are due to induction of IFN-&ggr;. Th1 and Th2 cells have been identified in humans, in vivo as well as in vitro.
The Th2 cytokines, IL-4, IL-5, and IL-13 (Grunig, et al.,
Science,
282, 2261-2263 (1998), Robinson et al.,
N. Engl. J. Med.,
326, 298-304 (1992), Wills-Karp et al.,
Science,
282, 2258-2261 (1998)), have been increasingly implicated in the inflammation of asthma. IL-4 amplifies allergic responses by inducing IgE production by uncommitted B-cells (Del Prete, et al.,
J. Immunol.,
140, 4193-8 (1988)) and is a growth factor for mast cells (Saito, et al.,
Proc. Natl. Acad. Sci. USA,
85, 2288-2292 (1988)). IL-5 also stimulates immunoglobulin secretion (Swain, et al.,
J. Immunol.,
145, 3796-3806 (1990), Takatsu et al.,
J. Immunol.,
124, 2414-2422 (1980)) as well as stimulating the proliferation and activation of eosinophils (Clutterbuck, et al.,
Blood
73, 1504-1512 (1988), Lopez et al.,
J. Exp. Med.,
167, 219-223 (1988), Walsh et al.,
Immunol.,
71, 258-265 (1990)) and basophils (Hirai, K. et al.,
J. Exp. Med.,
172, 1525-1528 (1990)). IL-13 has recently been shown to cause airway hyperresponsiveness and inflammation independently of eosinophils or IL-4 (Grunig et al.,
Science,
282, 2261-2263 (1998), Wills-Karp et al.,
Science,
282, 2258-2261 (1998)). In vitro, allergen-specific T-cell clones from atopic donors release Th2 cytokines after stimulation by specific allergens (Parronchi et al.,
Proc. Natl. Acad. Sci.
USA, 88, 4538-4542 (1991)). During asthma exacerbations, peripheral T-cell activation and increased serum IL-5 correlate with eosinophilia and asthma symptoms (Corrigan et al.,
Am. Rev. Respir. Dis.,
147, 540-547 (1993)), and bronchoalveolar lavage (BAL) T-cells release cytokines in a Th2-like pattern (Robinson et al.,
J. All. Clin. Immunol.,
92, 313-324 (1993)), Robinson et al.,
N. Engl. J. Med.,
326, 298-304 (1992), Robinson et al.,
J. All. Clin. Immunol.,
92, 397-403 (1993)). Non-atopic asthmatics also have increased levels of Th2-like cytokines; increased IL-5 release from BAL T-lymphocytes is characteristic of both atopic and non-atopic asthmatics (Walker et al.,
Am. Rev. Respir.
Dis., 146, 109-115 (1992)), and expression of peripheral T-cell IL-5 mRNA from non-atopic asthmatic subjects correlates with increased BAL (Marini et al.,
Chest
102, 661-669 (1992)) and peripheral blood (Walker et al.,
Am. Rev. Respir.
Dis., 146, 109-115 (1992)) eosinophilia.
Because of these observations, the focus of treatment in asthma has shifted from primarily addressing bronchospasm, to one of modulating inflammation. Recent guidelines to the management of asthma recommend that anti-inflammatory therapy be used for all but the most intermittent and benign cases of the disease. Current anti-inflammatory therapy, however, remains disappointingly broad and nonspecific; corticosteroids are the “gold standard” for asthma treatment, and inhaled corticosteroids are only incrementally better than they were 25 years ago. The much-touted leukotriene pathway antagonists which have been released in the last five years have been helpful only in a subset of asthmatics.
SUMMARY OF THE INVENTION
Positive tubercullin skin tests are associated with protection against atopy and asthma (Shirakawa et al., Science, 275, 77≠79 (1997)) as well as systemic Th1 responses; however, the antigen(s) responsible for this protection has not been identified. The Fibronectin Attachment Protein of
Mycobacterium bovis
-BCG (FAP-B) has been identified and cloned. FAP-B is responsible for binding of the organism to fibronectin and for epithelial entry. Other FAPs have been isolated (
M. vaccae
FAP-V) and in some cases cloned (
M. leprae
FAP-L and
M. avium
FAP-A). Functional studies show FAP-B to bind fibronectin via the highly conserved attachment regions previously identified for FAP-A and FAP-L and also to competitively inhibit attachment of BCG to matrix fibronectin.
Surprisingly and unexpectedly, the FAP-B polypeptide is capable of protecting against the induction of an atopic/asthmatic inflammatory response. FAP-B and related polypeptides offer potential therapeutic benefit in asthma. Without intending to be bound by theory, it is expected that the mechanism of action through which FAP-B offers protection against Th2-mediated responses is through induction of Th1 responses, such as IFN-&ggr; and IL-12, which can downregulate Th2 responses.
Accordingly, the present invention provides methods for treating at least one symptom of an inflammatory response in a mammal. In one embodiment, a method includes administering an effective amount of a microbial polypeptide to the mammal such that at least one symptom of an inflammatory response, for instance a Th2 mediated inflammatory response, is inhibited. Optionally, the microbial polypeptide is isolated. The microbial polypeptide can be administered prior to exposure to at least one suspected or known inflammation response-inducing agent, or administered during or after exposure to at least one suspected or known inflammation response-inducing agent.
The microbial polypeptide can be encoded by a nucleotide sequence, where the complement of the nucleotide sequence hybridizes to the nucleotide sequence set forth at nucleotides 79 to 1056 of SEQ ID NO:1 in a solution containing 50% formamide, 6×SSC, 7×Denhardt's reagent, 0.7% SDS, 150 &mgr;g/ml salmon sperm DNA at 42° C. for at least about 12 hours, followed by one wash for 30 minutes at 25° C. in a solution containing 1×SSC, one wash for 30 minutes at 42° C. in a solution containing 1×SSC, and one wash for 30 minutes at 42° C. in a solution containing 0.1×SSC. For instance, the nucleotide sequence encoding the microbial polypeptide can be nucleotides 79 to 1056 of SEQ ID NO:1. The

Affiliated with

Also associated with

Rating

Method for inhibiting inflammatory responses does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Method for inhibiting inflammatory responses, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for inhibiting inflammatory responses will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3171070