Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-09-28
2004-05-18
Chen, Shin-Lin (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C424S085100
Reexamination Certificate
active
06737398
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to a method to regulate airway hyperresponsiveness by modulating the action of &ggr;&dgr; T cells in a patient. The present invention further relates to methods for identifying compounds that regulate airway hyperresponsiveness by modulating &ggr;&dgr; T cell action.
BACKGROUND OF THE INVENTION
Diseases involving inflammation are characterized by the influx of certain cell types and mediators, the presence of which can lead to tissue damage and sometimes death. Diseases involving inflammation are particularly harmful when they afflict the respiratory system, resulting in obstructed breathing, hypoxemia, hyperapnia and lung tissue damage. Obstructive diseases of the airways are characterized by airflow limitation (i.e., airflow obstruction or narrowing) due to constriction of airway smooth muscle, edema and hypersecretion of mucus leading to increased work in breathing, dyspnea, hypoxemia and hypercapnia.
A variety of inflammatory agents can provoke airflow limitation including allergens, cold air, exercise, infections and air pollution. In particular, allergens and other agents in allergic or sensitized mammals (i.e., antigens and haptens) cause the release of inflammatory mediators that recruit cells involved in inflammation. Such cells include lymphocytes, eosinophils, mast cells, basophils, neutrophils, macrophages, monocytes, fibroblasts and platelets. Inflammation results in airway hyperresponsiveness (AHR). A variety of studies have linked the degree, severity and timing of the inflammatory process with the degree of airway hyperresponsiveness. Thus, a common consequence of inflammation is airway hyperresponsiveness.
Currently, therapy for treatment of inflammatory diseases involving AHR, such as moderate to severe asthma and chronic obstructive pulmonary disease, predominantly involves the use of glucocorticosteroids and other anti-inflammatory agents. These agents, however, have the potential of serious side effect, including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression. Thus, such drugs are limited in their clinical use for the treatment of lung diseases associated with airway hyperresponsiveness. The use of anti-inflammatory and symptomatic relief reagents is a serious problem because of their side effects or their failure to attack the underlying cause of an inflammatory response. There is a continuing requirement for less harmful and more effective reagents for treating inflammation. Thus, there remains a need for processes using reagents with lower side effect profiles, less toxicity and more specificity for the underlying cause of AHR.
Airway hyperresponsiveness (AHR) is the result of complex pathophysiological changes in the airway. A variety of studies have linked the degree, severity and timing of the inflammatory process with the degree of airway hyperresponsiveness. However, the mechanisms leading to AHR are still poorly understood and can be attributed to both immune-dependent and immune-independent mechanisms. Essentially all of the T cell-mediated effects described so far are in the former category. However, T cells from hyperresponsive mice can increase baseline airway tone in hyporesponsive mice after cell transfer. Because of their constitutive presence in the normal lung, &ggr;&dgr; T cells have been investigated with regard to their potential role in airway responses.
&ggr;&dgr; T cells have been observed to proliferate and produce cytokines in many diseases. In addition, studies in animal models have provided evidence that these cells contribute to host resistance against infections (Hiromatsu et al., 1992
, J. Exp. Med
. 175:49), and that they can influence inflammation (Fu et al., 1994
, J. Immunol
. 153:3101), epithelial regeneration (Boismenu et al., 1994
, Science
266:1253), and mucosal tolerance to antigens (Fujihashi et al., 1992
, J. Exp. Med
. 175:695; McMenamin et al., 1994, supra). Investigators are still determining what stimuli trigger &ggr;&dgr; T cell reactivity, and to what extent &ggr;&dgr; T cell activating stimuli differ from those of &agr;&bgr; T cells and B lymphocytes. It is known that &ggr;&dgr; T cells respond during bacterial and viral infections, although they have not been readily linked to antigen-specific adaptive immunity.
A number of studies have investigated the presence and role of &ggr;&dgr; T cells in diseases of the airways. Pawankar et al. noted the mucosal changes at the site of allergic inflammation in patients with perennial allergic rhinitis and chronic infective rhinitis includes an oligoclonal expansion and activation of V&ggr;1/V&dgr;1
+
T cells (Pawankar and Ra, 1996
, J. Allergy Clin. Immunol
. 98:S248-62). Molfino et al. showed that much of the &ggr;&dgr; T cell population found in broncho alveolar lavage (BAL) fluid in humans derives from clonally expanded T cells (Molfino et al., 1996
, Clin. Exp. Immunol
. 104:144-153). Spinozzi et al., measuring &ggr;&dgr; T cells in the BAL fluid from patients with asthma, concluded that allergen-specific, steroid-sensitive &ggr;&dgr; T cells maybe one of the cellular components involved in the airway inflammation that characterizes allergic bronchial asthma (Spinozzi et al., 1996
, Ann. Intern. Med
. 124:223-227 and 1995
, Mol. Med
. 1:821-826).
Moreover, it has been noted that in patients with respiratory conditions including Bordetella pertussin infection (whooping cough) and asthma, circulating &ggr;&dgr; T cells are decreased. It has been suggested that the reason for this decrease is the dispatch of &ggr;&dgr; T cells to the site of inflammation in the lung. (Bertotto et al., 1997
, Acta Paediatr
. 86:114-115; Schauer et al., 1991
, Clin. Exp. Immunol
. 86:440-443; Krejsek et al., 1998
, Allergy
53;73-77).
Many of the studies directed to &ggr;&dgr; T cells and airway diseases have directly suggested that &ggr;&dgr; T cells are proinflammatory, promoting acute airway sensitization, increases in cytokine levels suggested to be involved in allergic inflammation, regulation of allergic &agr;&bgr; T-cell and allergen specific B-cell responses, and/or allergen-induced eosinophilia and IgE responses (e.g., McMenamin et al., 1994
, Science
265:1869-1871; Zuany-Amorim et al., 1998, supra; Schramm et al., 2000
, Am. J. Respir. Cell Mol. Biol
. 22:218-225; Schramm et al., 1999, International Conference of the American Thoracic Society; vol. 159:A255 (American Journal of Respiratory and Critical Care Medicine, San Diego, Calif.)). Some investigators, alternatively, have concluded that &ggr;&dgr; T cells do not play a significant role in airway allergic inflammation. For example, Chen et al. noted, similar to other investigators discussed above, that allergic asthmatics have reduced &ggr;&dgr; T cells in the peripheral blood. However, Chen et al. concluded that no significant correlation existed between the levels of &ggr;&dgr; T cells and IgE present in the peripheral blood (Chen et al., 1996
, Clin. Exp. Immunol
. 26:295-302). Although allergic asthmatics have reduced &ggr;&dgr; T cells with reciprocally elevated eosinophil numbers in the peripheral blood, Chen et al. asserted that this does not indicate that the reduction of &ggr;&dgr; T cells correlates with the predominance of eosinophilia or IgE levels in diseased populations. Jaffar et al. described a role for &agr;&bgr;, but not &ggr;&dgr;, T cells in allergen-induced Th2 cytokine production from asthmatic bronchial tissue (Jaffar et al., 1999
, J. Immunol
. 163:6283-6291). Fajac et al., 1997
, Eur. Resp. J
. 10:633-638 investigated the role of heat shock proteins and &ggr;&dgr; T cells in patients with mild atopic asthma, and concluded that neither heat shock proteins nor &ggr;&dgr; T cells play an important role in inflammatory and immune responses in mild asthma.
Therefore, prior to the present invention, those of skill in the art either considered &ggr;&dgr; T cells to play an insignificant role, if any, in diseases of the airways, or believed that &ggr;&
Born Willi K.
Gelfand Erwin
Kanehiro Arihiko
Lahn Michael F.
Chen Shin-Lin
Li Q Janice
National Jewish Medical and Research Center
Sheridan & Ross P.C.
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