Methods for treating inflammatory conditions

Details Methods for treating inflammatory conditions Methods for treating inflammatory conditions

1998-06-15

2001-02-20

Brouillette, D. Gabrielle (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C514S859000, C514S861000, C514S863000, C514S886000, C514S887000, C604S020000

Reexamination Certificate

active

06190691

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the field of inflammation and immunology. More particularly, the present invention provides screening methods for the identification of agents which are capable of suppressing cytokine production. Additionally, the present invention provides compositions which are useful as medicaments in the treatment of a variety of acute and chronic, systemic or skin conditions having an inflammatory and/or immunological component.
BACKGROUND OF THE INVENTION
Inflammation represents a cascade of physiological and immunological reactions that nature has designed as the first cellular response to noxious stimuli in an effort to localize toxic materials or prevent tissue injury. Clinically, inflammation is a primary disease under acute conditions or is a manifestation of underlying pathophysiological abnormalities in chronic disease, characterized by classic signs of redness, pain, swelling and loss of function. Inflammatory diseases are a significant cause of morbidity and mortality in humans.
Regardless of the etiology, most forms of inflammation are propagated as a result of the recruitment of humoral and cellular components of the immune system. Current research indicates that a class of proteins known as cytokines, products of immune-competent cells including macrophages, T-lymphocytes, endothelial cells, etc., are crucial in the initiation and maintenance of inflammation. Cytokines are small- to medium-sized (usually less than 30 kDa), hormone-like proteins governing numerous biological responses such as cell growth, cell maturation, and defense against infection. The major cytokines include interferons (IFNs), colony stimulating factors (CSFs), interleukins (ILs), and tumor necrosis factors (TNF and lymphotoxin). Due to their unique biological and extremely potent pharmacological properties, several cytokines have also been considered as therapeutic agents since their discovery in the 1950s. The importance of cytokines biologically and as potential therapeutic agents is well-recognized by the medical and pharmaceutical communities.
With respect to inflammation, TNF, IL-1 and IL-8 have all been characterized as proinflammatory cytokines. The release of these cytokines triggers a cascade of multiple cellular and molecular events including the expression of adhesion molecules, i.e. intercellular adhesion molecule-1 (ICAM-1), E-selectin, etc., the production of secondary inflammatory mediators (prostaglandins, leukotrienes), and growth factors (transforming growth factor alpha, TGF-&agr;). Under acute inflammatory conditions (e.g., endotoxemia), it is well known that TNF is one of the earliest mediators produced, appearing earlier than IL-1 or other cytokines (see, Michalek, et al.,
J. Inf. Dis.
141:55-63 (1980); Freudenberg, et al.,
Inf. Immun.
51:891-895 (1986); Beutler, et a.,
J. Immunol.
135:3972-3977 (1985) and Fong, et al.,
J. Exp. Med.
170:1627-1633 (1989)). Furthermore, administration of TNF to animals reproduces the pathologic is effects of endotoxin (see Tracey, et al.,
Surg. Gyn. Obstet.
164:415-422 (1987) and Tracey, et al.,
Science
234:470-474 (1986)). In other correlative studies, the level of TNF observed is a predictive indicator of the outcome in endotoxin shock (see Waage, et al.,
Lancet
(1)8529:355-357 (1987)). There are significant overlaps between the current understanding of the pathophysiology leading to the development of acute skin disorders and acute systemic inflammatory conditions like endotoxemia. In both scenarios, TNF production by hematopoietic cells is the primary event which initiates and orchestrates the inflammatory cascade.
In chronic inflammatory conditions, elevated tissue levels of several mediators including the cytokines IL-1, IL-8, GM-CSF, and TNF have been found in the inflamed joints of patients with rheumatoid arthritis (RA) (see Yocum, et al.,
Cellular Immunol.
122:131-145 (1989) and Hopkins, et al.,
Clin. Exp. Immunol.
73:88-92 (1988)). With synovial culture systems, it was demonstrated that TNF regulated the production of GM-CSF and IL-1 in addition to expression of more TNF receptors making TNF seminal in this disease pathogenesis. Similarly, there is an increased level of TNF in the intestinal mucosa (Olson, et al.,
J. Pediatric Gastroenterology and Nutrition
16:241-246 (1993)) and in the feces (Nicholls, et al.,
J. Clin. Pathol.
46:757-760 (1993)) in patients with inflammatory bowel diseases (IBD, includes Crohn's disease and ulcerative colitis). While it is generally recognized that chronic inflammation is a complex cellular and molecular event, it has been suggested that cytokine mediators do not act in parallel, but in series. This view has been verified recently by clinical results demonstrating a clear resolution of both severe RA (Elliott, et al.,
Arthritis and Rheumatism
36:1681-1690 (1993)) and IBD upon administration of anti-TNF antibody. Thus, TNF is found to be the key mediator in these two diseases and, in various other inflammatory conditions including psoriasis, asthma, cancer, infection, and cachexia associated with AIDS and cancer.
In principle, the inflammatory response can be regulated through the use of drugs. Unfortunately, anti-inflammatory drugs presently available produce cytotoxic effects which reflect their initial employment as cancer chemotherapeutics, typically antineoplastics. Such drugs effectively kill cells indiscriminately. Corticosteroids are also mainstay anti-inflammatory agents but manifest significant adverse effects, such as inducing Cushingoid features, skin thinning, increased susceptibility to infection, and suppression of the hypothalamic-pituitary-adrenal axis. The use of other immunosuppressive agents such as cyclosporin A also may induce the development of severe side effects, e.g., hypertension and nephrotoxicity.
What is needed in the art are new and more effective methods of treating inflammation which specifically target TNF production and which carry fewer significant and undesirable side effects. Methods which suppress TNF production will find application not only in inflammation of the skin, but also in systemic inflammation. Surprisingly, the present invention provides such methods of suppressing TNF production and treating inflammation.


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