Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific... – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1999-06-02
2001-12-11
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
Bacterium or component thereof or substance produced by said...
C424S278100, C424S248100, C424S234100, C424S190100, C424S184100, C514S002600, C514S863000, C514S886000, C514S885000, C530S350000, C530S825000
Reexamination Certificate
active
06328978
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to the treatment by vaccination or immunotherapy of skin disorders such as psoriasis, atopic dermatitis, allergic contact dermatitis, alopecia areata, and the skin cancers basal cell carcinoma, squamous cell carcinoma and melanoma. In particular, the invention is related to the use of compounds which are present in or have been derived from
Mycobacterium vaccae
(
M. vaccae
) or from the culture filtrate of
M. vaccae.
BACKGROUND OF THE INVENTION
This invention deals with treatment of disorders of skin which appear to be associated with factors that influence the balance of thymus-derived (T) immune cells known as Th1 and Th2. These T cells are identified by their cytokine secretion phenotype. A common feature of treatment is the use of compounds prepared from
M. vaccae
which have immunomodulating properties that alter the balance of activities of these T cells as well as other immune cells.
Psoriasis is a common, chronic inflammatory skin disease which can be associated with various forms of arthritis in a minority of patients. The defect in psoriasis appears to be overly rapid growth of keratinocytes and shedding of scales from the skin surface. Drug therapy is directed at slowing down this process. The disease may become manifest at any age. Spontaneous remission is relatively rare, and life-long treatment is usually necessary. Psoriasis produces chronic, scaling red patches on the skin surface. Psoriasis is a very visible disease, it frequently affects the face, scalp, trunk and limbs. The disease is emotionally and physically debilitating for the patient, detracting significantly from the quality of life. Between one and three million individuals in the United States have psoriasis with nearly a quarter million new cases occurring each year. Conservative estimates place the costs of psoriasis care in the United States currently at $248 million a year.
There are two major hypotheses concerning the pathogenesis of psoriasis. The first is that genetic factors determine abnormal proliferation of epidermal keratinocytes. The cells no longer respond normally to external stimuli such as those involved in maintaining epidermal homeostasis. Abnormal expression of cell membrane cytokine receptors or abnormal transmembrane signal transduction might underlie cell hyperproliferation. Inflammation associated with psoriasis is secondary to the release of pro-inflammatory molecules from hyperproliferative keratinocytes.
A second hypothesis is that T cells interacting with antigen-presenting cells in skin release pro-inflammatory and keratinocyte-stimulating cytokines (Hancock, G. E. et al.,
J. Exp. Med
. 168:1395-1402, 1988). Only T cells of genetically predetermined individuals possess the capacity to be activated under such circumstances. The keratinocytes themselves may be the antigen-presenting cell. The cellular infiltrate in psoriatic lesions show an influx of CD4+ T cells and, more prominently, CD8+ T cells (Bos, J. D. et al.,
Arch. Dermatol. Res
. 281:23-3, 1989; Baker, B. S.,
Br. J. Dermatol
. 110:555-564, 1984).
As the majority (90%) of psoriasis patients have limited forms of the disease, topical treatments which include dithranol, tar preparations, corticosteroids and the recently introduced vitamin D3 analogues (calcipotriol, calcitriol) can be used. A minority (10%) of psoriasis patients have a more serious condition, for which a number of systemic therapeutic modalities are available. Specific systemic therapies include UVB, PUVA, methotrexate, vitamin A derivatives (acitretin) and immuno-suppressants such as Cyclosporin A. The effectiveness of Cyclosporin and FK-506 for treating psoriasis provides support for the T cell hypothesis as the prime cause of the disease (Bos, J. D. et al.,
Lancet II
:1500-1502, 1989; Ackerman, C. et al.,
J. Invest. Dermatol
. 96:536 [abstract], 1991).
Atopic dermatitis is a chronic pruritic inflammatory skin disease which usually occurs in families with an hereditary predisposition for various allergic disorders such as allergic rhinitis and asthma. Atopic dermatitis occurs in approximately 10% of the general population. The main symptoms are dry skin, dermatitis (eczema) localised mainly in the face, neck and on the flexor sides and folds of the extremities accompanied by severe itching. It typically starts within the first two years of life. In about 90% of the patients this skin disease disappears during childhood but the symptoms can continue into adult life. It is one of the commonest forms of dermatitis world-wide. It is generally accepted that in atopy and in atopic dermatitis, a T cell abnormality is primary and that the dysfunction of T cells which normally regulate the production of IgE is responsible for the excessive production of this immunoglobulin.
Allergic contact dermatitis is a common non-infectious inflammatory disorder of the skin. In contact dermatitis, immunological reactions cannot develop until the body has become sensitised to a particular antigen. Subsequent exposure of the skin to the antigen and the recognition of these antigens by T cells result in the release of various cytokines, proliferation and recruitment of T cells and finally in dermatitis (eczema).
Only a small proportion of the T cells in a lesion of allergic contact dermatitis are specific for the relevant antigen. Activated T cells probably migrate to the sites of inflammation regardless of antigen-specificity. Delayed-type hypersensitivity can only be transferred by T cells (CD4
+
cells) sharing the MHC class II antigens. The ‘response’ to contact allergens can be transferred by T cells sharing either MHC class I (CD8
+
cells) or class II (CD4
+
cells) molecules (Sunday, M. E. et al.,
J. Immunol
. 125:1601-1605, 1980). Keratinocytes can produce interleukin-1 which can facilitate the antigen presentation to T cells. The expression of the surface antigen intercellular adhesion molecule-1 (ICAM-1) is induced both on keratinocytes and endothelium by the cytokines tumor necrosis factor (TNF) and interferon-gamma (IFN-&ggr;).
If the causes can be identified, removal alone will cure allergic contact dermatitis. During active inflammation, topical corticosteroids are useful. An inhibitory effect of cyclosporin has been observed in delayed-type hypersensitivity on the pro-inflammatory function(s) of primed T cells in vitro (Shidani, B. et al.,
Eur. J. Immunol
. 14:314-318, 1984). The inhibitory effect of cyclosporin on the early phase of T cell activation in mice has also been reported (Milon, G. et al.,
Ann. Immunol
. (
Inst. Pasteur
) 135d:237-245, 1984).
Alopecia areata is a common hair disease, which accounts for about 2% of the consultations at dermatological outpatient clinics in the United States. The hallmark of this disease is the formation of well-circumscribed round or oval patches of nonscarring alopecia which may be located in any hairy area of the body. The disease may develop at any age. The onset is usually sudden and the clinical course is varied.
At present, it is not possible to attribute all or indeed any case of alopecia areata to a single cause (Rook, A. and Dawber, R,
Diseases of the Hair and Scalp
, Blackwell Scientific Publications 1982: 272-30). There are many factors that appear to be involved. These include genetic factors, atopy, association with disorders of supposed autoimmune etiology, Down's syndrome and emotional stress. The prevalence of atopy in patients with alopecia areata is increased. There is evidence that alopecia areata is an autoimmune disease. This evidence is based on consistent histopathological findings of a lymphocytic T cell infiltrate in and around the hair follicles with increased numbers of Langerhans cells, the observation that alopecia areata will respond to treatment with immunomodulating agents, and that there is a statistically significant association between alopecia areata and a wide variety of autoimmune diseases (Mitchell, A. J. et al.,
J. Am. Acad. Dermatol
. 11:763-775, 1984). Alopecia areata i
Prestidge Ross
Tan Paul L. J.
Watson James D.
Devi S.
Genesis Research & Development Corp. Ltd.
Sleath Janet
Speckman Ann W.
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