Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-05-08
2002-10-15
Ketter, James (Department: 1632)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C536S024500
Reexamination Certificate
active
06465187
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method of treatment of mast cell mediated inflammatory disorders in mammals.
BACKGROUND OF THE INVENTION
The occurrence of allergic diseases has increased during the last decades, especially in the western world. Most allergic diseases are caused by IgE-mediated (immunoglobulin E) hypersensitivity reactions. Upon activation, during an allergic reaction, IgE molecules bind, via a cell-binding constant domain to specific receptors (Fc&egr;RI) on mast cells.
Mast cells are generally considered to be long living cells, that are widely distributed throughout vascularized tissues and certain epithelia where they play a fundamental role in the pathogenesis of immediate hypersensitivity reactions. In inflammatory disorders, such as allergies and asthma increased numbers of mast cells in affected tissues have been documented with a positive correlation between mast cell number and the severity of the allergic response symptoms. (Otsuka, H., J. Denburg, J. Dolovich, D. Hitch, P. Lapp, R. S. Rajan, J. Bienenstock, and D. Befus. 1985. Heterogeneity of metachromatic cells in human nose: Significance of mucosal mast cells.
J. Allergy Clin. Immunol.
76:695-702.)
Upon activation and Fc&egr;RI aggregation, mast cells release preformed mediators such as histamine, proteases, tryptase and heparin, and synthesize lipid mediators and cytokines causing the allergic response observed in sensitized individuals. Survival, growth and differentiation of mast cells are regulated by cytokines such as interleukin-3 (IL-3) and stem cell factor (SCF). Mast cells have the capacity to survive the activation induced degranulation process, and to subsequently regranulate, enabling them to be activated again. Multiple rounds of mast cell activation may underlie the mechanism regulating the reoccurring inflammatory attacks of allergic patients during a pollen season. The possibility of regulating the longevity of activated mast cells could thus provide a treatment for mast cell mediated inflammatory disorders, such as allergies and asthma. However, the molecular mechanisms enabling activated mast cells to survive have not been elucidated.
A well documented mechanism for regulating cell longevity and survival is through the up-regulation of pro-survival genes belonging to the bcl-2 protein family. This is a growing family of apoptosis-regulatory genes, which may either be death antagonists (bcl-2, bcl-XL, bcl-w, mcl-1 and Al) or death agonists (bax, bak, bcl-XS, bad, bid, bik and hrk) [Reed, J. 1994. Bcl-2 and the regulation of programmed cell death.
J. Cell Biol
124:1-6)]. Although the precise mechanism by which bcl-2 family members influence apoptosis is unkown, several lines of evidence suggest that bcl-2 proteins function at a critical decision point immediate upstream of an irreversible commitment to cell death [Dragovich, T., C. M. Rudin, and C. B. Thompson. 1998 Signal dransduction pathways that regulate cell survival and cell death.
Oncogene
17:3207-13.]. It has been demonstrated that nerve growth factor (NGF) markedly increases bcl-2 expression in mast cells. When overexpressed, bcl-2 prolongs survival of mast cells following IL-3 deprivation. SCF and IL-3 induce suppression of apoptosis in mast cells by different mechanisms since IL-3 can induce bcl-2 induction but SCF cannot [Yec, N. S., I. Peak and P. Besmer, 1994 role of the c-kit ligand in proliferation and suppression of apoptosis in mast cells. Basis for radiosensitivity of white spotting and steel mutants.
J. Exp. Med.
179:1777-1787.]. Despite the wide-ranging ability of bcl-2 to promote cell survival, there are circumstances where bcl-2 is not found to be responsible for protecting the cells from apoptosis [Hueber, A., G. Raposo, M. Pierres and H. He. 1994. Thy-1 triggers mouse thymocyte apoptosis through a bcl-2-resistant mechanism.
J Exp Med
179:785-96.]. Therefore, it is possible that other members of the bcl-2 family may provide protective effects in some specific biological processes. In monocytes IgE-receptor aggregation leads to up-regulation of bcl-X
L
and bcl-2 (N. Katoh, S. Kraft, J. H. M. Wessendorf, T. Bieber. The high-affinity IgE receptor (Fe&egr;RI) blocks apoptosis in normal human monocytes.
J. Clin. Invest.
105: 183-190 (2000)).
Al was originally identified from mouse bone marrow culture induced with granulocyte macrophage colony stimulating factor (GM-CSF) and bears structural homology to bcl-2 [Lin, E., A. Orlofsky, M. Berger and M. Prystowsky. 1993. Characterization of Al, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2.
J Immunol
151:1979-88.]. Al was described as an early-response gene, expressed in multiple tissues such as thymus, spleen and bone marrow, and also expressed in a number of hemotopoietic cell lineages under various stimulations. These cells include T and B lymphocytes, macrophages, neutrophils [Chuang, P. I., E. Yee, A. Karsan, R. K. Winn and J. M. Harlan. 1998 Al is a constitutive and inducible Bcl-2 homologue in mature human neutrophils.
Biochem. Biophys. Res. Commun,
249:361-5.], and endothelial cells [Lin, 1993, supra]. Al or the human homologue bfl-1 [S. S. Choi, S. H. Park, U. -J. Kim, H. -S. Shin. Bfl-1, a Bcl-2-related gene, is the human homolog of the murine Al and maps to Chromosome 15q24.3.
Mammalian Genome
8, 781-782 (1997); Choi S. S., Park I. C., Yun J. W., Sung Y. C., Hong S. I., Shin H. S. A novel Bcl-2 related gene, Bfl-1 is overexpressed in stomach cancer and preferentially expressed in bone marrow.
Oncogene
Nov. 2, 1995; 11(9):1693-8] is the only bcl-2 family member that is inducible by inflammatory cytokines such as tumor necrosis factor-&agr; and IL-1&bgr; suggesting a possible role in mast cell biology.
Available drugs for allergic diseases treat the symptoms of the disease which occurs as a consequence of released mediators from inflammatory cells. A treatment that more specifically would prevent the allergic response, with reduced side effects, compared to current drugs, would be desirable.
Accordingly an object of the present invention is to provide a method for treatment of mast cell mediated inflammation.
SUMMARY OF THE INVENTION
The object of the invention is obtained by a method as claimed in the claims. According to the invention a method of treatment of mast cell mediated inflammatory disorders in mammals is provided. The method comprises regulating the longevity and activity of activated mast cells by inhibiting the expression and/or function of the anti-apoptotic A-
1
/bfl-1 gene or gene product. In a preferred embodiment the inhibition of the expression and/or function of the A-
1
/bfl-1 gene or gene product is obtained by targeting inflamed tissue in the affected mammal with a drug that inhibits the function.
According to a further aspect of the invention there is provided use of a compound capable of inhibiting the expression and/or function of the anti-apoptotic A-
1
/bfl-1 gene or gene product for the manufacture of a medicament for treating mast cell mediated inflammatory disorders in mammals by regulating the longevity and activity of activated mast cells.
According to a further aspect of the invention, a biological or chemical assay for identifying compounds for treatment of mast cell mediated inflammatory disorders in mammals is provided. The assay comprises using the anti-apoptotic A-
1
/bfl-1 gene or gene product as a molecular target.
According to another aspect of the invention, a method for development of drugs for treatment of mast cell mediated inflammatory disorders in mammals is provided. The method comprises using the anti-apoptotic A-
1
/bfl-1 gene or gene product as a molecular target.
According to the invention it was surpringly found that by inhibiting the anti-apoptotic function of A-
1
/bfl-1 gene or gene product the activated mast cells undergo apoptosis, preventing re-granulation and re-activation. In that way the number of activated mast cells in the inflammatory
Nilsson Gunnar
Xiang Zou
Burns Doane , Swecker, Mathis LLP
Innoventus Project AB
Ketter James
Li Q. Janice
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