Methods of modulating IL-174 response

Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds antigen or epitope whose amino acid sequence is...

Reexamination Certificate

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C424S130100, C424S133100, C424S141100, C530S351000, C514S002600

Reexamination Certificate

active

06676939

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compositions related to proteins which function in controlling physiology, development, and differentiation of mammalian cells, e.g., cells of a mammalian immune system. In particular, it provides nucleic acids, proteins, antibodies, and mimetics which regulate cellular physiology, development, differentiation, or function of various cell types, including hematopoietic cells.
BACKGROUND OF THE INVENTION
The immune system of vertebrates consists of a number of organs and several different cell types. Two major cell types include the myeloid and lymphoid lineages. Among the lymphoid cell lineage are B cells, which were originally characterized as differentiating in fetal liver or adult bone marrow, and T cells, which were originally characterized as differentiating in the thymus. See, e.g., Paul (ed. 1998)
Fundamental Immunology
(4th ed.) Raven Press, New York.
In many aspects of the development of an immune response or cellular differentiation, soluble proteins known as cytokines play a critical role in regulating cellular interactions. These cytokines apparently mediate cellular activities in many ways. They have been shown, in many cases, to modulate proliferation, growth, and differentiation of hematopoietic stem cells into the vast number of progenitors composing the lineages responsible for an immune response.
However, the cellular molecules which are expressed by different developmental stages of cells in these maturation pathways are still incompletely identified. Moreover, the roles and mechanisms of action of signaling molecules which induce, sustain, or modulate the various physiological, developmental, or proliferative states of these cells is poorly understood. Clearly, the immune system and its response to various stresses had relevance to medicine, e.g., infectious diseases, cancer related responses and treatment, allergic and transplantation rejection responses. See, e.g., Thorn, et al.
Harrison's Principles of Internal Medicine
McGraw/Hill, N.Y.
Medical science relies, in large degree, on appropriate recruitment or suppression of the immune system in effecting cures for insufficient or improper physiological responses to environmental factors. However, the lack of understanding of how the immune system is regulated or differentiates has blocked the ability to advantageously modulate the normal defensive mechanisms to biological challenges. Medical conditions characterized by abnormal or inappropriate regulation of the development or physiology of relevant cells thus remain unmanageable. The discovery and characterization of specific cytokines will contribute to the development of therapies for a broad range of degenerative or other conditions which affect the immune system, hematopoietic cells, as well as other cell types. The present invention provides solutions to some of these and many other problems.
SUMMARY OF THE INVENTION
The present invention is based, in part, upon biological activities of the cytokine known as IL-174. In particular, a number of assays indicate that this cytokine has functions in regulating establishment of Th2 type immune responses, innate immunity, inflammatory responses, mucosal and fibroblast growth, certain hematopoietic activities, and granuloma formation.
The present invention provides methods: directing a mammalian immune response towards a Th2 type response, the method comprising administering an IL-174 agonist to immune cells of the mammal; stimulating an mammalian innate immune response, the method comprising administering an IL-174 agonist to immune cells of the mammal; augmenting a mammalian inflammatory response from epithelial or fibroblast cells, the method comprising further administering an IL-174 agonist to the mammal; inducing gut cell growth, the method comprising administering an IL-174 agonist to the cell; promoting mammalian extra medulary hematopoiesis, the method comprising administering an IL-174 agonist to the mammal; or augmenting antibody responses in serum and fecal material, comprising administering an IL-174 agonist to the cell.
In various embodiments, the method involves administering an agonist, wherein the administering: induces cytokine production by a hematopoietic, fibroblast, epithelial, or endothelial cell; downregulates an inflammatory response which accompanies an infection; stimulates growth of an epithelial cell; or induces growth of gut epithelial, fibroblast, or goblet cells. In some embodiments, the method involves administering an agonist, wherein the mammal exhibits, or has experienced conditions to stimulate: an autoimmune condition; an infectious disease immune response; a wound healing response; or a Th1 mediated condition. In further embodiments, the autoimmune condition is selected from: multiple sclerosis, systemic lupus erythematosis, rheumatoid arthritis, diabetes, or psoriasis; the infectious response is symptomatic of: an Aspergillis infection, a fungal infection (including Candidaisis, Blastomycosis, or Aspergillosis), a parasitic infection (including Schistosomiasis, fluke worm, Helminth, or Filariasis); or a viral infection (including hepatitis); or the Th1 mediated condition is an inflammatory condition (including Crohn's disease, ulcerative colitis, pancreatitis, or hepatitis). Additionally, the invention provides methods treating an infectious response, further comprising administering another therapeutic entity to treat the infection.
The invention also provides other methods, e.g., directing a mammalian immune response away from a Th2 type response, the method comprising administering an IL-174 antagonist to immune cells of the mammal; or preventing mammalian inflammation or granuloma formation, comprising administering an IL-174 antagonist to immune system cells. Often, the antagonist is a monoclonal or polyclonal antibody against IL-174. The method may involve administering an antagonist, wherein: the administering blocks eosinophil attraction, tissue remodeling, or fibrosis; or the mammal exhibits, or has experienced conditions to stimulate: an allergic condition; an inflammatory condition; or a Th2 mediated condition. In further embodiments, the eosinophils are attracted to the lung (i.e., asthma), liver or intestine (i.e., eosinophilic gastritis); the fibrosis is pancreatic duct or peribiliary fibrosis; the antagonist suppresses production of IL-4, IL-5, and/or IL-13; the antagonist decreases eotaxin, CCR4, and/or CCR4 expression in BAL; symptoms of the allergic condition are in the lung; the allergic condition is a systemic anaphylactic response, skin hypersensitivity response, or a food allergy; or the inflammatory or Th2 mediated condition is a dermatitis or asthmatic inflammation. In yet other embodiments, the mammal exhibits, or has experienced conditions to stimulate: an allergic condition; an inflammatory condition; or a Th2 mediated condition.
The invention also provides a composition comprising: an IL-174 agonist and: an antimicrobial (including an antibiotic, antiviral, or antifungal compound) or a chemotherapy agent; or an IL-174 antagonist and: an allergy medicament, an asthma medicament, a dermatitis medicament, a fibrosis medicament, or eosinophilic gastritis medicament.
DETAILED DESCRIPTION OF THE INVENTION
Outline
I. General
II. Cytokine Agonists and Antagonists
A. IL-174 and Variants
B. Antibodies
C. Other Molecules
III. Immunoassays
IV. Uses
I. General
The invention is based, in part, on the surprising discovery that the cytokine designated IL-174 has roles in various aspects of immune responses. The IL-174 is one of a family of genes encoding proteins which exhibit structural features characteristic of cytokines, particularly misted to the cytokine designated CTLA-8 (also referred to as IL-17). Rat, mouse, human forms and a viral homolog of CTLA-8 have been described and their sequences available from GenBank. See Rouvier, et al. (1993)
J. Immunol.
150:5445-5456; Yao, et al. (1995)
Immunity
3:811-821; Yao, et. al. (1995)
J. Immunol.
155:5483-5486; and Kennedy et al. (199

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