Cytokines are small proteins that mediate signaling and communication between cells of the immune system, e.g., T cells, B cells, dendritic cells, and macrophages. These proteins mediate a number of cellular activities, including proliferation, growth, differentiation, migration, cell activation, and response to infection, foreign antigens, and wounds.
A particularly important family of cytokines is interleukin-6 (IL-6) family. These cytokines exhibit a wide range of often overlapping biological functions that are transmitted via multichain cell surface receptors, which are typically formed by high-affinity, cytokine-specific receptor chains and lower-affinity, signal-transducing chains. Receptor subunits are often shared among members of this cytokine subfamily.
Recently, a novel helical cytokine was identified that has structural homology to the IL-6 family of cytokines. This protein was designated p19, and was shown to be part of a novel composite factor consisting of a disulfide-bridged complex between p19 and the p40 subunit of IL-12. This novel p19p40 complex, also known as IL-23, is naturally expressed by activated mouse and human dendritic cells and has biological activities that are similar to but distinct from IL-12 (see, e.g., Oppmann et al. (2000) Immunity 13:715-725). The p19 subunit of IL-23 is also known as “IL-23p19.”
The present invention identifies and provides IL-23, IL-23 agonists, and variants and derivatives thereof, as modulators of skin disorders, for example, for use in the treatment or diagnosis of skin conditions and disorders or wound healing, see, e.g., Fitzpatrick, et al. (eds.) (1993) Dermatology in General Medicine 4th ed., McGraw-Hill, N.Y.; Bos (ed.) (1989) Skin Immune System, CRC Press, Boca Raton, Fla.; Callen (1996) General Practice Dermatology, Appleton and Lange, Norwalk, Conn.; Rook, et al. (eds.) (1998) Textbook of Dermatology, Blackwell Publ., Malden, Mass.; Habifor and Habie (1995) Clinical Dermatology: A Color Guide to Diagnosis and Therapy, Mosby, Phila., Pa.; Grob (ed.) (1997) Epidemiology, Causes and Prevention of Skin Diseases, Blackwell, Malden, Mass.; Hess and Salcido (2000) Wound Care, Springhouse Pub. Co., Springhouse, Pa.; Mani, et al. (1999) Chronic Wound Healing: Clinical Measurement and Basic, Balliere Tindall Ltd., London, UK; Wyngaarden and Smith (eds.) (1985) Cecil's Textbook of Medicine, W.B. Saunders Co., Phila., Pa.; Berkow (ed.) (1982) The Merck Manual of Diagnosis and Therapy, Merck Sharp & Dohme Research Laboratories, West Point, Pa.; Braunwald, et al. (eds.) (1991) Harrison's Principles of Internal Medicine, 12th Ed., McGraw-Hill, Inc., N.Y., all of which are incorporated herein by reference.
The present invention provides methods and reagents for the treatment, prevention, and diagnosis of wounds and wound healing, e.g., burns, wounds of cartilage, nerves and spinal cord, muscle, soft tissues, blood vessels and angiogenesis, ulcers and pressure sores, bone fractures and osteoporosis, and for promoting skin growth, e.g., at harvested or donor sites used in skin grafting (see, e.g., Yamaguchi and Yoshikawa (2001) J. Dermatol. 28:521-534; Cairns, et al. (1993) Arch. Surg. 128:1246-1252; Hom, et al. (2002) Facial Plast. Surg. 18:41-52; Hackam and Ford (2002) Surg. Infect. (Larchmt.) 3(Suppl. 1):S23-S35; Oshima, et al. (2002) Hum. Cell. 15:118-128; Lal, et al. (2000) Growth Horm. IGF Res. 10 (Suppl. B):S39-S43; Rose and Herndon (1997) Burns 23:S19-S26; Schryvers, et al. (2000) Arch. Phys. Med. Rehabil. 81:1556-1562; Hidaka, et al. (2002) Orthhop. Clin. North Am. 33:439-446; Dagum (1998) J. Hand Ther. 11:111-117; Coutts, et al. (2001) Clin. Orthop. 391 (Suppl.):S271-S279; Larsson (2002) Scand. J. Surg. 91:140-146; Goldstein (2000) Clin. Orthop. 379 (Suppl.):S113-119; Lieberman, et al. (2002) Mol. Therapy 6:141-147; Tuli, et al. (2003) Arthritis Res. Ther. 5:235-238; Li, et al. (2003) Microsc. Res. Tech. 60:107-114; van Hinsbergh, et al. (2001) 936:426-437; Conway, et al. (2001) Cardiovasc. Res. 49:507-521).
Skin wound healing involves a number of phases: inflammation, first with neutrophil and later monocyte/macrophage inflammation, new tissue formation, including matrix formation and differentiation of a neoepithelium, and finally remodeling and maturation. The initial inflammatory phase allows clot formation, controls infection, and promotes vascularization, and produces growth factors. If not controlled properly, the inflammation can lead to pathological healing, e.g., ulcers or scars.
Fibroblasts deposit provisional matrix or granulation tissue, while the newly formed provisional matrix is later degraded in a tissue remodeling process. Degradation of extracellular matrix is mediated by proteases, such as matrix metalloproteases (MMP), gelatinase, and collagenase, as well as protease inhibitors. An imbalance in matrix formation and degradation leads, at one extreme, to chronic ulcers and, on the other extreme, to fibrosis. For example, keloids, an “overhealed response,” are fibrous tissue outgrowths (Michalik, et al. (2001) J. Cell Biol. 154:799-814; Okada, et al. (1997) J. Cell Biol. 137:67-77; Fedyk, et al. (2001) J. Immunol. 166:5749-5755; Ravanti and Kahari (2000) Int. J. Mol. Med. 6:391-407; Peled, et al. (2000) Clin. Past. Surg. 27:489-500).
Matrix formation and reepithelialization depend on angiogenesis (Montesinos, et al. (1997) J. Exp. Med. 186:1615-1620; Malinda, et al. (1998) J. Immunol. 160:1001-1006).
Growth factors used in wound healing induce expression of anti-microbial factors, e.g., defensins, cathelicidins, secretory protease inhibitor, and gelatinase-associated lipocalin (from neutrophils) (Sorensen, et al. (2003) J. Immunol. 170:5583-5589).
In wound healing, cells such as platelets, monocyte/macrophages, T cells, and other immune cells, infiltrate the wound and produce factors that regulate growth of tissue. These factors include TGF, tumor necrosis factor (TNF), IL-1, IL-4, IL-6, oncostatin M, GRO-alpha, various angiogenic factors, and chemokines. In turn, these factors stimulate, for expression of, e.g., extracellular matrix and tissue inhibitor of metalloproteases (TIMP). (Ihn and Tamaki (2000) J. Immunol. 165:2149-2155; Feugate, et al. (2002) J. Cell. Biol. 156:161-172). Myofibroblasts, cells that are fibrogenic, are important for wound closure and contraction. Disease states characterized by accumulation of myofibroblasts include pulmonary fibrosis and scleroderma (Feugate, et al. (2002) J. Cell Biol. 156:161-172).
Wound healing of skin and other tissues is a complex process involving proliferation and migration of immune cells, endothelial cells, fibroblasts, stromal cells, myofibroblasts, smooth muscle cells, pericytes, and keratinocytes.
Parameters used to measure healing include rate of healing, breaking strength of healed wounds, degree of epithelialization, thickness of granulation tissue, and density of extracellular matrix (Matsuda, et al. (1998) J. Exp. Med. 187:297-306).
Ischemia or ischemia reperfusion, as occurs with traumatic injury and “muscle unloading” (chronic bedrest), results in neutrophil infiltration, where the neutrophils often produce tissue damage in excess to the damage caused by the ischemia. Consistent with this adverse effect of neutrophils on healing is that administration of cytokine antagonists, including antagonists to IL-1 or TNF, can also improve wound healing under certain conditions, even where the cytokine is ultimately required for normal repair (see, e.g., Ley (2003) Am. J. Physiol. Regul. Integr. Comp. Physiol. 285:R718-R719; Graves, et al. (2001) J. Immunol. 167:5316-5320). The present invention provides methods using an IL-23 antagonist to inhibit neutrophil-induced tissue injury, e.g., after trauma, wounding, or prolonged bedrest.
Improper wound healing, e.g., of cutaneous wounds, can result in chronic discomfort or disfigurement, and can lead to further complications, e.g., infections or dehydration. Thus, a need exists for effective treatment, both prophylactic and curative, to alleviate the symptoms of those conditions. Alternatively, methods of diagnosis, e.g., of abnormal or modified health of those tissues will be useful. The present invention provides both.
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