Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
1999-12-08
2002-06-25
Nguyen, Dave T. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C424S009200, C424S093710, C435S325000, C435S375000, C530S351000
Reexamination Certificate
active
06410824
ABSTRACT:
BACKGROUND
Psoriasis is a chronic skin disease, characterized by scaling and inflammation. Psoriasis affects 1.5 to 2 percent of the United States population, or almost 5 million people. It occurs in all age groups and about equally in men and women. People with psoriasis suffer discomfort, restricted motion of joints, and emotional distress. When psoriasis develops, patches of skin thicken, redden, and become covered with silvery scales, referred to as plaques. Psoriasis most often occurs on the elbows, knees, scalp, lower back, face, palms, and soles of the feet. The disease also may affect the fingernails, toenails, and the soft tissues inside the mouth and genitalia. About 10 percent of people with psoriasis have joint inflammation that produces symptoms of arthritis.
When skin is wounded, a wound healing program is triggered, also known as regenerative maturation. Lesional psoriasis is characterized by cell growth in this alternate growth program. In many ways, psoriatic skin is similar to skin healing from a wound or reacting to a stimulus such as infection, where the keratinocytes switch from the normal growth program to regenerative maturation. Cells are created and pushed to the surface in as little as 2-4 days, and the skin cannot shed the cells fast enough. The excessive skin cells build up and form elevated, scaly lesions. The white scale (called “plaque”) that usually covers the lesion is composed of dead skin cells, and the redness of the lesion is caused by increased blood supply to the area of rapidly dividing skin cells.
The exact cause of psoriasis in humans is not known, although it is generally accepted that it has a genetic component, and a recent study has established that it has an autoimmune component. Whether a person actually develops psoriasis is hypothesized to depend on something “triggering” its appearance. Examples of potential “trigger factors” include systemic infections, injury to the skin (the Koebner phenomenon), vaccinations, certain medications, and intramuscular injections or oral steroid medications.
The chronic skin inflammation of psoriasis is associated with hyperplastic epidermal keratinocytes and infiltrating mononuclear cells, including CD4+ memory T cells, neutrophils and macrophages. Because of this highly mixed inflammatory picture and the resulting complex interrelationships between these different cells, it has been very difficult to dissect the mechanisms that underlie the induction and progression of the disease.
Research into the pathogenesis and treatment of psoriasis has long been hindered by the lack of suitable animal models. Although several rodent models of skin inflammation have been recently introduced, none of these models have the specific T cell abnormalities that have been demonstrated as a primary cause for the induction of disease. The development of improved animal models having the clinical features associated with human psoriasis would be of great benefit for screening potential therapies and drugs.
Relevant Literature
Schon et al. (1997)
Nat Med.
3:183-8 induced a murine psoriasis-like disorder by reconstituting scid/scid mice with naive CD4
+
T cells. This model, however, lacked certain distinctive histological hallmarks of the human disease and included some characteristics that are absent from human patients with psoriasis, Nickoloff et al. (1997).
Nat Med.
3:475-6. Other mouse models for psoriasis have also utilized immunodeficient animals. Sugai et al. (1998)
J Dermatol Sci
17:85-92 transplanted human psoriatic lesions onto SCID mice. The human skin grafts were generally well maintained during this period, but the histological and immunohistochemical findings characteristic of psoriasis, except for acanthosis and hyperkeratosis, gradually disappeared as lymphocytic infiltration of the psoriatic lesions declined. Yamamoto et al. (1998)
J Dermatol Sci
17:8-14 injected staphylococcal enterotoxin B-stimulated lymphocytes subcutaneously under full-thickness psoriatic skin grafted onto severe combined immunodeficient (SCID) mice.
Gottlieb et al. (1995)
Nat Med.
1:442-7 treated patients with fragments of diphtheria toxin linked to human interleukin-2 (DAB389IL-2), which selectively targets activated T cells but not keratinocytes. They showed significant clinical improvement, indicating that T cells and not keratinocytes are the primary pathogenic component in the disease.
Sundberg et al. (1997) Pathobiology 65(5):271-86 describe the development and progression of psoriasiform dermatitis and systemic lesions in the flaky skin (fsn) mouse mutant. Flaky skin (fsn) mutant mice were originally described as a mouse model for psoriasis accompanied by hematological abnormalities. However, homozygous (fsn/fsn) mice develop a number of other pathological changes.
Hong et al. (1999) J. Immunol. 162:7480-7491 (which is herein incorporated by reference for all purposes) describe improved animal models of psoriasis.
SUMMARY OF THE INVENTION
Non-human animal models are provided for psoriasis. The animals develop a disease having many of the characteristics of human psoriasis. The animals are useful for testing and screening for biologically active agents for the treatment of psoriasis. Naive, immunocompetent T lymphocytes are transferred into an immunodeficient animal host, along with at least one pro-inflammatory cytokine and a polyclonal activating agent. The engrafted T cells are tolerant to the major histocompatibility antigens of the host animal, but are mismatched at one or more minor histocompatibility loci. The engrafted animals develop a chronic skin disorder that includes histological features observed in human psoriasis, e.g. rete pegs, severe acanthosis and infiltration of Th1 cells into the dermis. These animals provide a useful model for the specific pathogenic requirements of Th1 promoting cytokines and cells for the development of psoriasiform lesions, and into the prevention and treatment of psoriasis in humans.
In another embodiment, the animal model has been used to discover a treatment for psoriasis comprising administration to patients of monoclonal antibodies that bind to and neutralize interleukin 12 (IL-12) or gamma-interferon (&ggr;-IFN).
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Chang, Jennie C.C., et al., “CD8+T Cells in Psoriatic Lesions Preferentially Use T-Cell Receptor V&bgr;3 and/or V&bgr;13.1 Genes,”Proc. Natl. Acad. Sci. USA(Sep. 1994) vol. 91:9282-9286.
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Forman, James, et al., “H-40,
Ehrhardt Rolf
Hong Kenneth
Queen Cary
Halluin Albert P.
Howrey Simon Arnold & White , LLP
Kung Viola T.
Nguyen Dave T.
Nguyen Quang
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