ovalbumin and Psoriasis

elbion (formerly ASTA Medica) and GlaxoSmithKline are developing an inhaled formulation of AWD-12-281 for the potential treatment of chronic obstructive pulmonary disease (COPD). By May 2005, phase II trials of this 5-hydroxyindole PDE4 inhibitor for COPD were ongoing.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Inhalation; Administration, Topical; Amides; Aminopyridines; Animals; Benzamides; Clinical Trials as Topic; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Dermatitis, Atopic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Indoles; Inflammation; Lipopolysaccharides; Ovalbumin; Phosphodiesterase Inhibitors; Psoriasis; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases; Structure-Activity Relationship

Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-36α, IL-36β and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.

Topics: A549 Cells; Animals; Antibodies, Blocking; Antibodies, Monoclonal; Cell Line, Tumor; Disease Models, Animal; HEK293 Cells; Humans; Imiquimod; Inflammation; Interleukin-1; Interleukin-1 Receptor Accessory Protein; Interleukin-1beta; Interleukin-33; Male; Mice; Mice, Inbred C57BL; Ovalbumin; Peritonitis; Pneumonia; Psoriasis; Signal Transduction; Uric Acid

Systemic but not topical tacrolimus (TAC) is effective against psoriasis. Mechanical methods that enhance skin penetration by TAC increase its topical antipsoriatic effect. Liposomal delivery of TAC would increase its penetration of skin, allow for slow release and diminish its toxicity.. To test a liposomal TAC (LTAC) formulation in a murine model.. Drug penetration was assessed using radiolabelled LTAC, and the effect of TAC and LTAC on Balb/c skin graft survival and on ovalbumin-induced delayed-type hypersensitivity reactions was tested in C57BL/6 mice.. Radiotracer studies showed that topical application of LTAC achieved nine times the concentration of TAC at a target site than did systemic administration of TAC. Combination of systemic and topical LTAC significantly increased mean +/- SD skin graft survival (14.8 +/- 1.5 days) compared with systemic TAC (8.0 +/- 0.7 days) and control mice (8.4 +/- 1.2 days). LTAC was more effective systemically than TAC in the prevention of delayed-type hypersensitivity reactions. Topical LTAC also prevented this response.. Topical LTAC was effective in this model of immune-mediated skin disease. Because LTAC achieves higher skin concentrations than systemic TAC it may be an effective delivery system for TAC in the treatment of psoriasis.

Topics: Administration, Cutaneous; Animals; Graft Survival; Hypersensitivity, Delayed; Immunosuppressive Agents; Liposomes; Mice; Mice, Inbred C57BL; Models, Animal; Ovalbumin; Psoriasis; Skin Transplantation; Tacrolimus

Epidermal keratinocytes are the primary target of the midrange ultraviolet part (UVB, 280-320 nm) of terrestrial sunlight. Analysis of the resulting UV response at the transcriptional level by differential display PCR identified a formerly unrecognized large group of repressed genes. Among those UV-repressible genes, a novel serine proteinase inhibitor (serpin) termed hurpin (HaCaT UV-repressible serpin) has been identified. The isolated full-length cDNAs harbour a 1176 bp open reading frame encoding a potential protein with 391 amino acid residues and a predicted molecular mass of approximately 44 kDa. The novel serpin has nearly 59 % amino acid identity with the squamous cell carcinoma antigen 1 (SCCA1) and squamous cell carcinoma antigen 2 (SCCA2). In addition, it displays all of the structural features unique to the ovalbumin family of serpins (ov-serpins). The amino acid sequence of the hinge region in the reactive site loop suggests that hurpin has the potential for protease inhibition. The putative reactive center P1-P1'residues were identified as Thr356-Ser357 by alignment with other ov-serpins. The physiological target protease is unknown and the in vitro translated hurpin does not form SDS-stable complexes with a variety of known serine proteases. Expression of hurpin is restricted to epidermal cells where two distinct transcripts of 3.0 and 3.4 kb are detectable. Furthermore, expression of hurpin appears to be related to the activation or proliferation state of keratinocytes, since hurpin transcripts are more abundant in immortalized keratinocytes (HaCaT) and in cultured normal human keratinocytes, compared to the expression in normal skin. Moreover, in psoriasis, a skin disease characterized by hyperproliferation of keratinocytes and responsive to therapeutic UV irradiation, overexpression of hurpin is noted in psoriatic skin lesions compared to non-lesional skin.

Topics: Amino Acid Sequence; Antigens, Neoplasm; Binding Sites; Cell Line; Cloning, Molecular; Humans; Keratinocytes; Molecular Sequence Data; Ovalbumin; Psoriasis; Retina; Sequence Homology, Amino Acid; Serine Proteinase Inhibitors; Serpins; Skin; Ultraviolet Rays