Inhibition of keratin 17 expression with antisense and RNAi strategies: exploring novel therapy for psoriasis.

Psoriasis is now considered to be a chronic, immune-mediated and inflammatory skin disease. As the precise cause of psoriasis remains unknown, its treatment is challenging for dermatologists. Keratin 17 (K17), an intermediate filament protein, is highly expressed in psoriatic lesions, while not normally expressed in healthy epidermis. Studies have suggested that K17 plays a role in the pathogenesis of psoriasis. However, no study has been performed to determine the potential application of K17 down-regulation as a treatment option for psoriatic lesions. We hypothesized that anti-K17 interference may suppress the development and progression of psoriasis and potentially serve as a novel strategy for the treatment of psoriasis. Therefore, we down-regulated and silenced K17 gene expression in keratinocytes (KCs) using antisense and RNA interference (RNAi) techniques. We found that K17-specific antisense oligonucleotides (ASODN) or siRNAs inhibited proliferation and induced apoptosis in KCs as well as down-regulated K17 expression at both mRNA and protein levels. For our in vivo study, we constructed the SCID-hu xenogeneic transplantation psoriasis mouse model by grafting psoriatic lesions onto SCID mice and topically applied K17-specific ASODN and liposome-encapsulated siRNA to the grafts. We observed morphological and histological improvement in the treated psoriatic grafts. As a result, K17 mRNA and protein expression was significantly decreased in the grafts of the mouse model. Taken together, we conclude that anti-K17 therapy is an effective treatment option for psoriasis, and the K17 molecule, as a new target, may hold tremendous potential for the treatment of psoriasis in the future.

Human facial allotransplantation: a 2-year follow-up study.

BACKGROUND: Progress in composite tissue allotransplantation could provide a new treatment for patients with severe facial disfigurements. We did a partial facial allotransplantation in 2006, and report here the 2 year follow-up of the patient. METHODS: The recipient, a 30-year-old man from China, had his face severely injured by a bear in October, 2004. Allograft composite tissue transplantation was done in April, 2006, after careful systemic preparation. The surgery included anastomosis of the right mandibular artery and anterior facial vein, whole repair of total nose, upper lip, parotid gland, front wall of the maxillary sinus, part of the infraorbital wall, and zygomatic bone. Facial nerve anastomosis was done during the surgery. Quadruple immunomodulatory therapy was used, containing tacrolimus, mycophenolate mofetil, corticosteroids, and humanised IL-2 receptor monoclonal antibody. Follow-up included T lymphocyte subgroups in peripheral blood, pathological and immunohistochemical examinations, functional progress, and psychological support. FINDINGS: Composite tissue flap survived well. There were three acute rejection episodes at 3, 5, and 17 months after transplantation, but these were controlled by adjustment of the tacrolimus dose or the application of methylprednisolone pulse therapy. Hepatic and renal functions were normal, and there was no infection. The patient developed hyperglycaemia on day 3 after transplantation, which was controlled by medication. INTERPRETATION: Facial transplantation could be successful in the short term, but the procedure was not without complications. However, promising results could mean that this procedure might be an option for long-term restoration of severe facial disfigurement.

[Immunosuppressive treatment about the patient operated facial allotransplantation in perioperative period].

OBJECTIVE: To investigate the perioperation medication on the first patient who was operated facial allotransplantation, including immunosuppressive drug and adjunctive drug, so that to search a effective medication schedule to the patient operated facial allotransplantation. METHODS: FK506, MMF, Prednisone and Zenapax was performed as immunosuppressive regiment in perioperative treatment; meanwhile, anti-infectives was administered to take precautions against all sorts of infections, such as bacterium, virus and fungus. Furthermore, all kinds of adjunctive drug, Losec, glucurolactone and so on, was administered to protect those function of stomach, liver, kidney and so on. Clinical observations were made on the signs and symptoms of graft survival or rejection, as well as immunological indexes were tested in laboratory. Biopsies of graft were also made at 30 d after operation. Side effect and complication of drug was monitored, in case the body suffered harm. RESULTS: Facial allograft was survived, and the temperature and color of skin were normal. Swelling of tissue was gradually subsidise after 4 days, and recovered in a half month. The count and ratio between Th and Ts were normal, skin Biopsies of every time had no found of hyperacute or acute rejection, and side effect and complication of drug had no monitored. CONCLUSIONS: The regiment of perioperation medication was successfully performed.

[A hemifacial transplantation model in hares].

OBJECTIVE: To design an animal model to study the facial transplantation of allografts in rabbits. METHODS: Livid blue rabbits and New Zealand white rabbits was applied as experiment animal, to harvest hemifacial composite-tissue flap based in the common external carotid artery with the branch of the external mandibular artery and auricularis magna artery, then allotransplantation was performed with the livid blue rabbits as recipient while new Zealand rabbits as donor, the immunosuppressive agent comprised ciclosporin, azamun and prednisone. 25 couples of rabbits were divided three groups. Group A, 5 couples of rabbits, no administered immunosuppressive agent and the artery anastomosis with end-to-end. Group B, 10 couples of rabbits, administered immunosuppressive agent and the artery anastomosis with end-to-end. Group C, 10 couples of rabbits, administered immunosuppressive agent and the artery anastomosis with end-to-side. Postoperative, to observe the survive ratio of animal and composite-tissue flap, verified the practicability of model further. RESULTS: The blood supply of hemifacial composite-tissue flap is rich after allotransplantation. The survive ratio wasn't different with different procedure of the external carotid artery anastomosis. CONCLUSIONS: This is a successful model of composite face flap transplantation in the rabbits.