Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4 + CD45RB hi CD25 -cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis. IntroductionPsoriasis is a common, chronic autoimmune disease of the skin, which affects approximately 2% of the general population. The lesions are characterized by red, scaly, raised plaques at different body sites. Histologically, psoriasis is defined by thickening of the epidermis (acanthosis) due to increased proliferation of keratinocytes, epidermal rete peg formation (downward papillary projections of the epidermis), and parakeratosis (retention of keratinocyte nuclei in the stratum corneum) as well as inflammatory cell infiltrates in the epidermis and dermis (1). Psoriasis does not exist as a spontaneously occurring disease in the skin of animals other than humans. Although some features of psoriasis have been induced in mouse skin by genetic or immune manipulations, these previously described models do not have the full histopathological or immunological features of psoriatic lesions (2-6). In one model, Hong et al. adoptively transferred CD4 + CD45RB hi T cells into scid/scid recipient mice. Disease severity and incidence in this model were mild and improved by coadministration of IL-12 and LPS during disease induction (7). We have validated this model and developed it further by adoptively transferring CD4 + CD45RB hi T cells depleted of CD25 + regulatory cells into scid/scid recipient mice. Affected mice developed scaly and raised skin plaques with certain microscopic characteristics resembling human psoriasis.Although the exact cause of psoriasis is unknown, the data suggest that this disease is caused by a dysregulated interplay between keratinocytes and inflammatory cell infiltrates. This dysregulation results in the production of inflammatory cytokines and chemokines that

The 1.75-A crystal structure of the uracil-DNA glycosylase from herpes simplex virus type-1 reveals a new fold, distantly related to dinucleotide-binding proteins. Complexes with a trideoxynucleotide, and with uracil, define the DNA-binding site and allow a detailed understanding of the exquisitely specific recognition of uracil in DNA. The overall structure suggests binding models for elongated single- and double-stranded DNA substrates. Conserved residues close to the uracil-binding site suggest a catalytic mechanism for hydrolytic base excision.

Cells from diverse tissues detect mechanical load signals by similar mechanisms but respond differently. The diversity of responses reflects the genotype of the cell and the mechanical demands of the resident tissue. We hypothesize that cells maintain a basal equilibrium stress state that is a function of the number and quality of focal adhesions, the polymerization state of the cytoskeleton, and the amount of extrinsic, applied mechanical deformation. A load stimulus detected by a mechano-electrochemical sensory system, including mechanically sensitive ion channels, integrin-cytoskeleton machinery, and (or) a load-conformation sensitive receptor or nonreceptor tyrosine kinase, may activate G proteins, induce second messengers, and activate an RPTK or JAK/STAT kinase cascade to elicit a response. We propose the terms autobaric to describe a self-loading process, whereby a cell increases its stress state by contracting and applying a mechanical load to itself, and parabaric, whereby a cell applies a load to an adjacent cell by direct contact or through the matrix. We predict that the setpoint for maintaining this basal stress state is affected by continuity of incoming mechanical signals as deformations that activate signalling pathways. A displacement of the cytoskeletal machinery may result in a conformational change in a kinase that results in autophosphorylation and cascade initiation. pp60Src is such a kinase and is part of a mechanosensory protein complex linking integrins with the cytoskeleton. Cyclic mechanical load induces rapid Src phosphorylation. Regulation of the extent of kinase activation in the pathway(s) may be controlled by modulators such as G proteins, kinase phosphorylation and activation, and kinase inhibitors or phosphatases. Intervention at the point of ras-raf interaction may be particularly important as a restriction point.

Objective. Interleukin-21 (IL-21) is a T cellderived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL-21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL-21 contributes to their pathologic processes.Methods. DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL-21 receptor Fc fusion protein (IL-21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL-21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL-21R.Fc on the production of interferon-␥ (IFN␥) by T cells were examined.Results Conclusion. These findings demonstrate a pathogenic role for IL-21 in animal models of RA, and support consideration of IL-21 as a therapeutic target in human RA.

Abstract. A total of 340 cases of cutaneous neoplasia were diagnosed in 340 of 3,564 cats that were examined by biopsy or necropsy during a 41-month period from January I , 1986 through May 3 1, 1989. Eighteen types of tumor occurred, but four types comprised 77% of the cases. These were basal cell tum or, 89 cases (26%, mean age 10.3); mast cell tumor, 72 cases (21%, mean age 8.6); squamous cell carcinoma, 52 cases (15%, mean age 11.6); and fibrosarcoma, 50 cases (15%, mean age 10.2). For each of these four types of tumors , peak number of cases occurred in cats older than 10 years. Mast cell tum or was the only tumor diagnosed in cats younger than I year. The head was the most common site for basal cell tumors, mast cell tumors, and squamous cell carcinomas. The legs were the most common location of fi brosarcomas . Siamese cats had approximately three times as many mast cell tumors as statistically expected, but only one-fourth as many squamous cell carcinomas. Breed predilection for other skin tum ors was not apparent. Sex predilection was not detected for any skin tumor.Key words: Basal cell tumor; cat; cutaneous neoplasms; fibrosarcoma; mast cell tumor; squamous cell carcinoma. Resultssectioned, and stained with hemat oxylin and eosin, Other histologic stains (mainly, Giemsa and toluidine blue) were used at the discretion of the case pathologist.The histologic diagnosis, signalment, and sites of the tumors are summarized in Tables I , 2, and 3, Data were evaluated for statistical significance by adjusted chi-square analysis, Follow-up information was not available for these cats, Ski n tumors com prised 9. 6% of feline necr op sy or biopsy accessions during th e 41 -month study . The skin sites accounted for 29 .6% of all neoplasms diagnosed in the cats, m aking it the most common sit e for tumors in our laboratory, Eighteen different types ofcutane o us neoplasms were recognized . Sex di stribution and age ofaffected ca ts are su m marize d for each tumor in Table I. Sign ificant sex pred ilection wa s not apparent for an y skin tumor. Site d istribution of th e tumors is summarized in Table 3.Basal cell tumor, mast cell tumor, squamous cell carcinoma, and fibrosarcoma were the m ost commonly diagnosed tumors, com pris ing 77.1 % ofall skin tumors d iagnosed during th e study period. The in ciden ce of th ese four com m on tumors is su m marize d by breed in T able 2. Materials and MethodsIn most stud ies, skin has been second only to th e lymphoid syste m as the most co m m on site of tumors in th e caL I4.25.31.35 A lthough some ea rly surveys lack diagnoses of mast cell tumor,9,11 ,26 ba sal cell tumor,4.1 4.25.26 or fibrosarcoma," more recent British," German," and Swiss" reports have cited fibrosarcoma , basal cell tumor, squamous cell carcinoma, and mast cell tumor (with variation in order of prevalence) as th e most co m mon feline skin tumors. These fou r tumors had been reported as early as 1953 in a retrospec tive study of 26 feline skin tumors." Reports of breed,13,20,31 ,36 sex,23,31.34 and...