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

Examination of 1269 unique naive chicken VH sequences showed that the majority of positions in the framework (FW) regions were maintained as germline, with high mutation rates observed in the CDRs. Many FW mutations could be clearly related to the modulation of CDR structure or the VH–VL interface. CDRs 1 and 2 of the VH exhibited frequent mutation in solvent-exposed positions, but conservation of common structural residues also found in human CDRs at the same positions. In comparison with humans and mice, the chicken CDR3 repertoire was skewed toward longer sequences, was dominated by small amino acids (G/S/A/C/T), and had higher cysteine (chicken, 9.4%; human, 1.6%; and mouse, 0.25%) but lower tyrosine content (chicken, 9.2%; human, 16.8%; and mouse 26.4%). A strong correlation (R2 = 0.97) was observed between increasing CDR3 length and higher cysteine content. This suggests that noncanonical disulfides are strongly favored in chickens, potentially increasing CDR stability and complexity in the topology of the combining site. The probable formation of disulfide bonds between CDR3 and CDR1, FW2, or CDR2 was also observed, as described in camelids. All features of the naive repertoire were fully replicated in the target-selected, phage-displayed repertoire. The isolation of a chicken Fab with four noncanonical cysteines in the VH that exhibits 64 nM (KD) binding affinity for its target proved these constituents to be part of the humoral response, not artifacts. This study supports the hypothesis that disulfide bond-constrained CDR3s are a structural diversification strategy in the restricted germline v-gene repertoire of chickens.

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Background: Single domain variable regions of shark antibodies (V-NARs) are promising biotherapeutic candidates. Results: A V-NAR specific for human serum albumin was humanized, and its crystal structure in complex with the antigen was solved, revealing an unusual recognition mode. Conclusion: Humanization preserved antigen binding properties and activity of the parental shark antibody. Significance: A structural framework for humanization of shark antibodies was established.

In addition to parenchymal amyloid-␤ (A␤) plaques, Alzheimer's disease (AD) is characterized by A␤ in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular A␤ (VA␤) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-A␤ antibodies may clear parenchymal amyloid but increase VA␤ and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VA␤ and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VA␤ and microhemorrhage in PDAPP mice by comparing antibodies with different A␤ epitopes (3D6, A␤ 1-5 ; 266, A␤ 16 -23 ) and performing a 3D6 dose-response study. VA␤ and microhemorrhage were assessed using concomitant A␤ immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VA␤ in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VA␤ was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with A␤ deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VA␤ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VA␤. These observations raise the possibility that A␤ immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.