Objective. To determine whether eyedrop administration of an anti-CD4 monoclonal antibody (mAb) is effective in the treatment of Sjögren's syndrome (SS) using a mouse model of the disease.Methods. The anti-CD4 mAb was administered daily into the eyes of mice with SS from ages 4 to 8 weeks or ages 10 to 12 weeks. During treatment, tear volume was monitored and after final treatment, histologic features of the lacrimal and salivary glands, the phenotypes and function of T cells, and serum titers of anti-␣-fodrin antibody were examined.Results. Eyedrop administration of anti-CD4 mAb before the onset of SS prevented the autoimmune pathology seen in the lacrimal glands but not that in the salivary glands. Furthermore, eyedrop administration of anti-CD4 mAb after the development of SS inhibited mononuclear cell infiltration and the destruction of parenchyma only in the lacrimal glands. Eyedrop administration of anti-CD4 mAb suppressed the local activation of CD4؉ T cells rather than deleting CD4؉ T cells, which reduced the expansion of pathologic CD4؉ T cells against ␣-fodrin.Conclusion. These results demonstrate the remarkable efficacy of anti-CD4 mAb eyedrops in the treatment of SS eye symptoms, which illustrates a new antibody-based therapeutic strategy for patients with eye problems caused by SS as well as other diseases.
The diencephalon is the embryonic anlagen of the higher integration centers of the brain. Recent studies have elucidated how the cells in the rostral diencephalon acquire their regional identities. However, the understanding of the mechanisms under which the caudal diencephalon is formed is still limited. Here we focus on the role of Autotaxin (ATX), a lysophospholipid-generating exoenzyme, whose mRNA is detected in the caudal diencephalon. RNA interference against ATX altered the expression pattern of Pax6-regualted genes, Tcf4, Lim1, and En1, implying that ATX is required for the maintenance of the regional identity of the caudal diencephalon and the diencephalon-mesencephalon boundary (DMB). Furthermore, ATX-RNAi inhibited neuroepithelial cell proliferation on both sides of the DMB. We propose a dual role of ATX in chick brain development, in which ATX not only contributes to the formation of caudal diencephalon as a short-range signal, but also regulates the growth of mesencephalon as a long-range signal. Developmental Dynamics 239:2647-2658,
Orbital cartilage encircles the eye giving strength and support to the neural retina. It is derived from cranial neural crest cells (NCCs), cells that can generate a number of cell types including neurons, glia, and melanocytes. Uniquely in the head, NCCs also make skeletal derivatives that form the majority of the craniofacial skeleton. Differentiation of NCCs into cartilage requires inductive interactions between NCCs and the local environment. The nature of these interactions is largely unknown. We hypothesise that formation of the eye socket requires interactions between the eye and the NCCs during early development. This is supported by evidence in animals and humans where lack of eyes (anophthalmia) or formation of small eyes (microphthalmia) result in craniofacial abnormalities. Orbital cartilage is found in the majority of vertebrates but the ability to induce it has been lost to mammals. A comparison of chick and mouse should help us determine which tissues and molecules are necessary for this cartilage to form. We have examined the gene expression patterns of cartilage markers and the definitive cartilage stain Alcian Blue, to show the development of orbital cartilage in the chicken embryo, in addition to showing the initiation of cartilage formation in the mouse. We demonstrate cartilage formation is halted in chick following early eye removal and the neural ectoderm derived-retinal pigment epithelium can induce ectopic cartilage to form in cranial NCCs. Ligand and receptor gene expression patterns indicate a role for Fgfs in the development of this tissue. Funded by the Wellcome Trust.Gsk-3b is a constitutively active protein kinase which has regionalized expression in the developing face and skull.Phosphorylation of b-catenin by GSK-3b leads to proteasomal degradation and dampening of Wnt signaling. GSK-3b also regulates hedgehog (Hh) signaling, by converting GliA to GliR forms. GSK-3b null animals have a cleft palate and delayed skull osteogenesis. The craniofacial phenotypes in the GSK-3b null animals may be attributed to distinct roles in Wnt and Hh signaling. We hypothesize that changes in Wnt signaling are responsible for the skull ossification defects while the palatal defects may be Hh derived. We are using genetic approaches to test these hypotheses. We are utilizing the Axin2 mutation to manipulate the Wnt/ b-catenin pathway in GSK-3b-null animals. Our preliminary data suggests that GSK-3b and Axin2 synergize during ossification of the skull. In addition, we are exploring genetic interactions between GSK-3b and the Hh pathway members, Patched1, and Gli3. Here, we will present genetic evidence for GSK-3b regulation of both Hh and Wnt signaling in the development of the skull.Autotaxin (ATX) is a secreted, phospholipid-generating enzyme originally identified as a motility-promoting factor in a human melanoma cell line. We previously reported that chicken ATX is expressed in the developing diencephalon; however, its role has not been elucidated. To determine the role of ATX in chicken brain dev...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.