Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17(m-/-,h+)) mice that we recently produced. First, we generated immunodeficient Rag-2(-/-)/COL17-humanized mice by crossing Rag-2(-/-) mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2(-/-)/COL17-humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8(+) T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4(+) T cells as well as CD45R(+) B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models.
To study the mechanism of monocyte recruitment in atherogenesis and to clarify the effect of monocyte chemotactic protein-1 (MCP-1) in this process.Femoral arteries isolated from the rabbits which had been fed with a high cholesterol diet and locally perfused with MM-LDL within the artery beforehand, were used as the models. Antisense MCP-1cDNA was transferred into the arterial wall by injecting recombinant LNCX-anti-MCP-1/liposomal complex in the femoral sheath and the periarterial tissue.Expression of antisense MCP-1 mediated by recombinant LNCX plasmid/lipsomal complex gene transfer enabled to inhibit MCP-1 gene expression and adhesion of monocyte to the intima.MCP-1 plays an important role on the recruitment of monocytes in the arterial wall, which provides a potential clue in developing a gene therapy project for the prevention and treatment of atherogenesis.
ObjectiveTo study the expression of telomerase activity in patients with acute myelocytic leukemia(AML) and its clinical significance.MethodsAML patients(n=74),benign hematologic patients,and non-hematologic patients with normal bone marrow as controls,were included in this study.Modified TRAP-silver staining and Yalien analyzing software were used to analyze the corresponding data.ResultsExpression of telomerase of the controls was negative or low.For the AML patients,the telomerase activity increased significantly at the initial stage(F=36.76,q=14.65,P0.01),then decreased after complete remission(q=10.75,P0.01) and increased again at relapse(q=7.61,P0.01).High level of telomerase activity was associated with poor prognosis.ConclusionActivation of telomerase is closely related with the occurrence and development of(acute) myelocytic leukemia,which could be used as a molecular marker for evaluation of malignant clonal proliferation.
Gene therapy provides the possibility of long term treatment for the severest of congenital disorders. In this review we will examine the recent advances in gene therapy for genodermatoses. Congenital diseases of the skin exhibit a wide range of severity and underlying causes and there are many possible therapeutic avenues. Gene therapy approaches can follow three paths-in vivo, ex vivo and fetal gene therapy, though the later is currently theoretical only it can provide potential results for even the most severe congenital diseases. All approaches utilize the many different vector systems available, including viral and the emerging use of non- viral integrating vectors. In addition, the use of RNAi based techniques to prevent dominant mutant protein expression has been explored as a therapy for specific dominant disorders such as keratin mutation disorders. Progress has been rapid in the past few years with some initial successful clinical trials reported. However, there are still some issues surrounding long term expression, transgene sustainability and safety issues that need to be addressed to further shift from experimental to clinically therapeutic applications. With the continuing development, merger and refinement of existing techniques there is an ever increasing likelihood of gene therapies becoming available for the more severe genodermatoses within the next decade or shortly thereafter.
Viral protein R (Vpr) from the human immunodeficiency virus induces cell cycle arrest in proliferating cells, stimulates virus transcription, and regulates activation and apoptosis of infected T‐lymphocytes. We report that Jurkat cells overexpressing full‐length gelsolin show resistance to Vpr‐induced T‐cell apoptosis with abrogation of mitochondrial membrane potential loss and the release of cytochrome c . Co‐immunoprecipitation assays in HEK293T cells demonstrated that overexpression of full‐length or segment 5 (G5) but not G5‐deleted gelsolin (ΔG5) bound to the voltage‐dependent anion channel (VDAC), and that the G5 subunit can inhibit HIV‐1‐Vpr‐binding to VDAC. We also confirmed that full‐length gelsolin has the same effect in Jurkat cells. Clonogenic analysis showed that transfection of G5 but not ΔG5 cDNA protects Jurkat T cells from HIV‐Vpr‐Tet induced T‐cell apoptosis and promoted cell survival, as did full‐length gelsolin. These results suggest that the gelsolin G5 domain inhibits HIV‐Vpr‐induced T‐cell apoptosis by blocking the interaction between Vpr and VDAC, and might be used as a protective treatment against HIV‐Vpr‐induced T‐cell apoptosis.
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