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JCI online early table of contents: March 6, 2008
Date:3/6/2008

EDITOR'S PICK: Pinpoint accuracy: DNA vaccines that home in on DCs are more potent

One strategy being pursued to develop new vaccines against infectious diseases is DNA vaccination. The idea is that following administration of a DNA vaccine, the body converts the information in the DNA vaccine into a protein that activates an immune response. However, current DNA vaccines induce relatively weak immune responses even if administered multiple times. New data, generated in mice, by Ralph Steinman and colleagues, at the Rockefeller University, New York, has now identified a way to make DNA vaccines more potent.

In the study, mice were administered a DNA vaccine that included the information to make a single protein comprised of the HIV protein gp41 fused to a single-chain Fv antibody specific for DEC205. DEC205 is expressed by immune cells known as DCs, which show proteins from infectious organisms to immune cells known as T cells that then attack the infectious organism. The authors found that the single-chain Fv antibody specific for DEC205 targeted the protein made from the information in the DNA vaccine to DCs, such that it was expressed exclusively in DCs. Furthermore, this DNA vaccine induced a much stronger T cell response than DNA vaccines including information to make the HIV protein gp41 fused to an irrelevant single-chain Fv antibody, and it protected mice more efficiently from a virus engineered to express the HIV protein gp41. These data led to the suggestion that DNA vaccines might be more potent if the information they contain generates a protein that is targeted to DCs, for example by fusion to a single-chain Fv antibody specific for a DC surface molecule.

TITLE: The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells

AUTHOR CONTACT:
Ralph M. Steinman
The Rockefeller University, New York, New York, USA.
Phone: (212) 327-8107; Fax: (212) 327-8875; E-mail: steinma@mail.rockefeller.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34224


EDITOR'S PICK: Genetic manipulation might model cystic fibrosis

Cystic fibrosis (CF) is caused by mutations in the gene responsible for making the protein CFTR. Progress toward understanding the disease-causing mechanisms and developing new therapies has been hampered by the lack of a good animal model; e.g., CF mice fail to develop many of the symptoms seen in patients with CF. However, two independent reports in the April issue of the Journal of Clinical Investigation have described the first steps toward developing large animal (pig and ferret) models of the disease.

A team of researchers from the University of Iowa, Iowa City, and the University of Missouri Columbia, used recombinant adeno-associated virus (rAAV) vectors to alter the CFTR gene in pig fibroblasts such that was disrupted or contained the most common CF-associated mutation (delta-F508). The nucleus of these cells was used to fertilize the eggs of female pigs, and male piglets carrying one or other the mutated CFTR genes were generated. A similar approach rAAV targeting of the CFTR gene in ferret fibroblasts, followed by the transfer of the nucleus of the cells to the eggs of female ferrets was taken by John Engelhardt and colleagues, at the University of Iowa, Iowa City, to generate male ferrets carrying a mutated CFTR gene. As noted by the authors of both papers, these studies have not only provided animals that might lead to the development of a good animal model of CF, but also have described approaches that might be useful for the development of large animals models of other human genetic diseases.

TITLE: Production of CFTR-null and CFTR-delta-F508 heterozygous pigs by adeno-associated virusmediated gene targeting and somatic cell nuclear transfer

AUTHOR CONTACT:

Michael J. Welsh
University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Phone: (319) 335-7619; Fax: (319) 335-7623; E-mail: michael-welsh@uiowa.edu.

Randall S. Prather
University of Missouri Columbia, Columbia, Missouri, USA.
Phone: (573) 882-6414; Fax: (573) 884-7827; E-mail: pratherr@missouri.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34773

RELATED MANUSCRIPT

TITLE: Adeno-associated virustargeted disruption of the CFTR gene in cloned ferrets

AUTHOR CONTACT:
John F. Engelhardt
University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Phone: (319) 335-7744; Fax: (319) 335-6581; E-mail: john-engelhardt@uiowa.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34599


HEMATOLOGY: Protein mutated in Shwachman-Diamond syndrome provides stability

Shwachman-Diamond syndrome (SDS) is an inherited disorder, caused by genetic mutations in the SBDS gene and characterized by, among other things, bone marrow failure and an increased risk of acute myeloid leukemia. New insight into the mechanisms underlying these symptoms has now been generated by a team of researchers from Childrens Hospital Boston and the University of Washington, Seattle, who analyzed human bone marrow stromal cells (BMSCs) and skin fibroblasts.

In BMSCs from healthy individuals the SBDS protein was found to be located at the mitotic spindle, a structure that forms when a cell is dividing, where it bound to and stabilized microtubules, protein filaments that function as structural components of a cell. Consistent with a role for SBDS in mitotic spindle stability, BMSCs from individuals with SDS exhibited increased abnormal mitosis. Further studies using drugs that modify microtubule stability supported this idea and led the authors to suggest that microtubule-stabilizing agents might provide a new approach to the treatment of individuals with SDS.

TITLE: Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome

AUTHOR CONTACT:
Akiko Shimamura
University of Washington, Seattle, Washington, USA.
Phone: (206) 685-5282; Fax: (206) 616-4082; E-mail: shima2@u.washington.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33764


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Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation
Source:Eurekalert

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