News From The Journal Of Clinical Investigation: July 13, 2009

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Immune System / Vaccines;  Biology / Biochemistry;  Cancer / Oncology
Article Date: 14 Jul 2009 - 3:00 PDT

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PARASITOLOGY: Immune protection against lethal parasitic disease

Kala azar is a lethal disease caused by infection with the protozoan parasite Leishmania donovani. Alain Dessein and colleagues, at INSERM UMR 906, France, have now obtained new insight into the human immune responses responsible for protection against kala azar.

Although the immune molecules IL-17 and IL-22, which are produced by immune cells known as Th17 cells, provide protection against some bacteria and fungal pathogens in animal models, their role in protection against microbes has not been determined in humans. In this study, analysis of a subset of blood cells (peripheral blood mononuclear cells) from individuals who were infected with Leishmania donovani and developed kala azar and those who were infected with the protozoan parasite but did not develop kala azar showed that IL-17 and IL-22 were strongly and independently associated with resistance to kala azar. Further analysis indicated that peripheral blood mononuclear cells from individuals who developed kala azar produced lower levels of the factors required for the induction of Th17 cells. As peripheral blood mononuclear cells from healthy individuals produced high levels of IL-17 and IL-22 when exposed to Leishmania donovani in vitro, the authors conclude that IL-17 and IL-22 have important complementary roles in protecting individuals from developing kala azar following infection with Leishmania donovani.

Title:
IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani https://www.the-jci.org/article.php?id=38813

Author:
Alain Dessein
INSERM UMR 906, Marseille, France.

TUMOR IMMUNOLOGY: Two in one: gene-specific siRNA-PEI nanocomplexes provide two ways to generate antitumor immunity

Aggressive forms of cancer have the ability to actively suppress the immune system. Therapies designed to stimulate the body's own immune system to attack a tumor must therefore overcome and/or reverse this immunosuppressive environment. Jose Conejo-Garcia and colleagues, at Dartmouth Medical School, Lebanon, have established a new way to overcome the tumor immunosuppressive environment and induce antitumor immunity in mice.

Short strands of RNA known as siRNA can be used to silence genes, with the specific gene silenced being determined by the RNA sequence. In the study, linear PEI-based nanoparticles encapsulating siRNA were found to convert immune cells known as DCs from immunosuppressive to immune activating in a mouse model of ovarian cancer. This transformation occurred through recognition of PEI by the protein TLR5 and recognition of the siRNA by the proteins TLR3 and TLR7. Importantly, it led to immune-mediated tumor regression and prolonged survival in the mouse model of ovarian cancer. An enhanced effect was achieved if the siRNA was designed to silence the gene responsible for making the immune protein PD-L1. The authors conclude that these effects synergize to make gene-specific siRNA-PEI nanocomplexes effective antitumor agents, at least in mice.

Title:
Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity https://www.the-jci.org/article.php?id=37716

Author:
Jose R. Conejo-Garcia
Dartmouth Medical School, Lebanon, New Hampshire, USA.

INFLAMMATION: A new potential target for inflammatory diseases

Although expression of the short form of the protein DSCR-1 (DSCR-1s) is known to be induced in cells that line blood vessels (endothelial cells) by VEGF, a molecule involved in the formation of new blood vessels, the functional significance of this induction has not been determined. In a new study, a team of researchers at the University of Tokyo, Japan, and Harvard Medical School, Boston, has now demonstrated that DSCR-1s dampens the mouse immune response to the inflammatory bacterial component LPS.

The team, led by Takashi Minami and William Aird, found that expression of DSCR-1s was induced in vivo in mouse endothelial cells in a number of different inflammatory settings, including following administration of LPS and following transplantation with a tumor xenograft. A protective role for this protein in controlling the immune response was indicated by the demonstration that following administration of LPS DSCR-1-deficient mice displayed increased mortality rates, while DSCR-1-overexpressing mice were protected. The authors therefore conclude that DSCR-1s dampens the immune response to inflammation and may serve as a novel target in inflammatory diseases.

Title:
The Down syndrome critical region gene 1 short variant promoters direct vascular bed-specific gene expression during inflammation in mice https://www.the-jci.org/article.php?id=35738

Author:
Takashi Minami
The University of Tokyo, Tokyo, Japan.

William C. Aird
Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA.

Source:
Karen Honey
Journal of Clinical Investigation

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