Same therapy might treat infections like flu and ebola along with autoimmune illnesses involving chronic inflammation

[Emily]

https://www.alnmag.com/news/2016/08/...izontalcontent

Mouse Study Shows Halt in Harmful Immune Response in Lupus


Thu, 08/18/2016 - 10:53am Comments by Duke Medicine News and Communications

...

“This debris left by dead cells can mistakenly signal to the body that there is an infection that warrants immune action, triggering the innate immune system,” said Bruce A. Sullenger, Ph.D., director of the Duke Translational Research Institute. Sullenger is senior author of a study published online in the Proceedings of the National Academy of Sciences.
“By selectively targeting the source of the immune activation rather than shutting off the innate immune system downstream, these nucleic acid scavengers are able to limit pathological inflammation without compromising one’s ability to fight a viral infection,” Sullenger said.
Pathological inflammation, a major cause of illness and death around the world, is a hallmark of autoimmune diseases, including lupus and diabetes, as well as chronic conditions such as heart disease and some cancers. It also fuels the organ failure associated with severe infectious diseases such as Ebola or even flu.
Current therapies to treat pathological inflammation generally focus on quieting the overactive immune response, but in suppressing the immune system, patients are vulnerable to severe infections arising from other sources.
Intrigued by the ability of certain polymers to mop up DNA and RNA for gene transfer, Sullenger and colleagues tested the idea that these chemical compounds might also be effective targeting such nucleic acids as they arise in cell death.
“Essentially what you have in an autoimmune disease is a vicious cycle,” said lead author Eda K. Holl, Ph.D., assistant professor in Duke’s Department of Surgery. “Our goal was to break this cycle at its onset. What we saw in animals with lupus when we used these compounds was a dramatic reduction in inflammation, which gave the body a chance to heal.”
Sullenger and Holl said the approach was further tested to see if it compromised the mice’s ability to fight outside infections. When they exposed the treated mice to the influenza virus, the animals recovered from the illness even better than healthy mice infected with flu that had not undergone the treatment...

 

[tetano]

[h=1]Scavenging nucleic acid debris to combat autoimmunity and infectious disease[/h]

• Eda K. Holl[SUP]a[/SUP],[SUP]b[/SUP],
• Kara L. Shumansky[SUP]a[/SUP],[SUP]b[/SUP],[SUP]c[/SUP],
• Luke B. Borst[SUP]d[/SUP],
• Angela D. Burnette[SUP]a[/SUP],[SUP]b[/SUP],
• Christopher J. Sample[SUP]e[/SUP],[SUP]f[/SUP],
• Elizabeth A. Ramsburg[SUP]e[/SUP],[SUP]f[/SUP], and
• Bruce A. Sullenger[SUP]a[/SUP],[SUP]b[/SUP],[SUP]c[/SUP],[SUP]1[/SUP]

• [SUP]a[/SUP]Department of Surgery, Duke University, Durham, NC 27710;
• [SUP]b[/SUP]Duke Translational Research Institute, Duke University, Durham, NC 27599;
• [SUP]c[/SUP]Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710;
• [SUP]d[/SUP]Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC 27607;
• [SUP]e[/SUP]Department of Medicine, Duke University, Durham, NC 27710;
• [SUP]f[/SUP]Duke Human Vaccine Institute, Duke University, Durham, NC 27710

• Edited by Joseph M. DeSimone, University of North Carolina at Chapel Hill, Chapel Hill, NC, and Carbon, Inc., Redwood City, CA, and approved July 1, 2016 (received for review May 2, 2016)

[h=2]Significance[/h] Pathological inflammation resulting from autoimmune, inflammatory, and infectious diseases remains the major cause of morbidity and mortality around the world. We explored the utility of nucleic acid-binding polymers to limit pathological activation of the innate immune response by scavenging nucleic acid-containing debris. We evaluated such polymers following local and systemic delivery for treatment of cutaneous and systemic lupus erythematosus in mice and observed dramatic therapeutic benefit. Remarkably, such treatment does not limit the ability of lupus-prone mice to combat influenza infection. Thus, by selectively targeting activators of the pathogenic immune response rather than the effectors of the innate immune system, nucleic acid scavengers are able to limit pathological inflammation without compromising one?s ability to fight a viral infection.

[h=2]Abstract[/h] Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal?s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.

http://www.pnas.org/content/113/35/9728.abstract?sid=021e2496-f0c5-40f7-b8b7-f950ab1e1598