Editors' ChoiceAutoimmunity

Gobbling up inflammation to ameliorate autoimmunity

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Science Translational Medicine  07 Sep 2016:
Vol. 8, Issue 355, pp. 355ec145
DOI: 10.1126/scitranslmed.aah6435

Given its pervasive role in the development of many diseases, including autoimmune disorders, infections, and cancer, controlling inflammation is a significant challenge of modern medicine. During disease progression, dying cells release nucleic acid–containing debris that activates Toll-like receptors (TLRs). These receptors up-regulate the expression of proinflammatory cytokines and can lead to antibody production, causing inflammation that further exacerbates the disease. Therapeutic interventions to limit inflammation must walk a fine line between suppressing the immune response to self-antigens while retaining the body’s ability to fight infectious disease.

In a new study, Holl and colleagues describe the ability of nucleic acid–binding polyamidoamine (PAMAM) polymers to scavenge loose RNA and DNA fragments before they have a chance to interact with TLRs. This approach stands in contrast to previously developed treatments that have targeted TLRs directly, with only modest therapeutic effect. The authors used third-generation, positively charged PAMAM dendrimers that act like a sponge to sequester negatively-charged nucleic acid debris and limit the inflammatory response.

PAMAM scavengers demonstrated therapeutic potential in both cutaneous and systemic mouse models of lupus, an autoimmune disease that can attack many parts of the body, including joints, kidneys, and lungs. In the systemic model, normal disease pathology includes kidney damage, deposition of complement C3c, high levels of anti-DNA antibodies, and reduced platelet counts. Animals dosed with PAMAM scavengers twice a week for 10 weeks exhibited significant reductions in these symptoms compared with control groups. Importantly, PAMAM treatment did not affect the ability of mice to resist infection with influenza virus. In fact, healthy mice infected with influenza and treated with PAMAM scavengers had an improved survival rate (86%) compared with PBS treated mice (25%) despite having similar anti-influenza antibody titers. Together, these data suggest that the clearance of nucleic acid debris during the course of both autoimmune and infectious disease facilitates better outcomes. The mechanism of enhanced survival of lethal influenza infection following treatment is still unknown. Future work is needed to move these results towards the clinic, including the use of more advanced lupus models, such as canines.

E. K. Holl et al., Scavenging nucleic acid debris to combat autoimmunity and infectious disease. Proc. Natl. Acad. Sci. U.S.A. 113, 9728–9733 (2016). [Abstract]

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