Nucleic acid scavenging polymers inhibit extracellular DNA-mediated innate immune activation without inhibiting anti-viral responses.
Toll-like receptor (TLR) family members, 3, 7 and 9 are key components in initiation and progression of autoimmune disorders such as systemic lupus erythematosus (SLE). These TLRs are often referred to as nucleic acid-sensing TLRs based on their ability to recognize DNAs or RNAs produced by pathogens or damaged cells. During autoimmune disease progression these receptors recognize self nucleic acids as well as self nucleic acid-containing complexes and contribute to inflammatory cytokine production and subsequent enhancement of serum autoantibody levels. We have recently discovered that nucleic-acid scavenging polymers (NASPs) can neutralize the proinflammatory effects of nucleic acids. Here, we begin to explore what effects such NASPs have on normal immune function. We show that such NASPs can inhibit TLR activation without affecting nucleic acid-independent T cell activation. Moreover, we observe that stimulation of immune cells by encapsulated nucleic acids, such as those found in viral particles, is unaffected by NASPs. Thus NASPs only limit the activation of the immune system by accessible extra-cellular nucleic acid and do not engender non-specific immune suppression. These important findings suggest that NASPs represent a new approach toward anti-inflammatory drug development as these agents can potentially be utilized to block overt autoimmune disorders and inflammation while allowing normal immune responses to occur.
Department of Surgery, Duke University, Durham, North Carolina, United States of America.
Eda K
EK
Holl
Kara L
KL
Shumansky
George
G
Pitoc
Elizabeth
E
Ramsburg
Bruce A
BA
Sullenger
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D017951:Antigen Presentation / Q000187:drug effects; D000941:Antigens / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000276:immunology*; D050091:Dendrimers / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D011108:Polymers / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology / Q000473:pathology
D000941:Antigens; D000998:Antiviral Agents; D050091:Dendrimers; D000949:Histocompatibility Antigens Class II; C104700:PAMAM Starburst; D011108:Polymers; D011971:Receptors, Immunologic; D010047:Ovalbumin; D004247:DNA