Immunotherapy with CpG oligonucleotides and antibodies to TNF-alpha rescues neonatal mice from lethal arenavirus-induced meningoencephalitis.
Viral encephalitides are life-threatening diseases in neonates partly due to the irreversible damage inflammation causes to the CNS. This study explored the role of proinflammatory cytokines in the balance between controlling viral replication and eliciting pathologic immune responses in nonlytic viral encephalitis. We show that neonatal mice challenged with arenavirus Tacaribe (TCRV) develop a meningoencephalitis characterized by high IFN-gamma and TNF-alpha levels and mild T cell infiltration. Neutralization of the TNF-alpha using mAb was associated with lower chemokine expression, reduced T cell infiltration, and lower levels of IFN-gamma, and TNF-alpha in the CNS and led to 100% survival. Moreover, treatment with Abs to TNF-alpha improved mobility and increased survival even after the mice developed bilateral hind limb paralysis. Of note, animals treated with anti-TNF-alpha Abs alone did not clear the virus despite generating Abs to TCRV. Direct activation of the innate immune response using CpG oligodeoxynucleotides in combination with anti-TNF-alpha Abs resulted in 100% survival and complete viral clearance. To our knowledge, this is the first demonstration of the use of innate immune modulators plus Abs to TNF-alpha as therapeutics for a lethal neurotropic viral infection.
Laboratory of Immunology, Division of Therapeutic Proteins, Office of Biotechnology, Center for Drug Evaluation and Review, FDA, Bethesda, MD 20892, USA.
João A
JA
Pedras-Vasconcelos
Montserrat
M
Puig
Christian
C
Sauder
Candie
C
Wolbert
Mikhail
M
Ovanesov
David
D
Goucher
Daniela
D
Verthelyi
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000096:biosynthesis; D006477:Arenaviruses, New World / Q000276:immunology*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D002908:Chronic Disease; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D008590:Meningoencephalitis / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; C408982:CPG-oligonucleotide; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha