Lymphocytes in Enhanced RSV Disease

ACOSTA, PL; WIMMENAUER, V; SCALZO PM; BRUM-ORNELAS C; PRINCE G; HIJANO DR; NEWCOMB D; PEEBLES RS; POLACK FP

Nashville

Simposio; Department of Pediatrics Research Retreat 2011; 2011

Introduction:  Approximately 50% of infants are infected with RSV during their first year of life. There is still no vaccine licensed against the virus. A major obstacle to vaccine development has been the enhanced respiratory disease (ERD) that affected children immunized with a formalin-inactivated vaccine against RSV (FIRSV) in the 1960s. Pathogenesis of ERD was associated with a polarization Th-2 of the immune response.  This data suggest that ERD was due a polarization Th-17 instead Th-2.  Objetive:   Determine the role of T helper type 17 lymphocyte in the enhanced disease (ERD) caused by respiratory syncytial virus (RSV) in toddlers immunized with an inactivated RSV vaccine.    Study Design:   Mice: 4-6 week old female BALB/c and C57BL/6 mice.  Immunization: FIRSV 1x 105 pfu, RSV 1x 105 pfu, PBS (placebo) administered in footpad. Challenge: 60 days post-immunization, mice were challenged with RSV A2 106 pfu intranasally.   Histopathology: Lung sections were stained with H&E and PAS. Cytokine responses and Th transcription factors were assayed in bronchoalveolar lavage fluids and regional lymph nodes by immunoasssay and real time RT-PCR.   Lung sections from toddlers who died of ERD in 1967 were stained by immunohistochemistry.    Results:   1) FIRSV enhances IL-17 production in regional lymph nodes after immunization compared to the response elicited by RSV or placebo.  2) The Th-17 lymphocyte response is enhanced in the lungs of mice with ERD.  3) ROR-ãt (Th-17 master transcription factor) levels are increased in the lungs of mice with ERD.  4) Airways hyperreactivity and bronchopneumonia are significantly decreased in mice treated with anti-IL-17 antibody.  5) IL-17 positive cells are abundant in the lungs of toddlers killed by ERD in 1967.