Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 5, Pages 1560-1565Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812689106
Keywords
immunopathology; dendritic cells; cytokine storm; T cells
Categories
Funding
- USPHS [AI074564, AI009484, AI05509, AI069274]
- Ministries of Education, Culture, Sports, Science and Technology and of Health, Labor, and Welfare of Japan
- Kyorin Pharmaceutical Company
- Le Fonds de la Rechercheen Santedu Quebec, Canada
- [NIMH-074404]
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Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cell-mediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8(+) T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.
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