TREATMENT WITH A SPHINGOSINE ANALOG DIMINSHES IMMUNOPATHOLOGY FOLLOWING INFLUENZA VIRUS INFECTION (45.2)

• Published in: The Journal of immunology (1950) 2009-04, Vol.182 (1_Supplement), p.45-45.2
• Main Authors: Walsh, Kevin Barry, Marsolais, David, McGavern, Dorian, Hatta, Yasuko, Kawaoka, Yoshihiro, Rosen, Hugh, Oldstone, Michael B.A.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.182.Supp.45.2

Highly pathogenic strains of influenza virus can result in high mortality rates due to severe tissue damage caused by direct injury induced by the virus or by the immune response against the virus (immunopathology). Immune-mediated pulmonary tissue damage is a result of cytokine/chemokine release and the antiviral activity by cells of the innate and adaptive immune responses. Here we report that intratracheal treatment with a sphingosine analog, AAL-R, results in the inhibition of dendritic cell (DC) activation and antigen presentation to T cells in the mediastinal lymph nodes and the lung. Diminished DC function restricts virus-specific T cell proliferation causing a subsequent reduction in the accumulation of T cells in the lungs. The immunosuppressive effect involves signaling through S1P receptors on DC, but is independent of S1P1, S1P2 and S1P3. Inhibition of the accumulation of virus-specific T cells in the lungs occurs without impinging the production of anti-viral neutralizing antibodies. AAL-R treatment hinders cytokine/chemokine production which leads to a reduction in polymorphonuclear leukocyte and macrophage infiltration resulting in reduced lung injury. Importantly, local AAL-R administration into the lung was effective in controlling CD8+ T cell accumulation in the lungs when given four days following influenza virus infection. Administration of sphingosine analogs during influenza virus infection offers a potentially powerful therapeutic for alleviating pulmonary immunopathology.