Respiratory Syncytial (RS) virus is the major cause of lower respiratory tract infections during the first year of life in humans. There is evidence that the T lymphocyte plays an important role in protection from infection, in the pathogenesis disease and in the pathogenesis of enhanced pulmonary disease observed during a trial with a formalin killed vaccine in the 1960's. The precise role of the T cell in RS virus infection and the mechanisms involved are poorly understood. We propose to study T cells to specific RS virus proteins in mice in order to gain further insight into their function in vivo and in vitro. Helper (Th) and cytotoxic (Tc) T cell lines and clones will be produced and used to define the antigenic composition of RS virus as seen by the T cell repertoire of the mouse. A series of experimental vaccines of RS virus will be prepared. These will include live virus, killed virus, purified F, G and N proteins of the virus, and fragments of these proteins. These vaccines will be used to stimulate Th and Tc lines and clones in vitro to determine how the physical form of RS virus antigens influence whether they are expressed on antigen presenting cells with class 1 or class II MHC molecules, and thus stimulate Th or Tc in vitro. Whether the conditions required for in vitro stimulation can predict those in vivo will be determined. The potential of these vaccines to stimulate Th or Tc will then be correlated with their ability to induce protective immunity or immunopathology. The protective or immunopathological effects of Th and Tc lines and clones to RS virus specific proteins will be directly examined by administering these T cells intravenously to RS virus infected mice and measuring the effect on limiting infection clearing the virus from the lungs, and diminishing or enhancing the pathological change in the lungs. These experiments will contribute to our understanding of immunity to virus, pathogenesis of RS virus infection, and will suggest approaches for rational vaccine design. They will have general implication for the role of the T cell in immunity and pathogenesis of lung infections. The results of the proposed experiment will also provide information relevant to any viral vaccine problem where one wishes induce T cell immunity without use of live or whole killed vaccines, such as Herpes Simplex, parainfluenza and the AIDS virus, HIV.
| Munoz, J L; McCarthy, C A; Clark, M E et al. (1991) Respiratory syncytial virus infection in C57BL/6 mice: clearance of virus from the lungs with virus-specific cytotoxic T cells. J Virol 65:4494-7 |
