ENHANCED PULMONARY HISTOPATHOLOGY INDUCED BY RESPIRATORY SYNCYTIAL VIRUS (RSV) CHALLENGE OF FORMALIN-INACTIVATED RSV-IMMUNIZED BALB C MICE IS ABROGATED BY DEPLETION OF INTERLEUKIN-4 (IL-4) AND IL-10/

In previous studies, children immunized with a formalin-inactivated re spiratory syncytial virus vaccine (FI-RSV) developed severe pulmonary disease with greater frequency than did controls during subsequent nat ural RSV infection. In earlier efforts to develop an animal model for this phenomenon, extensive pulmonary histopathology developed in FI-RS V-immunized cotton rats and mice subsequently challenged with RSV. In mice, depletion of CD4(+) T cells at the time of RSV challenge complet ely abrogated this histopathology. Furthermore, the predominant cytoki ne mRNA present in lungs of FI-RSV-immunized mice during subsequent in fection with RSV was that characteristically secreted by Th2 T cells, namely interleukin-4 (IL-4). In the present studies, we sought to dete rmine the relative contributions of gamma interferon (IFN-gamma), IL-2 , IL-4, and IL-10 to the lymphocytic infiltration into the lungs obser ved following RSV challenge of mice previously immunized with FI-RSV. Mice previously immunized with FI-RSV or infected with RSV were deplet ed of IFN-gamma, IL-2, IL-4, or IL-10 immediately before RSV challenge , and the magnitude of inflammatory cell infiltration around bronchiol es and pulmonary blood vessels was quantified. The phenomenon of pulmo nary-histopathology potentiation by FI-RSV was reproduced in the prese nt study, thereby allo,wing us to investigate the effect of cytokine d epletion on the process. Simultaneous depletion of both IL-4 and IL-10 completely abrogated pulmonary histopathology in FI-RSV-immunized mic e. Depletion of IL-4 alone significantly reduced bronchiolar, though n ot perivascular, histopathology. Depletion of IL-10 alone had no effec t. Depletion of IFN-gamma, IL-2, or both together had no effect on the observed histopathology. These data indicate that FI-RSV immunization primes for a Th2-, IL-4-, and IL-10-dependent inflammatory response t o subsequent RSV infection. It is possible that this process played a role in enhanced disease observed in infants and children immunized wi th FI-RSV.