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

Abstract

In previous studies, children immunized with a formalin-inactivated respiratory syncytial virus vaccine (FI-RSV) developed severe pulmonary disease with greater frequency than did controls during subsequent natural RSV infection. In earlier efforts to develop an animal model for this phenomenon, extensive pulmonary histopathology developed in FI-RSV-immunized cotton rats and mice subsequently challenged with RSV. In mice, depletion of CD4+ T cells at the time of RSV challenge completely abrogated this histopathology. Furthermore, the predominant cytokine mRNA present in lungs of FI-RSV-immunized mice during subsequent infection with RSV was that characteristically secreted by Th2 T cells, namely interleukin-4 (IL-4). In the present studies, we sought to determine the relative contributions of gamma interferon (IFN-y), IL-2, IL-4, and IL-10 to the lymphocytic infiltration into the lungs observed following RSV challenge of mice previously immunized with FI-RSV. Mice previously immunized with FI-RSV or infected with RSV were depleted of IFN-y, IL-2, IL-4, or IL-10 immediately before RSV challenge, and the magnitude of inflammatory cell infiltration around bronchioles and pulmonary blood vessels was quantified. The phenomenon of pulmonary-histopathology potentiation by FI-RSV was reproduced in the present study, thereby allowing us to investigate the effect of cytokine depletion on the process. Simultaneous depletion of both IL-4 and IL-10 completely abrogated pulmonary histopathology in FI-RSV-immunized mice. Depletion of IL-4 alone significantly reduced bronchiolar, though not perivascular, histopathology. Depletion of IL-10 alone had no effect. Depletion of IFN-y, 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 to subsequent RSV infection. It is possible that this process played a role in enhanced disease observed in infants and children immunized with FI-RSV.

Cytokines and CD8 T cell immunity during respiratory syncytial virus infection

“…2b). The Th2 cytokine IL-4 is primarily associated with exacerbating RSV immunopathology but can also function as a regulator of RSV-specific CD8 T cell effector functions [109,110]. Infection with a recombinant RSV strain expressing IL-4 generates reduced numbers of total CD8 T cells, RSV-specific CD8 T cells, and CD8 T cells producing IFN-γ in the lung compared to WT RSV after peptide stimulation [111,112].…”

Respiratory viruses and eosinophils: Exploring the connections

“…Gene-deletion and cytokine depletion mouse model studies all point to Th2 cytokines (IL-4, IL-5 and IL-13) as crucial to eliciting pulmonary eosinophilia in response to formalin-inactivated RSV (Connors et al, 1994;Castilow et al, 2008a,b). A recent study by Moghaddam et al (2006) suggested that the oxidation of RSV antigens resulting from formalin exposure elicits a Th2 response in vivo.…”

Respiratory Virus Vaccines

“…Vaccine-mediated enhancement of disease also occurred in murine models, with poor induction of neutralizing antibodies probably due to denaturation of antigen in the vaccine or a lack of antibody affinity maturation after poor TLR stimulation (Delgado et al, 2009). In addition, an exaggerated Th2 response and a loss of regulatory T cells contributed to disease (Connors et al, 1992(Connors et al, , 1994de Swart et al, 2007;Loebbermann et al, 2013;Waris et al, 1996). Therefore, it is clear that in addition to a neutralizing antibody response, a balanced CD4 and CD8 T cell response is also desirable.…”