Influence of vector-encoded cytokines on anti-Salmonella immunity: Divergent effects of interleukin-2 and tumor necrosis factor alpha

Attenuated Salmonella strains are of interest as new vaccine candidates and as vectors of cloned genes of other organisms, Attenuated strains expressi ng specific cytokines were constructed as a means of manipulating the immun e response in various disease settings. In the present study, interleukin-2 (IL-2)-expressing (GIDIL2) or tumor necrosis factor alpha (TNF-alpha)-expr essing (GIDTNF) strains were compared with the parent strain (BRD509) for t he effect of cytokines on anti-Samonella immunity. Expression of IL-2 resul ted in a rapid clearance of the organism soon after vaccination. The reduct ion in GIDIL2 CFU was 50- to 300-fold higher than that of BRD509 and correl ated with a markedly decreased splenomegaly. Furthermore, no evidence for a ny significant activation, including upregulation of surface markers and pr oduction of nitric oxide (NO), was observed in spleens of GIDIL2-injected m ice. In contrast, the host response to GIDTNF was marked by an early, stron g, splenic cellular influx, but surprisingly, the degree of induced splenom egaly and NO secretion was only 50% of that observed in BRD509-treated mice . Despite this, bacterial colonization of the spleen in GIDTNF-immunized an imals was either slightly decreased from or equivalent to that of the BRD50 9-treated group, suggesting the induction of additional antimicrobial mecha nisms by TNF-alpha. In vivo protection studies demonstrated that, at limiti ng doses, GIDIL2 was inferior to GIDTNF and BRD509 in its capacity to prote ct against virulent challenge. At high doses, however, all three strains ex hibited equal protective efficacy, These results demonstrate that the immun e response against intracellular bacteria can be manipulated by pathogen-ex pressed cytokines and open the way for further fine tuning of immune respon ses not only to Salmonella strains themselves but also to the heterologous gene(s) carried by them.