THE ROLE OF CYTOKINES IN EXPERIMENTAL LISTERIOSIS

Listeria monocytogenes is a Gram-positive, intracytoplasmatically repl icating pathogen that elicits host reactions which are very similar in man and rodents. Using murine listeriosis as a highly reproducible an d convenient experimental model for studying the immune response to in fections with facultative intracellular bacteria, MACKANESS developed the concept of T cell-mediated macrophage activation as the pivotal me chanism in host defense against this type of infectious agents. Contin ued research in listeriosis itself, however, provided paradoxical find ings that challenged the original dogma. In particular, the finding th at T cell-mediated inflammatory events, like DTH and granuloma formati on, can be dissociated from protective effector mechanisms has provide d a new impetus and experimental access to characterizing the molecula r mediators responsible for these diverging phenomena: This review fir st summarizes the cellular basis for the dichotomy of immunological ph enomena outlined above and will then relate recent findings on cytokin e expression in infected tissues to these dual categories of the host response to infection. The authors will focus on data obtained from in vivo experiments and draw on evidence from in vitro systems only when appropriate in vivo verification is still lacking. The data presented will cover the developments made in the field of cytokine research si nce our previous review in 1981 (Rev. Infect. Dis. 3: 1221-1250). Dete ctable numbers of listeria-specific T cells become apparent on day 4 t o 5 of a primary infection. Whereas the localized and sustained releas e of TNF and IFN-gamma, mediated by CD4(+) cells seems to be the focus ing event triggering mononuclear cell accumulation, the coincidental e radication of bacteria critically depends on CD8(+) and/or CD4(-)CDS(- )Thy1(+) cells. Their effector functions, however, remain obscure, sin ce cytokines cannot be identified that will substitute for their prese nce. None of the cytokines studied thus far has been demonstrated to e ffectively cure an established infection. In addition, the increased p roduction of cytokines characteristic of an anamnestic response (IL-2, IL-3, IL-4, IFN-gamma and TNF) can be dramatically reduced by depleti ng CD4(+) T cells without any effect on the animal's ability to eradic ate high lethal doses of bacteria and Listeria-specific CD8(+) T cells can mediate protection even in the presence of neutralizing antibodie s to IFN-gamma. In conclusion, the murine model of Listeria infection provides an interesting experimental approach for the development of i mmunotherapeutic strategies aimed at reducing T cell-mediated immunopa thology without interfering with innate resistance and T cell-mediated cure and prevention of disease.