EFFECT OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR ON RAT ALVEOLAR MACROPHAGE ANTICRYPTOCOCCAL ACTIVITY IN-VITRO

Cryptococcus neoformans, a pathogenic fungus usually acquired by inhal ation, causes the most common lethal mycosis in AIDS. The resident lun g phagocytes, alveolar macrophages (AMo), inhibit growth of C neoforma ns poorly unless activated by cytokines such as IFN-gamma. In this stu dy, we examined the effect on rat AMo of the potent hematopoietic and Mo-activating cytokine, granulocyte-macrophage CSF (GM-CSF), alone and in combination with other cytokines. Rat AMo monolayers were preincub ated with 0.1 to 1 000 U/ml GM-CSF without or with other recombinant c ytokines, and then were incubated with viable C neoformans (strain H99 /C3D). Growth inhibition was assessed by counting cryptococcal CFU at 24 and 48 h of coculture; AMo proliferation was assessed by measuring both uptake of [H-3]TdR and AMo numbers. AMo preincubated with GM-CSF for 5 days (but not for shorter periods) inhibited growth of C. neofor mans. Anticryptococcal activity required direct contact of AMo with C neoformans, but once induced by preincubation, did not require continu ed exposure to GM-CSF. Induction of anticryptococcal activity by GM-CS F was dose dependent (maximal induction at 250 U/ml), and was due to b oth increased ingestion and killing. GM-CSF induced AMo proliferation, but anticryptococcal activity was not due totally to increases in AMo numbers, indicating AMo activation by GM-CSF. GM-CSF-induced AMo prol iferation was increased by IL-6, unchanged by IL-8, and abolished by L PS or IFN-gamma. However, IL-6 did not increase GM-CSF-induced anticry ptococcal activity. The combination of GM-CSF and IFN-gamma showed rap id and sustained anticryptococcal activity, unlike either cytokine alo ne. Our in vitro data suggest that the combination of GM-CSF and IFN-g amma may have beneficial effects on host defense against C. neoformans in vivo.