BEHAVIOR OF VISCERAL LEISHMANIA-DONOVANI IN AN EXPERIMENTALLY-INDUCEDT-HELPER CELL-2 (TH2)-ASSOCIATED RESPONSE MODEL

Although implicated in the clinical expression of human visceral leish maniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immu ne response involving interleukin-4 (IL-4) and/or IL-10 is not readily detectable in experimental visceral infection. To overcome this obsta cle to analyzing visceral Leishmania donovani in this relevant immunop athogenetic environment, we sought a model in which a Th2 response ind uces noncuring infection. Four initial approaches were tested primaril y in BALB/c mice which control intracellular L. donovani via an IL-12- and interferon-gamma (IFN-gamma)-dependent Th1 mechanism: (a) modifyi ng the cytokine milieu when the parasite is first encountered (treatme nt with exogenous IL-4 or anti-IL-12), (b) providing sustained endogen ous exposure to a TH2 cytokine (infection of IL-4 transgenic mice), (c ) increasing the parasite challenge inoculum, and (d) injecting heat-k illed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 re sponse to live L. donovani. Only the last approach generated a functio nal Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly. In HKLMP-primed BALB/c mice, prophylaxis with anti-IL-4, anti-IL-10, or exogenous IL-12 (but not I FN-gamma) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-gamma also suc cessfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in c oncert Ito prevent acquisition of resistance to L. donovani, (6) reemp hasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-gamma) have therapeuti c action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response.