Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.
Although implicated in the clinical expression of human visceral leishmaniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immune response involving interleukin-4 (IL-4) and/ or IL-10 is not readily detectable in experimental visceral infection. To overcome this obstacle to analyzing visceral Leishmania donovani in this relevant immunopathogenetic environment, we sought a model in which a Th2 response induces noncuring infection. Four initial approaches were tested primarily in BALB/c mice which control intracellular L. donovani via an IL-12- and interferon-gamma (IFN-gamma)-dependent Th1 mechanism: (a) modifying the cytokine milieu when the parasite is first encountered (treatment with exogenous IL-4 or anti-IL-12), (b) providing sustained endogenous exposure to a Th2 cytokine (infection of IL-4 transgenic mice), (c) increasing the parasite challenge inoculum, and (d) injecting heat-killed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 response to live L. donovani. Only the last approach generated a functional 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 IFN-gamma) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-gamma also successfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in concert to prevent acquisition of resistance to L. donovani, (b) reemphasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-gamma) have therapeutic action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response.
Murray
H W
HW
Department of Medicine, Cornell University Medical College, New York 10021, USA.
Hariprashad
J
J
Coffman
R L
RL
D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan; D004195:Disease Models, Animal; D005260:Female; D006099:Granuloma; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007893:Leishmania donovani / Q000254:growth & development / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000276:immunology*
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D018664:Interleukin-12; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma