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*Leishmaniasis
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© The Rockefeller University Press, 0022-1007/1997/3/867/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 5, March 3, 1997 867-874

Articles

Behavior of Visceral Leishmania donovani in an Experimentally Induced T Helper Cell 2 (Th2)-Associated Response Model

Henry W. Murray*, June Hariprashad*, and Robert L. Coffman{ddagger}

From the * Department of Medicine, Cornell University Medical College, New York 10021; and {ddagger} Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304

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.

Address correspondence to Dr. Murray, Department of Medicine, Cornell University Medical College, Box 130, 1300 York Ave., New York, NY 10021.

This research was supported by National Institutes of Health research grant AI 16963. The DNAX Research Institute is supported by the Schering-Plough Corporation.

1Abbreviations used in this paper: HKLPM, heat-killed L. major promastigotes; LDU, Leishman–Donovan units; r, recombinant.


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