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Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.

Murray HW, Hariprashad J, Coffman RL - J. Exp. Med. (1997)

Bottom Line: 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.Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Cornell University Medical College, New York 10021, USA.

ABSTRACT
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.

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Preliminary experiments to determine the course of visceral infection in five different populations of mice. (A) BALB/c mice not treated (•)  or injected once with IL-4/anti–IL-4 complex one day before (day −1) L. donovani challenge (○). (B) BALB/c mice not treated (•) or injected with  IL-4/anti–IL-4 starting on day −1 and twice per week for the first four weeks after challenge (○). (C) Control 129/Sv/Ev (•) and 129/Sv/PEP IL-4  transgenic mice (○). (D) BALB/c mice treated three times per week for 2 wk with normal sheep IgG (•) or sheep anti–IL-12 IgG (○) starting 2 h after  challenge. (E) BALB/c mice challenged with 107 (•) or 2 × 107 (○) amastigotes. In mice challenged with 2 × 108 amastigotes, week 8 LDU were 761 ±  61 (n = 4 mice). Results in A–E indicate mean values (SE <16% in each case) from the single experiment performed with 4–5 mice per group. Note  different vertical axis scale in B and C.
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Figure 1: Preliminary experiments to determine the course of visceral infection in five different populations of mice. (A) BALB/c mice not treated (•) or injected once with IL-4/anti–IL-4 complex one day before (day −1) L. donovani challenge (○). (B) BALB/c mice not treated (•) or injected with IL-4/anti–IL-4 starting on day −1 and twice per week for the first four weeks after challenge (○). (C) Control 129/Sv/Ev (•) and 129/Sv/PEP IL-4 transgenic mice (○). (D) BALB/c mice treated three times per week for 2 wk with normal sheep IgG (•) or sheep anti–IL-12 IgG (○) starting 2 h after challenge. (E) BALB/c mice challenged with 107 (•) or 2 × 107 (○) amastigotes. In mice challenged with 2 × 108 amastigotes, week 8 LDU were 761 ± 61 (n = 4 mice). Results in A–E indicate mean values (SE <16% in each case) from the single experiment performed with 4–5 mice per group. Note different vertical axis scale in B and C.

Mentions: Initial efforts were directed at identifying a suitable model of exacerbated visceral infection that was associated with induction of a Th2-type response. Fig. 1 summarizes preliminary experiments in which several different approaches were tested.


Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.

Murray HW, Hariprashad J, Coffman RL - J. Exp. Med. (1997)

Preliminary experiments to determine the course of visceral infection in five different populations of mice. (A) BALB/c mice not treated (•)  or injected once with IL-4/anti–IL-4 complex one day before (day −1) L. donovani challenge (○). (B) BALB/c mice not treated (•) or injected with  IL-4/anti–IL-4 starting on day −1 and twice per week for the first four weeks after challenge (○). (C) Control 129/Sv/Ev (•) and 129/Sv/PEP IL-4  transgenic mice (○). (D) BALB/c mice treated three times per week for 2 wk with normal sheep IgG (•) or sheep anti–IL-12 IgG (○) starting 2 h after  challenge. (E) BALB/c mice challenged with 107 (•) or 2 × 107 (○) amastigotes. In mice challenged with 2 × 108 amastigotes, week 8 LDU were 761 ±  61 (n = 4 mice). Results in A–E indicate mean values (SE <16% in each case) from the single experiment performed with 4–5 mice per group. Note  different vertical axis scale in B and C.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196164&req=5

Figure 1: Preliminary experiments to determine the course of visceral infection in five different populations of mice. (A) BALB/c mice not treated (•) or injected once with IL-4/anti–IL-4 complex one day before (day −1) L. donovani challenge (○). (B) BALB/c mice not treated (•) or injected with IL-4/anti–IL-4 starting on day −1 and twice per week for the first four weeks after challenge (○). (C) Control 129/Sv/Ev (•) and 129/Sv/PEP IL-4 transgenic mice (○). (D) BALB/c mice treated three times per week for 2 wk with normal sheep IgG (•) or sheep anti–IL-12 IgG (○) starting 2 h after challenge. (E) BALB/c mice challenged with 107 (•) or 2 × 107 (○) amastigotes. In mice challenged with 2 × 108 amastigotes, week 8 LDU were 761 ± 61 (n = 4 mice). Results in A–E indicate mean values (SE <16% in each case) from the single experiment performed with 4–5 mice per group. Note different vertical axis scale in B and C.
Mentions: Initial efforts were directed at identifying a suitable model of exacerbated visceral infection that was associated with induction of a Th2-type response. Fig. 1 summarizes preliminary experiments in which several different approaches were tested.

Bottom Line: 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.Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Cornell University Medical College, New York 10021, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus