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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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Photomicrograph of  liver sections from untreated  control (A) and HKLMP-primed  BALB/c mice (B) 4 wk after L.  donovani infection. (A) shows a  large, well-developed mature  granuloma at an infected focus in  normal mice. The granuloma  contains few amastigotes. In B,  HKLMP-primed mice show  fused, heavily parasitized Kupffer  cells (arrows), but little or no surrounding mononuclear cell infiltrate. ×200.
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Figure 5: Photomicrograph of liver sections from untreated control (A) and HKLMP-primed BALB/c mice (B) 4 wk after L. donovani infection. (A) shows a large, well-developed mature granuloma at an infected focus in normal mice. The granuloma contains few amastigotes. In B, HKLMP-primed mice show fused, heavily parasitized Kupffer cells (arrows), but little or no surrounding mononuclear cell infiltrate. ×200.

Mentions: Since successful resistance to L. donovani in BALB/c mice is expressed in the tissues by granuloma formation (22, 47), we also examined liver sections from HKLMP-pretreated animals. In normal BALB/c mice, granuloma assembly in the liver proceeds in an orderly fashion; each infected focus, consisting initially of single, infected resident macrophages (Kupffer cells), gives rise to a core of fused parasitized Kupffer cells which comes to be surrounded by a mononuclear cell mantle comprised of influxing T cells and monocytes (22, 27, 47). This histologic reaction is detectable by week 2 after challenge and is fully developed by or after week 4 (22, 47). The early tissue reaction to L. donovani at week 2 was similar in HKLMP-treated and control BALB/c animals: (a) no cellular reaction was present at 32 ± 6% versus 40 ± 4% of infected foci, respectively; (b) developing granulomas were present at 56 ± 8% versus 48 ± 7% of sites; and (c) 12 ± 1% versus 12 ± 2% of foci were scored as mature granulomas (two experiments, n = 4 mice). However, after week 2, responses diverged. While normal mice converted the bulk of infected foci to mature granulomas by week 8, HKLMP-primed mice did not, and in these animals the tissue reaction failed to properly progress to yield formed granulomas at the majority of infected sites (Fig. 4). In normal BALB/c mice, single parasitized Kupffer cells with no surrounding mononuclear cell reaction were seldom encountered 4 (3 ± 1%) or 8 wk (1 ± 1%) after infection (two experiments, n = 4 mice). Thus, observing little or no histologic reaction at these latter two time points at 23 ± 4% and 29 ± 5% of parasitized foci in HKLMP-primed mice also demonstrated the extent of inhibition of mononuclear cell recruitment (Fig. 5). Together, these data emphasized the overall failure of granuloma assembly in this Th2 response environment.


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)

Photomicrograph of  liver sections from untreated  control (A) and HKLMP-primed  BALB/c mice (B) 4 wk after L.  donovani infection. (A) shows a  large, well-developed mature  granuloma at an infected focus in  normal mice. The granuloma  contains few amastigotes. In B,  HKLMP-primed mice show  fused, heavily parasitized Kupffer  cells (arrows), but little or no surrounding mononuclear cell infiltrate. ×200.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196164&req=5

Figure 5: Photomicrograph of liver sections from untreated control (A) and HKLMP-primed BALB/c mice (B) 4 wk after L. donovani infection. (A) shows a large, well-developed mature granuloma at an infected focus in normal mice. The granuloma contains few amastigotes. In B, HKLMP-primed mice show fused, heavily parasitized Kupffer cells (arrows), but little or no surrounding mononuclear cell infiltrate. ×200.
Mentions: Since successful resistance to L. donovani in BALB/c mice is expressed in the tissues by granuloma formation (22, 47), we also examined liver sections from HKLMP-pretreated animals. In normal BALB/c mice, granuloma assembly in the liver proceeds in an orderly fashion; each infected focus, consisting initially of single, infected resident macrophages (Kupffer cells), gives rise to a core of fused parasitized Kupffer cells which comes to be surrounded by a mononuclear cell mantle comprised of influxing T cells and monocytes (22, 27, 47). This histologic reaction is detectable by week 2 after challenge and is fully developed by or after week 4 (22, 47). The early tissue reaction to L. donovani at week 2 was similar in HKLMP-treated and control BALB/c animals: (a) no cellular reaction was present at 32 ± 6% versus 40 ± 4% of infected foci, respectively; (b) developing granulomas were present at 56 ± 8% versus 48 ± 7% of sites; and (c) 12 ± 1% versus 12 ± 2% of foci were scored as mature granulomas (two experiments, n = 4 mice). However, after week 2, responses diverged. While normal mice converted the bulk of infected foci to mature granulomas by week 8, HKLMP-primed mice did not, and in these animals the tissue reaction failed to properly progress to yield formed granulomas at the majority of infected sites (Fig. 4). In normal BALB/c mice, single parasitized Kupffer cells with no surrounding mononuclear cell reaction were seldom encountered 4 (3 ± 1%) or 8 wk (1 ± 1%) after infection (two experiments, n = 4 mice). Thus, observing little or no histologic reaction at these latter two time points at 23 ± 4% and 29 ± 5% of parasitized foci in HKLMP-primed mice also demonstrated the extent of inhibition of mononuclear cell recruitment (Fig. 5). Together, these data emphasized the overall failure of granuloma assembly in this Th2 response environment.

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