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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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Course of visceral infection in HKLMP-primed BALB/c  mice. Mice were not pretreated (•) or were injected with HKLMP (○)  once per week for 4 wk before being challenged with L. donovani 7 d  later. Results are from four to five experiments, and indicate mean ±  SEM values for 12–20 mice at each time point.
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Figure 2: Course of visceral infection in HKLMP-primed BALB/c mice. Mice were not pretreated (•) or were injected with HKLMP (○) once per week for 4 wk before being challenged with L. donovani 7 d later. Results are from four to five experiments, and indicate mean ± SEM values for 12–20 mice at each time point.

Mentions: Finally, we tested whether BALB/c mice could be induced by presensitization with four once-per-week injections of HKLMP to cross-react to L. donovani with a Th2-associated response. This technique provokes a disease-exacerbating effect upon subsequent infection with live L. major (35). In a preliminary experiment, mice pretreated with four once-per-week injections of saline alone controlled and eradicated L. donovani; 4 wk after infection, mean (± SEM) liver parasite burdens were 1,144 ± 86 versus 947 ± 61 in uninjected controls, and at week 8, were 241 ± 26 versus 260 ± 31, respectively (n = 4 mice per group at each time point). In contrast, mice pretreated in a similar fashion with HKLMP failed to express acquired resistance 2 wk after L. donovani challenge, and liver burdens at week 4 were 3.2-fold higher than in control mice (Fig. 2). Visceral infection in HKLMPtreated mice then plateaued, and liver parasite burdens remained high at week 8 (8.7-fold greater than in untreated controls).


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)

Course of visceral infection in HKLMP-primed BALB/c  mice. Mice were not pretreated (•) or were injected with HKLMP (○)  once per week for 4 wk before being challenged with L. donovani 7 d  later. Results are from four to five experiments, and indicate mean ±  SEM values for 12–20 mice at each time point.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Course of visceral infection in HKLMP-primed BALB/c mice. Mice were not pretreated (•) or were injected with HKLMP (○) once per week for 4 wk before being challenged with L. donovani 7 d later. Results are from four to five experiments, and indicate mean ± SEM values for 12–20 mice at each time point.
Mentions: Finally, we tested whether BALB/c mice could be induced by presensitization with four once-per-week injections of HKLMP to cross-react to L. donovani with a Th2-associated response. This technique provokes a disease-exacerbating effect upon subsequent infection with live L. major (35). In a preliminary experiment, mice pretreated with four once-per-week injections of saline alone controlled and eradicated L. donovani; 4 wk after infection, mean (± SEM) liver parasite burdens were 1,144 ± 86 versus 947 ± 61 in uninjected controls, and at week 8, were 241 ± 26 versus 260 ± 31, respectively (n = 4 mice per group at each time point). In contrast, mice pretreated in a similar fashion with HKLMP failed to express acquired resistance 2 wk after L. donovani challenge, and liver burdens at week 4 were 3.2-fold higher than in control mice (Fig. 2). Visceral infection in HKLMPtreated mice then plateaued, and liver parasite burdens remained high at week 8 (8.7-fold greater than in untreated controls).

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