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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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Effect of anti–IL-4 or anti–IL-10 treatment on visceral infection of HKLPM-primed mice. BALB/c mice were pretreated once per  week for 4 wk with HKLMP and then challenged with L. donovani. The  day before challenge and once per week thereafter for 4 wk, mice received no further treatment (filled bar), injections of control antibody  (hatched bar), or anti-cytokine mAb (open bar). Results are from two experiments, and indicate mean ± SEM LDU values for six to seven mice  per group.
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Figure 3: Effect of anti–IL-4 or anti–IL-10 treatment on visceral infection of HKLPM-primed mice. BALB/c mice were pretreated once per week for 4 wk with HKLMP and then challenged with L. donovani. The day before challenge and once per week thereafter for 4 wk, mice received no further treatment (filled bar), injections of control antibody (hatched bar), or anti-cytokine mAb (open bar). Results are from two experiments, and indicate mean ± SEM LDU values for six to seven mice per group.

Mentions: In normal unmanipulated BALB/c mice, L. donovani infection induces both IL-4 and IL-10 mRNA expression in the liver and serum IgE levels increase as well (26). Nevertheless, we concluded that this Th2 response is not functional and/or is rapidly overshadowed by a Th1 mechanism in normal mice since treatment with anti–IL-4 (26) or anti– IL-10 (unpublished) does not affect the kinetics of visceral infection and resistance is acquired (22, 26). In contrast, as judged by overt increases in serum IgE levels both before and after L. donovani challenge (Table 1), and more importantly, by the effects of injecting anti–IL-4 and anti–IL-10, HKLMP-primed mice showed clear-cut evidence of an active, disease-promoting Th2-associated cytokine response. As shown in Fig. 3, treatment with either anti–IL-4 or anti–IL-10 permitted HKLMP-sensitized mice to exert essentially normal control over intracellular visceral infection at week 4. Thus, whereas both IL-4 and IL-10 were required, neither by itself appeared sufficient to mediate the suppressive, antihost defense effect of the provoked Th2 response. We concluded from these results that IL-4 and IL-10 likely acted in concert in this model.


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)

Effect of anti–IL-4 or anti–IL-10 treatment on visceral infection of HKLPM-primed mice. BALB/c mice were pretreated once per  week for 4 wk with HKLMP and then challenged with L. donovani. The  day before challenge and once per week thereafter for 4 wk, mice received no further treatment (filled bar), injections of control antibody  (hatched bar), or anti-cytokine mAb (open bar). Results are from two experiments, and indicate mean ± SEM LDU values for six to seven mice  per group.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Effect of anti–IL-4 or anti–IL-10 treatment on visceral infection of HKLPM-primed mice. BALB/c mice were pretreated once per week for 4 wk with HKLMP and then challenged with L. donovani. The day before challenge and once per week thereafter for 4 wk, mice received no further treatment (filled bar), injections of control antibody (hatched bar), or anti-cytokine mAb (open bar). Results are from two experiments, and indicate mean ± SEM LDU values for six to seven mice per group.
Mentions: In normal unmanipulated BALB/c mice, L. donovani infection induces both IL-4 and IL-10 mRNA expression in the liver and serum IgE levels increase as well (26). Nevertheless, we concluded that this Th2 response is not functional and/or is rapidly overshadowed by a Th1 mechanism in normal mice since treatment with anti–IL-4 (26) or anti– IL-10 (unpublished) does not affect the kinetics of visceral infection and resistance is acquired (22, 26). In contrast, as judged by overt increases in serum IgE levels both before and after L. donovani challenge (Table 1), and more importantly, by the effects of injecting anti–IL-4 and anti–IL-10, HKLMP-primed mice showed clear-cut evidence of an active, disease-promoting Th2-associated cytokine response. As shown in Fig. 3, treatment with either anti–IL-4 or anti–IL-10 permitted HKLMP-sensitized mice to exert essentially normal control over intracellular visceral infection at week 4. Thus, whereas both IL-4 and IL-10 were required, neither by itself appeared sufficient to mediate the suppressive, antihost defense effect of the provoked Th2 response. We concluded from these results that IL-4 and IL-10 likely acted in concert in this model.

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