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. 2003 Aug;47(8):2513-7.
doi: 10.1128/AAC.47.8.2513-2517.2003.

Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis

Affiliations

Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis

Henry W Murray et al. Antimicrob Agents Chemother. 2003 Aug.

Abstract

To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-gamma), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-gamma, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-gamma, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-gamma. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.

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Figures

FIG. 1.
FIG. 1.
Serum IFN-γ levels before (day 0) and after L. donovani infection in normal mice (open circles), IL-10 transgenic mice (open squares), and IL-10−/− BALB/c mice (filled circles). The result for each time point indicates the mean ± standard error of the mean from single experiments performed with IL-10−/− mice (n = 4 mice) and transgenic mice (n = 3 to 4) and from two experiments performed with normal mice (n = 6 to 10 mice in total).
FIG. 2.
FIG. 2.
Response to low-dose AMB in IL-10−/− mice. Seven days after infection, normal mice (open bars) and IL-10−/− mice (filled bars) were injected with 1 mg of AMB per kg either on days +7 and +10 or on day+ 7 only, and liver parasite burdens (LDU) were determined on day +14. On day +7, the liver parasite burdens in normal and IL-10−/− mice were 726 ± 92 and 642 ± 45 LDU, respectively. The results are from two experiments (n = 6 to 7 total mice per group) and the indicate percent parasite killing on day +14 compared to that on day +7, calculated as [(mean LDU on day +7 − mean LDU on day +14)/mean LDU on day + 7] ×ばつ 100.

References

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