Combined Interleukin‐12 and Topical Chemotherapy for Established Leishmaniasis Drastically Reduces Tissue Parasitism and Relapses in Susceptible Mice

Abstract

The efficacy of the association of paromomycin sulfate (PA) with recombinant (r) interleukin (IL)-12 was investigated by topical treatment of BALB/c mice infected with Leishmania major that displayed fully developed cutaneous lesions. Although healing was observed in PA-treated groups, lesions recurred in 100% of these animals 70 days after treatment. In contrast, lesions were absent in a high proportion of PA- and rIL-12-treated mice 120 days after treatment. The PA/rIL-12-treated mice had a switch in cytokine response, from high IL-4 and low interferon (IFN)-gamma levels to low IL-4 and high IFN-gamma levels, and reductions in parasite load, dissemination of parasites, and inflammation. Thus, the association of rIL-12 to topical chemotherapy for leishmaniasis may be an important strategy for increasing cure rates and decreasing the incidence of relapse.

Combination Therapy with Paromomycin-Associated Stearylamine-Bearing Liposomes Cures Experimental Visceral Leishmaniasis through Th1-Biased Immunomodulation

“…Similar therapeutic and prophylactic effects were observed with a combination regimen of PM and recombinant IL-12 against C. parvum, probably through activation of IFN-␥ production (19). This combination regimen was also found to be effective against established L. major infection, further inhibiting disease relapse in susceptible mice (16). The present study showed that PC-SA at a molar ratio of 7:2 significantly enhanced the levels of IL-12, IFN-␥, and NO and reduced significantly not only IL-10 but also TGF-␤, corroborating our previous observations (7).…”

Immune Responses Induced by theLeishmania(Leishmania)donovaniA2 Antigen, but Not by the LACK Antigen, Are Protective against ExperimentalLeishmania(Leishmania)amazonensisInfection

“…The A2 proteins are composed predominantly of multiple copies of a 10-amino-acid repeat, and depending on the number of repeats within each protein, the protein size may range from 45 to 100 kDa (38). Karyotype analysis, performed with a panel of samples representative of different Leishmania species, revealed that A2 genes are conserved in species of the L. donovani complex and the L. mexicana complex (10). Recently, it was demonstrated that immunization with A2, as protein or DNA, protects against L. donovani infection (13,14).…”

“…Splenocyte cultures and cytokine assays were performed as described previously (10). Briefly, single-cell preparations from spleen tissue were plated in duplicate in 24-well plates (Nunc) at 2 ϫ 10 6 cells/ml.…”

Concepts of immunostimulation to increase antiparasitic drug action

“…In contrast, lesions were absent in a high proportion of PAand rIL-12-treated mice, even 120 days after treatment and this was associated with reductions in parasite load, dissemination of parasites and inflammation. The combination of PA and rIL-12 induced a switch from high IL-4 and low IFN-c levels to low IL-4 and high IFN-c levels (Fernandes et al 2001).…”