Lysosomes of Leishmania Mexicana Sp. as Targets for Potential Therapeutic Agents

Rabinovitch, M.; Ramazeilles, Claude; Alfieri, Silvia C.; Zilberfarb, Vladimir; Shaw, E.; Chagas, Jair Ribeiro; Juliano, Luiz

doi:10.1007/978-3-642-84295-5_60

Cited by 3 publications

(5 citation statements)

References 20 publications

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“…As judged by microscopic examination, amastigotes are degraded in drug-treated macrophages within 24 h; concurrently, the large parasitophorous vacuoles typically induced by L. mexicana disappear (compare [22]). Alternatively and more physiologically, destruction can be induced by toxic nitrogen oxide, which is produced by macrophages activated by lympho- kines, e.g.…”

Section: Infection and Cure Of Bone Marrow-derived Macrophagesmentioning

confidence: 98%

“…Destruction of intracellular parasites can be achieved by treatment with Leu-OMe [22]. As judged by microscopic examination, amastigotes are degraded in drug-treated macrophages within 24 h; concurrently, the large parasitophorous vacuoles typically induced by L. mexicana disappear (compare [22]).…”

Section: Infection and Cure Of Bone Marrow-derived Macrophagesmentioning

confidence: 99%

“…Cells received 100 U/ml recombinant mouse rIFN-y (kindly provided by Dr. G. R. Adolf, Ernst Boehringer-Institut fur Arzneimittelforschung, Vienna, Austria) after 8 to 16 h and again after additional 24 h. At day 5 to 7 post-infection, cells received another dose of 100 U/ml rIFN-y in fresh medium. After 16 hours, medium was removed and infected BMM were cured of amastigotes by treatment with L-leucine methylester (Leu-OMe; 1 mM in DMEM, 3 YO heat-inactivated FCS, 90 min, 25 "C, [22]), washed with pre-warmed DMEM, 3 % heat-inactivated FCS, and cultured in T cell growth medium. Controls with uninfected BMM and cultures with infected macrophages were washed twice before addition of medium.…”

Section: Infection and Cure Of Bone Marrow-derived Macrophagesmentioning

confidence: 99%

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Antigen presentation by Leishmania mexicana‐infected macrophages: Activation of helper T cells specific for amastigote cysteine proteinases requires intracellular killing of the parasites

et al. 1995

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Leishmania mexicana amastigotes proliferate in the phagolysosomes of mammalian macrophages. The parasites abundantly synthesize lysosomal cysteine proteinases, which are encoded by the lmcpb gene family. One of these genes was overexpressed in Escherichia coli, and the purified recombinant protein was used as an antigen to induce and establish a T helper 1 (Th1) cell line. The T cells recognize epitopes shared by the native cysteine proteinases and the recombinant protein. Infected bone marrow-derived macrophages induced to express major histocompatibility complex class II molecules by interferon (IFN)-gamma do not affect parasite viability. These macrophages fail to stimulate the proliferation of the T cell line. In contrast, strong T cell stimulation is observed after the parasites are killed by treatment with L-leucine methylester, or after activation of macrophages by IFN-gamma and tumor necrosis factor-alpha. It is concluded that infected macrophages efficiently present this lysosomal Leishmania antigen once the parasites are inactivated and degraded. This observation may be of considerable relevance for the outcome of Leishmania infections provided that it can be extended to other parasite antigens.

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Section: Infection and Cure Of Bone Marrow-derived Macrophagesmentioning

confidence: 98%

Section: Infection and Cure Of Bone Marrow-derived Macrophagesmentioning

confidence: 99%

Section: Infection and Cure Of Bone Marrow-derived Macrophagesmentioning

confidence: 99%

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Antigen presentation by Leishmania mexicana‐infected macrophages: Activation of helper T cells specific for amastigote cysteine proteinases requires intracellular killing of the parasites

et al. 1995

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“…Cultures were kept at 34°C and received 200 U/ml rlFN-y (kindly provided by Dr. G. R. Adolf, Ernst Boehringer-Institut fur Arzneimittelforschung, Vienna, Austria) at day 2 and 3, and at day 7 together with fresh medium. At day 8, some cultures were cured of the infection by treatment with L-leucine methylester (Leu-OMe; [16,43]). Tcells (6 x lo4) were added at day 8 in a volume of 0.2 ml T cell growth medium.…”

Section: Antigen-presentation Assaysmentioning

confidence: 99%

Antigen presentation by Leishmania mexicana‐infected macrophages: activation of helper T cells by a model parasite antigen secreted into the parasitophorous vacuole or expressed on the amastigote surface

et al. 1996

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Leishmania are protozoan parasites which invade mammalian macrophages and multiply as amastigotes in phagolysosomes (parasitophorous vacuoles). Using L. mexicana and bone marrow-derived macrophages (BMM), the question is addressed whether infected BMM induced to express major histocompatibility complex class II molecules can present defined antigens to specific T helper type 1 cells. As a model antigen, a membrane-bound acid phosphatase (MAP), a minor protein associated with intracellular vesicles in amastigotes, was either overexpressed at the surface of the parasites or overexpressed in a soluble form leading to antigen secretion into the parasitophorous vacuole. Presentation of MAP epitopes by these three types of amastigotes was then compared for macrophages containing live parasites or amastigotes inactivated by drug treatment. It is shown that surface-exposed and secreted MAP can be efficiently presented to T cells by macrophages harboring live amastigotes. Therefore, the parasitophorous vacuole communicates by vesicular membrane traffic with the plasmalemma of the host cell. The intracellular MAP of wild-type cells or the abundant lysosomal cysteine proteinases are not or only inefficiently presented, respectively. After killing of the parasites, abundant proteins such as overexpressed MAP and the cysteine proteinases efficiently stimulate T cells, while wild-type MAP levels are not effective. We conclude that intracellular proteins of intact amastigotes are not available for presentation, while after parasite inactivation, presentation depends on antigen abundance and possibly stability. The cell biological and possible immunological consequences of these results are discussed.

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“…Liposome inclusion of clinically useful drugs has been more effective than free drugs for treatment of experimental leishmaniasis (Black et al, 1977;Alving et al, 1978;New et al, 1978New et al, , 1981, but this method has limitations. Selective destruction of intracellular amastigotes of Leishmania (L) amazonensis by lysosomotropic amino acid esters, which presumably enter macrophages by passive diffusion, has also been described (Rabinovitch et al, 1986;Alfieri et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of antimony complexes of yeast mannan and mannan derivatives and their effect on Leishmania-infected macrophages

Cantos

Barbiéri

Iacomini

et al. 1993

Biochemical Journal

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Antimony(Sb)-yeast mannan complexes were synthesized as a strategy to introduce Sb into macrophages infected with Leishmania amastigotes. The complexes were taken up by endocytosis after specific recognition by alpha-D-mannosyl receptors on the macrophage membrane. About 90% of the intracellular parasites were destroyed by Sb-mannan in vitro, whereas the corresponding Sb concentration used as the pentavalent antimonial drug glucantime destroyed about 60% of the amastigotes. None of the Sb complexes prepared with mannan acid or basic derivatives was as effective as the simple Sb-mannan complex in clearing macrophage infection by Leishmania (L) amazonensis. The leishmanicidal effect of Sb-mannan was also demonstrated in vivo with infected hamsters. The alternative use of Sb-mannan complex in the treatment of human leishmaniasis is envisaged on the basis of parasite-killing efficiency and the use of a low antimony dose.

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Lysosomes of Leishmania Mexicana Sp. as Targets for Potential Therapeutic Agents

Cited by 3 publications

References 20 publications

Antigen presentation by Leishmania mexicana‐infected macrophages: Activation of helper T cells specific for amastigote cysteine proteinases requires intracellular killing of the parasites

Antigen presentation by Leishmania mexicana‐infected macrophages: Activation of helper T cells specific for amastigote cysteine proteinases requires intracellular killing of the parasites

Antigen presentation by Leishmania mexicana‐infected macrophages: activation of helper T cells by a model parasite antigen secreted into the parasitophorous vacuole or expressed on the amastigote surface

Synthesis of antimony complexes of yeast mannan and mannan derivatives and their effect on Leishmania-infected macrophages

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