A dhfr-ts- Leishmania major Knockout Mutant Cross-protects against Leishmania amazonensis

Veras, Pst; Ci, Brodskyn; Balestieri, Fmp; Freitas, Lar de; Ramos, A.M.O.; Queiroz, A. Nogueira; Barral, Aldina; Beverley, S. M.; Barral‐Netto, Manoel

doi:10.1590/s0074-02761999000400011

Cited by 45 publications

(39 citation statements)

References 25 publications

(36 reference statements)

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“…long-term protection, the idea of using live-attenuated organisms as a vaccine against leishmaniasis has been pursued by several laboratories, but has been hampered by limited efficacy (11,22,23). We report here that lpg2 Ϫ parasites, which persist without causing overt cutaneous lesions (17), induce protection against virulent challenge in an experimental model, indicating that these parasites might be used as an attenuated vaccine for leishmaniasis.…”

Section: Discussionmentioning

confidence: 85%

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

The Journal of Immunology

119

115

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Long-term immunity to Leishmania may require the continued presence of parasites, but previous attempts to create attenuated parasites that persist without causing disease have had limited success. Since Leishmania major mutants that lack lipophosphoglycan and other secreted phosphoglycans, termed lpg2−, persist indefinitely in infected mice without inducing any disease, we tested their ability to provide protection to virulent L. major challenge. In response to leishmanial Ag stimulation, cells from lpg2−-infected mice produced minimal levels of IL-4 and IL-10, as well as very low levels of IFN-γ. Nevertheless, when BALB/c mice infected with lpg2− parasites were challenged with virulent L. major they were protected from disease. Thus, these findings report on attenuated parasites that may be used to induce long-term protection against leishmaniasis and indicate that the immunity induced can be maintained in the absence of a strong Th1 response.

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Section: Discussionmentioning

confidence: 85%

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Uzonna

Späth

Beverley

et al. 2004

The Journal of Immunology

119

115

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“…In mouse, L. major parasites lacking the gene encoding the enzyme dihydrofolate reductase-thymidylate synthetase (DHFR-TS) induced protection against infection with either L. major or L. amazonensis (26,27). An attenuated line of L. mexicana was also used successfully to protect against homologous infection (28,29).Taken together, these data strongly supported prophylactic vaccination with attenuated organisms as a useful approach to human vaccine development.…”

Section: Discussionmentioning

confidence: 99%

Vaccinations with live-attenuated <i>Leishmania major</i> promastigotes and challenge infection with <i>L. major</i> in balb/c mice

et al. 2005

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“…Based on our in vitro results, we hypothesized that giving L. amazonensis antigen-pulsed BM-DC plus IL-12 as an immunotherapy to mice chronically infected with L. amazonensis would promote a Th1 response in vivo. Variable degrees of protection to L. amazonensis infection have been achieved in mice by prophylactic administration of antigen (32,40), DNA (9), attenuated L. major promastigotes (16,42), and an L. amazonensis-derived Th1 CD4 ϩ T-cell line (17,34). DC-based vaccines have been used successfully prophylactically in experimental studies of cutaneous leishmaniasis caused by L. major (8,12,44), and protection has been linked to the ability of the DC to produce IL-12 (8).…”

Section: Discussionmentioning

confidence: 99%

CD4⁺Th1 Cells Induced by Dendritic Cell-Based Immunotherapy in Mice Chronically Infected withLeishmania amazonensisDo Not Promote Healing

Vanloubbeeck¹,

Ramer

Jie

et al. 2004

Infect Immun

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The susceptibility of mice to Leishmania amazonensis infection is thought to result from an inability to develop a Th1 response. Our data show that the low levels of gamma interferon (IFN-γ) produced by the draining lymph node (DLN) cells of chronically infected mice could be enhanced in vitro and in vivo with L. amazonensis antigen-pulsed bone marrow-derived dendritic cells (BM-DC) and the Th1-promoting cytokine interleukin-12 (IL-12). Given intralesionally to chronically infected mice, this treatment induced the upregulation of mRNA levels for IFN-γ, the transcription factor T-box expressed in T cells, and IL-12 receptor β2 in CD4+ T cells from the DLN and an increase in parasite-specific immunoglobulin G2a in the serum. However, this Th1 response was not associated with healing, and the antigen-specific enhancement of IFN-γ production remained impaired in the DLN. However, addition of IL-12 to the in vitro recall response was able to recover this defect, suggesting that antigen-presenting cell-derived IL-12 production may be limited in infected mice. This was supported by the fact that L. amazonensis amastigotes limited the production of IL-12p40 from BM-DC in vitro. Altogether, our data indicate that the immune response of mice chronically infected with L. amazonensis can be enhanced towards a Th1 phenotype but that the presence of Th1 CD4+ T cells does not promote healing. This suggests that the phenotype of the CD4+ T cells may not always be indicative of protection to L. amazonensis infection. Furthermore, our data support growing evidence that antigen-presenting cell function, such as IL-12 production, may limit the immune response in L. amazonensis-infected mice

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A dhfr-ts- Leishmania major Knockout Mutant Cross-protects against Leishmania amazonensis

Abstract: E10-5A3 is a dhfr-ts

Cited by 45 publications

References 25 publications

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Vaccinations with live-attenuated <i>Leishmania major</i> promastigotes and challenge infection with <i>L. major</i> in balb/c mice

CD4⁺Th1 Cells Induced by Dendritic Cell-Based Immunotherapy in Mice Chronically Infected withLeishmania amazonensisDo Not Promote Healing

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A dhfr-ts- Leishmania major Knockout Mutant Cross-protects against Leishmania amazonensis

Abstract: E10-5A3 is a dhfr-ts

Cited by 45 publications

References 25 publications

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Vaccination with Phosphoglycan-Deficient Leishmania major Protects Highly Susceptible Mice from Virulent Challenge without Inducing a Strong Th1 Response

Vaccinations with live-attenuated <i>Leishmania major</i> promastigotes and challenge infection with <i>L. major</i> in balb/c mice

CD4+Th1 Cells Induced by Dendritic Cell-Based Immunotherapy in Mice Chronically Infected withLeishmania amazonensisDo Not Promote Healing

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CD4⁺Th1 Cells Induced by Dendritic Cell-Based Immunotherapy in Mice Chronically Infected withLeishmania amazonensisDo Not Promote Healing