Leishmania major: Production of recombinant gp63, its antigenicity and immunogenicity in mice

Handman, Emanuela; Button, Linda L.; McMaster, Robert

doi:10.1016/0014-4894(90)90127-x

Cited by 61 publications

(29 citation statements)

References 24 publications

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“…Although the immunology of VL has received considerable attention (3)(4)(5)(6)(7), efforts toward vaccination against leishmaniasis have focused almost exclusively on localized cutaneous disease (8 -11). Although a number of candidate Ags, including gp63 (12)(13)(14)(15) and LACK (16 -19), have shown promise in mice, strong Th1-inducing adjuvants have usually been required, including IL-12 (18), CpG-containing DNA constructs (13,16,20), or delivery in recombinant bacteria (14,15). Progress with these Ags in primate vaccination studies has been limited, requiring the use of both alum and IL-12 to demonstrate immunogenicity and partial protection (21).…”

Section: H Uman Infection With Leishmania Donovani and Leishmaniamentioning

confidence: 99%

Immunization with a Recombinant Stage-Regulated Surface Protein fromLeishmania donovaniInduces Protection Against Visceral Leishmaniasis

Stäger

Smith

Kaye

2000

The Journal of Immunology

174

134

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Vaccination against visceral leishmaniasis has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine against visceral leishmaniasis is pressing. In this study, we demonstrate for the first time that a recombinant stage-specific hydrophilic surface protein of Leishmania donovani, recombinant hydrophilic acylated surface protein B1 (HASPB1), is able to confer protection against experimental challenge. Protection induced by rHASPB1 does not require adjuvant and, unlike soluble Leishmania Ag + IL-12, extends to the control of parasite burden in the spleen, an organ in which parasites usually persist and are refractory to a broad range of immunological and chemotherapeutic interventions. Both immunohistochemistry (for IL-12p40) and enzyme-linked immunospot assay (for IL-12p70) indicate that immunization with rHASPB1 results in IL-12 production by dendritic cells, although an analysis of Ab isotype responses to rHASPB1 suggests that this response is not sufficient in magnitude to induce a polarized Th1 response. Although both vaccinated and control-infected mice have equivalent frequencies of rHASPB1-specific CD4+ T cells producing IFN-γ, vaccine-induced protection correlates with the presence of rHASPB1-specific, IFN-γ-producing CD8+ T cells. Thus, we have identified a novel vaccine candidate Ag for visceral leishmaniasis, which appears to operate via a mechanism similar to that previously associated with DNA vaccination.

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Section: H Uman Infection With Leishmania Donovani and Leishmaniamentioning

confidence: 99%

Immunization with a Recombinant Stage-Regulated Surface Protein fromLeishmania donovaniInduces Protection Against Visceral Leishmaniasis

Stäger

Smith

Kaye

2000

The Journal of Immunology

174

134

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“…Therefore, it is imperative to identify parasite proteins that are recognized by T cells during human leishmanial infections. A number of Leishmania Ags have been cloned and characterized with respect to the immune responses that they elicit during experimental murine infections (12)(13)(14)(15)(16)(17). However, there is a paucity of information regarding the Ag specificity of T cells from humans that acquired persistent immunity after leishmanial infections.…”

Section: Identification and Characterization Of T Cell-stimulating Anmentioning

confidence: 99%

Identification and Characterization of T Cell-Stimulating Antigens from Leishmania by CD4 T Cell Expression Cloning

Probst

Stromberg

Ghalib

et al. 2001

The Journal of Immunology

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Persistent immunity against Leishmania infections in humans is mediated predominantly by CD4+ T cells of the Th1 phenotype. Herein we report the expression cloning of eight Leishmania Ags using parasite-specific T cell lines derived from an immune donor. The Ags identified by this technique include the flagellar proteins α- and β-tubulin, histone H2b, ribosomal protein S4, malate dehydrogenase, and elongation factor 2, as well as two novel parasite proteins. None of these proteins have been previously reported as T cell-stimulating Ags from Leishmania. β-tubulin-specific T cell clones generated against Leishmania major amastigotes responded to Leishmania-infected macrophages and dendritic cells. IFN-γ enzyme-linked immunospot analysis demonstrated the presence of T cells specific for several of these Ags in PBMC from self-healing cutaneous leishmaniasis patients infected with either Leishmania tropica or L. major. The responses elicited by Leishmania histone H2b were particularly striking in terms of frequency of histone-specific T cells in PBMC (1 T cell of 6000 PBMC) as well as the percentage of responding donors (86%, 6 of 7). Ags identified by T cells from immune donors might constitute potential vaccine candidates for leishmaniasis.

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“…gp63 has been shown either to induce protection (33,44) or to not induce protection (10) in mice, and adjuvant has been shown to augment protection (15,44) or to reverse protection (33,35). In addition, when gp63 is transfected into bacterial delivery systems, this can lead to protection (5,51).…”

Section: Discussionmentioning

confidence: 99%

“…As a source of antigen-presenting cells (APCs), 10 6 irradiated (1,500 rads) syngeneic C3H spleen cells (or congenic cells [see Fig. 5]) were seeded into the wells of 96-well flat-bottom microtiter plates (Costar 3997), and antigens (as described below) were added.…”

mentioning

confidence: 99%

Characterization of an I-E-Restricted, gp63-Specific, CD4-T-Cell Clone fromLeishmania major-Resistant C3H Mice That Secretes Type 2 Cytokines and Exacerbates Infection withL. major

et al. 2004

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A T-cell clone (designated KLmB-3) was derived from resistant C3H mice 2 weeks after infection with Leishmania major. KLmB-3 was a CD4-T-cell clone that utilized the V␤8.1 T-cell receptor. When adoptively transferred to naive C3H mice, KLmB-3 unexpectedly exacerbated infection with L. major (it increased the cutaneous lesion size and the parasite burden within the lesion). The ability of KLmB-3 to exacerbate disease correlated with its ability to produce the type 2-associated cytokines interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor beta. Interestingly, KLmB-3 was specific for an epitope in the amino-terminal end of the L. major surface gp63 zinc metalloproteinase (leishmanolysin) that has been shown to be capable of inducing a protective immune response. Moreover, KLmB-3 was activated when this epitope was presented in the context of H-2 I-E rather than H-2 I-A.Leishmania major is a protozoan parasite that causes cutaneous leishmaniasis. Our knowledge of the immune response generated against this parasite has been significantly advanced through the use of suitable murine models of infection. Infection of highly susceptible BALB/c mice, which succumb to L. major, represent one end of the spectrum. In contrast, the other end of the spectrum is represented by the majority of mouse strains, including C57BL/6 and C3H, which are relatively resistant and heal their cutaneous lesions (reviewed in references 8, 19, and 34).Of the T-cell lineages, CD4 T cells play an important role in determining the course of cutaneous leishmaniasis. Upon adoptive transfer into BALB/c mice, CD4 parasite-specific T cells can have either a beneficial (12,28,38,39) or a detrimental (12,39,48,49) effect on the outcome of infection. The observation that a single subset of parasite-specific T cells can have varied effects on the outcome of infection led to the current concept that L. major-specific CD4 Th1 T cells which secrete gamma interferon (IFN-␥) are protective in cutaneous leishmaniasis, while parasite-specific Th2 T cells which secrete interleukin-4 (IL-4) are detrimental in the disease (8,19,26,34).In contrast to adoptive transfer studies performed with BALB/c mice, relatively little work has been done with resistant mice, especially with highly resistant mice such as C3H (2). This is surprising since these mice more accurately mimic L. major infections that occur in humans. Thus, the present study was designed to characterize T-cell lines or clones derived from L. major-infected resistant C3H mice. The results presented here describe a CD4-T-cell clone (L. major-specific CD4 T-cell clone B-3 from C3H [k haplotype] mice, designated KLmB-3) that unexpectedly has the Th2 phenotype and thus exacerbates infection with L. major. Interestingly, KLmB-3 is restricted to H-2 I-E, not H-2 I-A. In contrast to Th2-T-cell clones obtained from susceptible BALB/c mice, which are frequently specific for LACK (Leishmania homologue of receptors for activated C kinase [20,27,32]), KLmB-3 is specific for an epitope in the N terminus of...

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Leishmania major: Production of recombinant gp63, its antigenicity and immunogenicity in mice

Cited by 61 publications

References 24 publications

Immunization with a Recombinant Stage-Regulated Surface Protein fromLeishmania donovaniInduces Protection Against Visceral Leishmaniasis

Immunization with a Recombinant Stage-Regulated Surface Protein fromLeishmania donovaniInduces Protection Against Visceral Leishmaniasis

Identification and Characterization of T Cell-Stimulating Antigens from Leishmania by CD4 T Cell Expression Cloning

Characterization of an I-E-Restricted, gp63-Specific, CD4-T-Cell Clone fromLeishmania major-Resistant C3H Mice That Secretes Type 2 Cytokines and Exacerbates Infection withL. major

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