Long-term protection of mice against Leishmania major with a synthetic peptide vaccine

Spitzer, Nina J.

doi:10.1016/s0264-410x(98)00363-6

Cited by 64 publications

(33 citation statements)

References 13 publications

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“…The L 1 peptide has been shown to induce protection against Leishmania in different protocols ofvaccination (24,25). Here, vaccination with DCs pulsed with Ll induced effective protection, similar to that observed by DCs pulsed with SPL.…”

Section: Discussionsupporting

confidence: 67%

Dendritic Cells Pulsed with Peptides of GP63 Induce Differential Protection against Experimental Cutaneous Leishmaniasis

Tsagozis

Karagouni

Dotsika

2004

Int J Immunopathol Pharmacol

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The need for a vaccine against Leishmania spp., a major cause of worldwide morbidity and mortality, is urgent. We tested the efficacy of an experimental vaccination in murine models of cutaneous leishmaniasis, using dendritic cells (DCs) pulsed with synthetic or native parasite antigens. DCs pulsed with peptide 154–169aa of gp63 or soluble promastigote lysate (SPL) triggered antigen-specific immune responses and efficiently reduced lesion formation and parasite load of genetically susceptible BALB/c mice infected with Leishmania major. This effect was accompanied by a modulation of the cellular immune response towards a Th1 profile. Vaccination of genetically resistant CBA mice with DCs pulsed with peptide 154–169aa or SPL did not affect the course of the disease, whereas pulsing with the epitope 467–482aa of gp63 resulted in disease exacerbation, accompanied by a switch to a Th2 profile. In view of our continuously growing knowledge about the immunobiology of DCs, these findings suggest that vaccination with DCs pulsed with defined peptides could be a strategy against infectious diseases. Peptide selection is a prerequisite as they can differentially regulate the type of immune response in susceptible or resistant hosts.

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Section: Discussionsupporting

confidence: 67%

Dendritic Cells Pulsed with Peptides of GP63 Induce Differential Protection against Experimental Cutaneous Leishmaniasis

Tsagozis

Karagouni

Dotsika

2004

Int J Immunopathol Pharmacol

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“…The 1980s were marked by a wave of enthusiasm concerning the use of peptide vaccines, in particular those considered to be T-cell epitopes (60,70,118,131). This enthusiasm seems to have waned in recent times, and the focus appears to have moved to the use of recombinant DNA-produced polypeptides and to naked DNA.…”

Section: Synthetic Peptidesmentioning

confidence: 99%

“…There are additional "holes" in the ability to respond to individual peptides due to failure of processing, cleavage, transport or due to deletion of certain T-cell specificities due to self-tolerance (57). Despite these caveats, several Leishmania gp63 peptides have been tested successfully in animal models (61,131). Importantly, host protection was long-lasting, indicating the induction of long-term T-cell memory (131).…”

Section: Synthetic Peptidesmentioning

confidence: 99%

Leishmaniasis: Current Status of Vaccine Development

2001

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Leishmaniae are obligatory intracellular protozoa in mononuclear phagocytes. They cause a spectrum of diseases, ranging in severity from spontaneously healing skin lesions to fatal visceral disease. Worldwide, there are 2 million new cases each year and 1/10 of the world's population is at risk of infection. To date, there are no vaccines against leishmaniasis and control measures rely on chemotherapy to alleviate disease and on vector control to reduce transmission. However, a major vaccine development program aimed initially at cutaneous leishmaniasis is under way. Studies in animal models and humans are evaluating the potential of genetically modified live attenuated vaccines, as well as a variety of recombinant antigens or the DNA encoding them. The program also focuses on new adjuvants, including cytokines, and delivery systems to target the T helper type 1 immune responses required for the elimination of this intracellular organism. The availability, in the near future, of the DNA sequences of the human and Leishmania genomes will extend the vaccine program. New vaccine candidates such as parasite virulence factors will be identified. Host susceptibility genes will be mapped to allow the vaccine to be targeted to the population most in need of protection

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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%

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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Long-term protection of mice against Leishmania major with a synthetic peptide vaccine

Cited by 64 publications

References 13 publications

Dendritic Cells Pulsed with Peptides of GP63 Induce Differential Protection against Experimental Cutaneous Leishmaniasis

Dendritic Cells Pulsed with Peptides of GP63 Induce Differential Protection against Experimental Cutaneous Leishmaniasis

Leishmaniasis: Current Status of Vaccine Development

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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