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Vaccination with DNA encoding the immunodominant LACK parasite antigen confers protective immunity to mice infected with Leishmania major.

Gurunathan S, Sacks DL, Brown DR, Reiner SL, Charest H, Glaichenhaus N, Seder RA - J. Exp. Med. (1997)

Bottom Line: We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein.Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12.Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

View Article: PubMed Central - PubMed

Affiliation: Lymphokine Regulation Unit, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-gamma (IFN-gamma) production. Moreover, both the enhancement of IFN-gamma production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8(+) T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8(+) T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

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LACK DNA vaccination induces a systemic and durable immune response to mice infected with L. major. (A) BALB/c mice (n = 6/ group) were initially immunized with LACK or control DNA (100 μg)  and boosted 2 wk later. 5 wk after the boost, mice were challenged in the  hind footpad with 105 live L. major metacyclic promastigotes. (B) In a separate experiment, BALB/c mice (n = 6/group) were initially immunized  and boosted 2 wk later with LACK or control DNA (100 μg) in the right  hind footpad. 2 wk after the boost, mice were challenged with 105 live L.  major metacyclic promastigotes in the same or the opposite footpad to  which they recieved LACK DNA vaccination.
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Figure 4: LACK DNA vaccination induces a systemic and durable immune response to mice infected with L. major. (A) BALB/c mice (n = 6/ group) were initially immunized with LACK or control DNA (100 μg) and boosted 2 wk later. 5 wk after the boost, mice were challenged in the hind footpad with 105 live L. major metacyclic promastigotes. (B) In a separate experiment, BALB/c mice (n = 6/group) were initially immunized and boosted 2 wk later with LACK or control DNA (100 μg) in the right hind footpad. 2 wk after the boost, mice were challenged with 105 live L. major metacyclic promastigotes in the same or the opposite footpad to which they recieved LACK DNA vaccination.

Mentions: It was of additional interest to determine whether effective immunity induced by LACK DNA vaccination was both systemic and durable over a prolonged period after infection. Moreover, it was important to determine whether the protective response induced by LACK DNA vaccination was maintained when mice were infected beyond 2 wk after the last vaccination. To this end, mice were infected 5 wk after the last vaccination with LACK DNA and measurements of footpad lesions were continued for at least 20 wk after infection. As shown in Fig. 4 A, mice vaccinated with LACK DNA maintained an effective immune response that was sustained for at least 20 wk, even when the infectious challenge was given 5 wk after the last vaccination. The ability of LACK DNA to induce effective immunity at a site distant from the point of vaccination was shown in a separate experiment by infecting mice in the opposite footpad to which they received LACK DNA vaccination. As shown in Fig. 4 B, mice were protected in a similar manner to those mice infected in the same footpad.


Vaccination with DNA encoding the immunodominant LACK parasite antigen confers protective immunity to mice infected with Leishmania major.

Gurunathan S, Sacks DL, Brown DR, Reiner SL, Charest H, Glaichenhaus N, Seder RA - J. Exp. Med. (1997)

LACK DNA vaccination induces a systemic and durable immune response to mice infected with L. major. (A) BALB/c mice (n = 6/ group) were initially immunized with LACK or control DNA (100 μg)  and boosted 2 wk later. 5 wk after the boost, mice were challenged in the  hind footpad with 105 live L. major metacyclic promastigotes. (B) In a separate experiment, BALB/c mice (n = 6/group) were initially immunized  and boosted 2 wk later with LACK or control DNA (100 μg) in the right  hind footpad. 2 wk after the boost, mice were challenged with 105 live L.  major metacyclic promastigotes in the same or the opposite footpad to  which they recieved LACK DNA vaccination.
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Related In: Results  -  Collection

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Figure 4: LACK DNA vaccination induces a systemic and durable immune response to mice infected with L. major. (A) BALB/c mice (n = 6/ group) were initially immunized with LACK or control DNA (100 μg) and boosted 2 wk later. 5 wk after the boost, mice were challenged in the hind footpad with 105 live L. major metacyclic promastigotes. (B) In a separate experiment, BALB/c mice (n = 6/group) were initially immunized and boosted 2 wk later with LACK or control DNA (100 μg) in the right hind footpad. 2 wk after the boost, mice were challenged with 105 live L. major metacyclic promastigotes in the same or the opposite footpad to which they recieved LACK DNA vaccination.
Mentions: It was of additional interest to determine whether effective immunity induced by LACK DNA vaccination was both systemic and durable over a prolonged period after infection. Moreover, it was important to determine whether the protective response induced by LACK DNA vaccination was maintained when mice were infected beyond 2 wk after the last vaccination. To this end, mice were infected 5 wk after the last vaccination with LACK DNA and measurements of footpad lesions were continued for at least 20 wk after infection. As shown in Fig. 4 A, mice vaccinated with LACK DNA maintained an effective immune response that was sustained for at least 20 wk, even when the infectious challenge was given 5 wk after the last vaccination. The ability of LACK DNA to induce effective immunity at a site distant from the point of vaccination was shown in a separate experiment by infecting mice in the opposite footpad to which they received LACK DNA vaccination. As shown in Fig. 4 B, mice were protected in a similar manner to those mice infected in the same footpad.

Bottom Line: We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein.Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12.Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

View Article: PubMed Central - PubMed

Affiliation: Lymphokine Regulation Unit, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-gamma (IFN-gamma) production. Moreover, both the enhancement of IFN-gamma production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8(+) T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8(+) T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

Show MeSH
Related in: MedlinePlus