Type 1 Immunity Provides Optimal Protection against Both Mucosal and Systemic<i>Trypanosoma cruzi</i>Challenges

Hoft, Daniel F.; Eickhoff, Christopher S.

doi:10.1128/iai.70.12.6715-6725.2002

Cited by 55 publications

(60 citation statements)

References 29 publications

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“…In addition to secreting IFN-␥, spleen cells from mice immunized with plasmids containing the clone 9 gene also produced NO, a potent inhibitor of T. cruzi development in vivo (22,24,31,44). Our results are compatible with those of recent studies showing that a strong Th1, but not Th2, immune response can provide a high degree of systemic immunity against experimental T. cruzi infection in BALB/c mice (11,12,37). However, the precise role of these IFN-␥-secreting CD4 ϩ T cells in protective immunity remains to be determined.…”

Section: Discussionsupporting

confidence: 82%

“…However, the precise role of these IFN-␥-secreting CD4 ϩ T cells in protective immunity remains to be determined. Until now, there has been no clear evidence that specific CD4 ϩ Th1 cells alone can provide protective immunity against T. cruzi infection (11,12,37). These cells most likely have to interact with other T-and B-cell subsets in order to provide optimal protection against systemic infection.…”

Section: Discussionmentioning

confidence: 99%

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Immunization with cDNA Expressed by Amastigotes ofTrypanosoma cruziElicits Protective Immune Response against Experimental Infection

et al. 2003

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Immunization of mice with plasmids containing Trypanosoma cruzi genes induced specific antibodies, CD4 ؉ Th1 and CD8؉ Tc1 cells, and protective immunity against infection. In most cases, plasmids used for DNA vaccination contained genes encoding antigens expressed by trypomastigotes, the nonreplicative forms of the parasite. In this study, we explored the possibility of using genes expressed by amastigotes, the form of the parasite which replicates inside host cells, for experimental DNA vaccination. For that purpose, we selected a gene related to the amastigote surface protein 2 (ASP-2), an antigen recognized by antibodies and T cells from infected mice and humans, for our study. Using primers specific for the asp-2 gene, four distinct groups of genes were amplified from cDNA from amastigotes of the Y strain of T. cruzi. At the nucleotide level, they shared 82.3 to 89.9% identity with the previously described asp-2 gene. A gene named clone 9 presented the highest degree of identity with the asp-2 gene and was selected for immunological studies. Polyclonal antisera raised against the C terminus of the recombinant protein expressed by the clone 9 gene reacted with an antigen of approximately 83 kDa expressed in amastigotes of T. cruzi. Immunization of BALB/c mice with eukaryotic expression plasmids containing the clone 9 gene elicited specific antibodies and CD4 ؉ T-cell-dependent gamma interferon secretion. Upon challenge with trypomastigotes, mice immunized with plasmids harboring the clone 9 gene displayed reduced parasitemia and survived lethal infection. We concluded that amastigote cDNA is an interesting source of antigens that can be used for immunological studies, as well as for vaccine development.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Immunization with cDNA Expressed by Amastigotes ofTrypanosoma cruziElicits Protective Immune Response against Experimental Infection

et al. 2003

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“…IL-4 plus anti-IFN-␥ induced type 2 polarized responses that failed to protect against systemic T. cruzi challenges (15). More recently, we extended these observations showing that despite the prediction that an ideal vaccine should induce optimal mucosal type 2 immunity protective against initial invasion in the relevant mucosal lymphoid tissue, type 1 polarized responses induced by intranasal vaccination were optimally pro-tective against both mucosal and systemic T. cruzi challenges (13).…”

mentioning

confidence: 48%

Type 1 Immunity Provides Both Optimal Mucosal and Systemic Protection against a Mucosally Invasive, Intracellular Pathogen

Hoft

Eickhoff

2005

Infect Immun

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It has been hypothesized that optimal vaccine immunity against mucosally invasive, intracellular pathogens may require the induction of different types of immune responses in mucosal and systemic lymphoid tissues. Mucosal type 2/3 responses (producing interleukin-4 [IL-4], IL-6 and/or transforming growth factor ␤) could be necessary for optimal induction of protective secretory immunoglobulin A responses. On the other hand, systemic type 1 responses (including gamma interferon [IFN-␥], tumor necrosis factor alpha, and optimal cytotoxic T-cell responses) are likely to be critical for protection against the disseminated intracellular replication that occurs after mucosal invasion. Despite these predictions, we recently found that vaccines inducing highly polarized type 1 immunity in both mucosal and systemic tissues provided optimal mucosal and systemic protection against the protozoan pathogen Trypanosoma cruzi. To further address this important question in a second model system, we now have studied the capacity of knockout mice to develop protective immune memory. T. cruzi infection followed by nifurtimox treatment rescue was used to immunize CD4, CD8, ␤2-microglobulin, inducible nitric oxide synthase (iNOS), IL-12, IFN-␥, and IL-4 knockout mice. Despite the previously demonstrated importance of CD4 ؉ T cells, CD8 ؉ T cells, and nitric oxide for T. cruzi immunity, CD4, CD8, and iNOS knockout mice developed mucosal and systemic protective immunity. However, IL-12, IFN-␥, and ␤2-microglobulin-deficient mice failed to develop mucosal or systemic protection. In contrast, IL-4 knockout mice developed maximal levels of both mucosal and systemic immune protection. These results strongly confirm our earlier conclusion from studies with polarizing vaccination protocols that type 1 immunity provides optimal mucosal and systemic protection against a mucosally invasive, intracellular pathogen.

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“…However, more sensitive parasite detection techniques have confirmed that parasites persist in tissues and correlated this persistence with tissue damage (31,32). Furthermore, it is well accepted that a T helper 1 (Th1) type of immune response is required for clearing the parasite from infected mice (18,28,33,38,42,49), while such a response has also been associated with the intensity of the pathology during the chronic phase in humans (1,16). All this controversy has interfered substantially with the development of immunotherapy and preventive vaccines as there is no clear agreement concerning whether the immune response should be stimulated (to eliminate the parasite) or inhibited (to avoid autoimmunity).…”

mentioning

confidence: 99%

Immunotherapy ofTrypanosoma cruziInfection with DNA Vaccines in Mice

et al. 2004

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The mechanisms involved in the pathology of chronic chagasic cardiomyopathy are still debated, and the controversy has interfered with the development of new treatments and vaccines. Because of the potential of DNA vaccines for immunotherapy of chronic and infectious diseases, we tested if DNA vaccines could control an ongoing Trypanosoma cruzi infection. BALB/c mice were infected with a lethal dose (5 ؋ 10 4 parasites) as a model of acute infection, and then they were treated with two injections of 100 g of plasmid DNA 1 week apart, beginning on day 5 postinfection. Control mice had high levels of parasitemia and mortality and severe cardiac inflammation, while mice treated with plasmid DNA encoding trypomastigote surface antigen 1 or Tc24 had reduced parasitemia and mild cardiac inflammation and >70% survived the infection. The efficacy of the immunotherapy also was significant when it was delayed until days 10 and 15 after infection. Parasitological analysis of cardiac tissue of surviving mice indicated that most mice still contained detectable parasite kinetoplast DNA but fewer mice contained live parasites, suggesting that there was efficient but not complete parasite elimination. DNA vaccine immunotherapy was also evaluated in CD1 mice infected with a low dose (5 ؋ 10 2 parasites) as a model of chronic infection. Immunotherapy was initiated on day 70 postinfection and resulted in improved survival and reduced cardiac tissue inflammation. These results suggest that DNA vaccines have strong potential for the immunotherapy of T. cruzi infection and may provide new alternatives for the control of Chagas' disease.

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Type 1 Immunity Provides Optimal Protection against Both Mucosal and SystemicTrypanosoma cruziChallenges

Cited by 55 publications

References 29 publications

Immunization with cDNA Expressed by Amastigotes ofTrypanosoma cruziElicits Protective Immune Response against Experimental Infection

Immunization with cDNA Expressed by Amastigotes ofTrypanosoma cruziElicits Protective Immune Response against Experimental Infection

Type 1 Immunity Provides Both Optimal Mucosal and Systemic Protection against a Mucosally Invasive, Intracellular Pathogen

Immunotherapy ofTrypanosoma cruziInfection with DNA Vaccines in Mice

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