Protective Immunity and Vaccination Against Cutaneous Leishmaniasis

Okwor, Ifeoma; Mou, Zhirong; Liu, Dong; Uzonna, Jude E.

doi:10.3389/fimmu.2012.00128

Cited by 48 publications

(42 citation statements)

References 180 publications

(187 reference statements)

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“…The best example of this is that persistent Leishmania skin infection protects from new lesions and visceral dissemination. To date, leishmanization remains the most successful vaccination protocol for this disease due to the persistence of the parasite and activated T cells in the healed lesion (13,53). Enhanced protection cannot be explained by exhaustion; therefore, antigen-specific T cells that survive due to continuous exposure can be helpful, as suggested by Zinkernagel and Hengartner (54).…”

Section: Discussionmentioning

confidence: 93%

Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis

Opata

Stephens

2017

Infect Immun

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Exposure to blood-stage malaria infection is often persistent, leading to generation of CD4 effector and effector memory T cells that contribute to protection. We showed previously that chronic exposure to blood-stage Plasmodium chabaudi offers the best protection from parasitemia and pathology in reinfection cases, correlating with an increase in Th1 cells. Although much is known about the features of resting or exhausted memory T cells (Tmem), little is known about the functional capacities of chronically stimulated but protective T cells. To determine the functional capacity of CD4 T cells generated by chronic infection upon reexposure to parasite, we compared their responses to known features of classical Tmem. The numbers of cytokine-producing T cells increased following infection in the polyclonal populations, suggesting an increase in pathogen-specific T cells. Malaria antigen-specific B5 T cell receptor (TCR) transgenic (Tg) T cells from chronic infection proliferated on reinfection and were highly sensitive to TCR stimulation without costimulation, as shown for Tmem in acute stimulations. However, B5 Tmem did not accumulate more than naive B5 T cells in vivo or in vitro and became apoptotic. Failure to accumulate was partly the result of chronic stimulation, since eliminating persistent parasites before reinfection slightly increased the accumulation of B5 Tg T cells upon reinfection. The levels of specific gamma interferon-positive, interleukin-10-positive T cells, which protect animals from pathology, increased after malaria infection. These data demonstrate that although chronic infection generates a protective T cell population with increased TCR sensitivity and cytokine production, they do not reexpand upon reexposure due to increased apoptosis. KEYWORDS T cells, immune memory, malaria, mouse Blood-stage malaria infection, like other chronic infections, generates effector memory T cells (Tem) in mice and humans (1, 2). Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3). This decrease in malarial incidence is associated with an increased number of gamma interferon (IFN-␥)-producing effector/effector memory CD4 T cells upon parasite exposure (1, 2). However, the levels of malaria-responsive T cells and malaria antigen-specific antibody titers decay over time (4-6), as does clinical immunity. These data support the conclusion that there are disease-protective memory B and T cells in individuals repeatedly infected with malaria that decay in the absence of exposure. However, the effector mechanisms by which these immune cells contribute to protection from repeated parasitemia and malaria disease are poorly understood.

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Section: Discussionmentioning

confidence: 93%

Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis

Opata

Stephens

2017

Infect Immun

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“…Uptake of promastigotes by phagocytic cells can provide a suitable environment for transformation of promastigotes into the amastigote form that is most well adapted to the intracellular environment of the ultimate host cell, the macrophage. Depending on the species of Leishmania and the host’s response, disease can present in various forms from isolated cutaneous lesions to disseminated visceral pathology [2-5]. Experimental subcutaneous injection of Leishmania into mice can cause disease that mimics many aspects of a natural infection.…”

Section: Introductionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin Slows the Progression of Experimental Cutaneous Leishmaniasis in Susceptible BALB/c and SCID Mice

et al. 2013

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In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg), TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID) mice were used. In mice infected with a moderate number of L. major (10,000), TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg). A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity.

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“…There have been vaccination attempts against Leishmania infection targeting TAT-antigen Tg from L. major, pDCs pulsed with L. major, and many others, but these are yet to be put into effect in the field [77][78][79][80][81][82]. A more recent study used an engineered L. major antigen conjugated to anti-DEC-205 monoclonal antibody in order to induce targeted anti-Leishmania effects, and this displayed promising results in the mouse model [83].…”

Section: Implications For Vaccine Strategiesmentioning

confidence: 99%