| | | Document Type | : | Latin Dissertation | | Language of Document | : | English | | Record Number | : | 53515 | | Doc. No | : | TL23469 | | Call number | : | MR49048 | | Main Entry | : | Ifeoma Benedette Okwor | | Title & Author | : | Maintenance and loss of immunologic memory in cutaneous leishmaniases: Implications for vaccine design and vaccination strategiesIfeoma Benedette Okwor | | College | : | University of Manitoba (Canada) | | Date | : | 2008 | | Degree | : | M.Sc. | | student score | : | 2008 | | Page No | : | 177 | | Abstract | : | Leishmaniases currently affects 12 million people worldwide with 360 million more at risk of getting infected. The incidence of leishmaniases is on the increase among travelers and military personnel serving in endemic regions like Afghanistan and Iraq. There is no effective vaccine against leishmaniasis. Although treatment is available, drugs are very expensive, toxic (cause over 20% morbidity in treated patients) and with increasing cases of drug resistant Leishmania strains, there is a great need for the development of an effective anti-Leishmania vaccine. Leishmanization, which is the injection of live virulent parasites into hidden parts of the body, confers lifelong protection. However, vaccination with killed parasites offers only a short term protection. It is believed that protection induced by live parasites is dependent on persistence of few parasites at the infection site leading to constant restimulation of Leishmania -specific effector cells and the production IFN-γ and very low IL-4 & IL-10. In this project, we sought to characterize and compare the immune response to live and killed Leishmania major and determine the factors that regulate the induction, maintenance and loss of Leishmania -specific memory cells. Naive mice were injected with live or killed L. major parasites. Three days later, mice were sacrificed and the draining lymphnodes (dLNs) were collected. There was no difference in the number of cells that emigrated into the dLN and also in the ability of these cells to proliferate both in vivo and in vitro. In spite of this, the early cytokine responses were different. Cells from mice vaccinated with killed parasites produced more antigen-specific IL-4 and less IFN-γ than those from mice vaccinated with live parasites. Interestingly, vaccination with killed parasites together with CpG ODN changed the early IL-4 response to killed parasites to a predominant IFN-γ response, resulting in better protection following secondary high dose virulent L. major challenge. Overall, these results suggest that the nature of primary immunity induced by killed and live parasites are qualitatively and quantitatively different and that these differences may account for the differential protection seen in mice following vaccination with live and killed parasites. It is commonly believed that persistent live parasites are obligatory for maintenance of anti-Leishmania immunity is synonymous to persistent parasites. We evaluated this using different vaccination protocols. Groups of naive mice were immunized with either a single injection of killed parasites or a single injection of killed parasites and additional weekly injections of killed parasites for five weeks or a single injection of killed parasites and weekly injection of recombinant interleukin (rIL-12) for another five weeks, or a single injection of live parasite or PBS. At thirteen weeks after the last immunization, all mice were challenged with virulent L. major parasites. We found that mice immunized with live parasites and those that received weekly immunizations with killed parasites were both protected against virulent L. major challenge while those that received a single injection of killed parasites or repeated injection of rIL-12 were not. These results suggest that anti-Leishmania immunity may not require the presence of live replicating parasites. To investigate the effects of killed parasites on immunity, we injected healed mice killed or live L. major and determined delayed type hypersensitivity (DTH, commonly used as a measure of resistance), cellular infiltration into the dLNs, proliferation and cytokine production by these cells. Some mice were also challenged with highly virulent L. major and secondary protection was determined after 3 weeks. We found that although injecting healed mice with killed and live parasites induced similar inflammatory responses (DTH and cellular infiltration), the nature of the immune (cytokine) response was completely different: Identical to the primary immune response, killed parasites were severely impaired in their ability to recall protective IFN-γ response. Surprisingly, killed parasites induced rapid expansion of IL-10-producing CD4+CD25+Foxp3+ regulatory T cells in lymph nodes draining the infection site. These cells block memory cell activities leading to loss of infection-induced resistance. In conclusion, we have shown that there are qualitative and quantitative differences in the both primary and secondary immune response to live and killed parasites. Furthermore, contrary to common believe, it is possible to induce protection in naïve mice in the absence of live replicating parasites and anti- Leishmania immunity can be lost even in the presence of live parasites. These findings will aid in effective vaccine design and vaccination strategy against cutaneous leishmaniasis. | | Subject | : | Health and environmental sciences; Immunology; 0982:Immunology | | Added Entry | : | University of Manitoba (Canada) |
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