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Previously, we reported that intraperitoneal administration of leishmanial antigens (LAg) entrapped in liposomes conferred protection to BALB\/c mice against<jats:italic>L. donovani<\/jats:italic>challenge infection. However, this vaccine failed to protect mice when administered subcutaneously. We therefore evaluated whether formulation of LAg in combination with two commonly used human-compatible adjuvants, alum and saponin, could improve the protective efficacy of subcutaneously administered LAg, to a level comparable to that of the intraperitoneal liposomal vaccination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Vaccine formulations of LAg with alum or saponin failed to reduce parasite burden in the liver, and alum + LAg immunized mice also failed to reduce parasite burden in the spleen. Interestingly, saponin + LAg vaccination actually resulted in an increased<jats:italic>L. donovani<\/jats:italic>parasitic load in the spleen following<jats:italic>L. donovani<\/jats:italic>challenge, suggesting this regimen exacerbates the infection. In contrast, mice immunized intraperitoneally with Lip + LAg demonstrated significant protection in both liver and spleen, as expected. Mechanistically, we found that failure of alum + LAg to protect mice was associated with elevated levels of IL-4, whereas both IL-4 and IL-10 levels were increased in saponin + LAg immunized mice. This outcome served to exacerbate<jats:italic>L. donovani<\/jats:italic>infection in the saponin + LAg group, despite a concurrent increase in proinflammatory IFN-\u03b3 production. On the contrary, protection against<jats:italic>L. donovani<\/jats:italic>challenge in Lip + LAg immunized mice was associated with elevated levels of IFN-\u03b3 in conjunction with low levels of IL-4 and IL-10 production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings indicate that elevated levels of IL-4 may contribute to LAg vaccine failure, whereas combined elevation of IL-4 together with IL-10 exacerbated the disease as observed in saponin + LAg immunized mice. In contrast, a robust IFN-\u03b3 response, in the absence of IL-4 and IL-10 production, was associated with protective immunity following administration of the Lip + LAg vaccine. Together these findings suggest that optimization of antigen\/adjuvant formulations to minimize IL-4 and IL-10 induction may be helpful in the development of high efficacy vaccines targeting<jats:italic>Leishmania<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2180-14-8","type":"journal-article","created":{"date-parts":[[2014,1,15]],"date-time":"2014-01-15T18:33:07Z","timestamp":1389810787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["IL-4 contributes to failure, and colludes with IL-10 to exacerbate Leishmania donovani infection following administration of a subcutaneous leishmanial antigen vaccine"],"prefix":"10.1186","volume":"14","author":[{"given":"Sudipta","family":"Bhowmick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Ravindran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahid","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,1,15]]},"reference":[{"key":"2177_CR1","unstructured":"World Health Organization \u2013 leishmaniasis.http:\/\/www.who.int\/leishmaniasis\/disease_epidemiology\/en\/index.html,"},{"key":"2177_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2012.00144","volume":"3","author":"VS Raman","year":"2012","unstructured":"Raman VS, Duthie MS, Fox CB, Matlashewski G, Reed SG: Adjuvants for Leishmania vaccines: from models to clinical application. 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