Tabbara KS, Peters NC, Afrin F et al.Conditions influencing the efficacy of vaccination with live organisms against Leishmania major infection. Infect Immun 73:4714-4722

NIAID, Laboratory of Parasitic Diseases, Bldg. 4, Rm. 126, Center Dr. MSC 0425, Bethesda, MD 20892-0425, USA.
Infection and Immunity (Impact Factor: 3.73). 09/2005; 73(8):4714-22. DOI: 10.1128/IAI.73.8.4714-4722.2005
Source: PubMed


Numerous experimental vaccines have been developed with the goal of generating long-term cell-mediated immunity to the obligate intracellular parasite Leishmania major, yet inoculation with live, wild-type L. major remains the only successful vaccine in humans. We examined the expression of immunity at the site of secondary, low-dose challenge in the ear dermis to determine the kinetics of parasite clearance and the early events associated with the protection conferred by vaccination with live L. major organisms in C57BL/6 mice. Particular attention was given to the route of vaccination. We observed that the rapidity, strength, and durability of the memory response following subcutaneous vaccination with live parasites in the footpad are even greater than previously appreciated. Antigen-specific gamma interferon (IFN-gamma)-producing T cells infiltrate the secondary site by 1.5 weeks, and viable parasites are cleared as early as 2.5 weeks following rechallenge, followed by a rapid drop in IFN-gamma(+) CD4(+) cell numbers in the site. In comparison, intradermal vaccination with live parasites in the ear generates immunity that is delayed in effector cell recruitment to the rechallenge site and in the clearance of parasites from the site. This compromised immunity was associated with a rapid recruitment of interleukin-10 (IL-10)-producing CD4(+) T cells to the rechallenge site. Treatment with anti-IL-10-receptor or anti-CD25 antibody enhanced early parasite clearance in ear-vaccinated mice, indicating that chronic infection in the skin generates a population of regulatory cells capable of influencing the level of resistance to reinfection. A delicate balance of effector and regulatory T cells may be required to optimize the potency and durability of vaccines against Leishmaniasis and other intracellular pathogens.

Download full-text


Available from: Khaled Tabbara,
  • Source
    • "Although the underlying pathomechanisms for the propensity for inflammatory skin diseases to occur at specific predilection sites remain unknown, infection studies suggest intrinsic differences in the skin immune system between different sites. Murine skin infections with Leishmania major, for example, lead to functionally divergent outcomes depending upon the site of challenge (Nabors and Farrell, 1994; Nabors et al., 1995; Baldwin et al., 2003; Tabbara et al., 2005). Although not studied systematically, anecdotal evidence suggests that topographical variations in immune cell densities exist for different body sites (Bos, 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Site-specific differences in skin response to pathogens and in the course of cutaneous inflammatory diseases are well appreciated. The composition and localization of cutaneous leukocytes has been studied extensively using histology and flow cytometry. However, the precise three-dimensional (3D) distribution of distinct immune cell subsets within skin at different body sites requires visualization of intact living skin. We used intravital multiphoton microscopy in transgenic reporter mice in combination with quantitative flow cytometry to generate a 3D immune cell atlas of mouse skin. The 3D location of innate and adaptive immune cells and site-specific differences in the densities of macrophages, T cells and mast cells at four defined sites (ear, back, footpad, tail) is presented. The combinatorial approach further demonstrates an as yet unreported age-dependent expansion of dermal gamma-delta T cells. Localization of dermal immune cells relative to anatomical structures was also determined. While dendritic cells were dispersed homogeneously within the dermis, mast cells preferentially localized to the perivascular space. Finally, we show the functional relevance of site-specific mast cell disparities using the passive cutaneous anaphylaxis model. These approaches are applicable to assessing immune cell variations and potential functional consequences in the setting of infection as well as the pathogenesis of inflammatory skin conditions.Journal of Investigative Dermatology accepted article preview online, 09 July 2014; doi:10.1038/jid.2014.289.
    Journal of Investigative Dermatology 07/2014; DOI:10.1038/jid.2014.289 · 7.22 Impact Factor
  • Source
    • "Scientists are trying to improve the safety of this practice because it is the only way against Leishmania that has proved efficient in humans. The severity of primary lesions is reduced and wound healing is accelerated by including killed parasites in the inoculums and using adjuvants that improve quick immune responses (14, 15). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vaccination with durable immunity is the main goal and fundamental to control leishmaniasis. To stimulate the immune response, small numbers of parasites are necessary to be presented in the mammalian host. Similar to natural course of infection, strategy using live vaccine is more attractive when compared to other approaches. Live vaccines present the whole spectrum of antigens to the host immune system in the absence of any adjuvant. Leishmanization was the first effort for live vaccination and currently used in a few countries against cutaneous leishmaniasis, in spite of their obstacle and safety. Then, live attenuated vaccines developed with similar promotion of creating long-term immunity in the host with lower side effect. Different examples of attenuated strains are generated through long-term in vitro culturing, culturing under drug pressure, temperature sensitivity, and chemical mutagenesis, but none is safe enough and their revision to virulent form is possible. Attenuation through genetic manipulation and disruption of virulence factors or essential enzymes for intracellular survival are among other approaches that are intensively under study. Other designs to develop live vaccines for visceral form of leishmaniasis are utilization of live avirulent microorganisms such as Lactococcus lactis, Salmonella enterica, and Leishmania tarentolae called as vectored vaccine. Apparently, these vaccines are intrinsically safer and can harbor the candidate antigens in their genome through different genetic manipulation and create more potential to control Leishmania parasite as an intracellular pathogen.
    Frontiers in Immunology 03/2014; 5:134. DOI:10.3389/fimmu.2014.00134
  • Source
    • "Enhancement of IL-10, an important regulatory cytokines has been observed after cure of CL [20]. Moreover, presence of IL-10-producing T cells in dermis of chronic L. major-infected mice prevented protection against challenge [30]. However, as assessed by ELISA, we could not find IL-10 production in cured CL and ML patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The main clinical forms of tegumentary leishmaniasis are cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). L.braziliensis infection is characterized by an exaggerated production of IFN-gamma and TNF-alpha, cytokines involved in parasite destruction, but also in the pathology. Maintenance of an antigen-specific immune response may be important for resistance to re-infection and will contribute for vaccine development. In the present work we investigated the immune response in CL and ML cured individuals. Participants in the present study included 20 CL and 20 ML patients, who were evaluated prior to, as well as 2 to 15 years after therapy. IFN-gamma, IL-2 and TNF-alpha production were determined by ELISA in supernatants of mononuclear cells stimulated with soluble L.braziliensis antigen (SLA). The frequency of memory CD4+ T cell populations was determined by FACS. Here we show that the majority of CL and ML patients did not produce in vitro IFN-gamma in response to SLA after cure. In the cured individuals who responded to SLA, effector memory (CD45RA-CCR7-) CD4+ T cells were the ones producing IFN-gamma. Because a large percent of CL and ML cured patients lost SLA-induced IFN-gamma production in peripheral blood, we performed Leishmania skin test (LST). A positive LST was found in 87.5% and 100% of CL and ML cured individuals, respectively, who did not produce IFN-gamma or IL-2 in vitro. This study shows that in spite of losing in vitro antigen-specific response to Leishmania, cured CL and ML subjects retain the ability to respond to SLA in vivo. These findings indicate that LST, rather than IFN-gamma production, may be a better assessment of lasting immunity to leishmaniasis in human studies, and thus a better tool for assessing immunization after vaccine. Furthermore, in cured individuals which maintains Leishmania-specific IFN-gamma production, effector memory CD4+ T cells were the main source of this cytokine.
    BMC Infectious Diseases 11/2013; 13(1):529. DOI:10.1186/1471-2334-13-529 · 2.61 Impact Factor
Show more