Role of T reg in live vaccination against leishmaniasis

Cornell University Ithaca, Ithaca NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Leishmania major (Lm) is the causative agent of zoonotic cutaneous leishmaniasis (ZCL), the most widely distributed form of ZCL in the Old World. The inoculation of live, non-attenuated Lm to produce a lesion that heals (leishmanization) is to date the only vaccine against leishmaniasis proven effective in humans. We have developed a live vaccine containing live Lm and immonostimulatory oligodeoxynucleotides (CpG ODNs) that ameliorates or abolish lesion due to vaccination and confers long term protection in the murine model. Our goal is to determine the role of regulatory T cells (Treg) in live vaccination against Lm. The specific hypothesis is that the absence of lesions due to live vaccination in the presence of CpG ODNs is caused by a downreagulation of Treg fuction caused by activation of dendritic cells (DCs) that leads to an enhanced immune response. We based this hypothesis on the observations that 1) CpG ODNs are known to activate DC function 2) Treg control the intensity of immune response by suppressing effector function and 3) DCs release IL-6 after CPG ODNs stimulation that partially suppress Treg function. Addition of CpG ODNs to live vaccination will stimulate DCs and therefore supersede Treg function, leading to an 1) enhanced effector immune response, 2) increased parasite killing and, thus, 3) absence of lesion due to vaccination. To prove that hypothesis, we present the following specific aims: 1. Define the relationship of CpG ODNs-activated APC and Treg in vitro. We will perform in vitro studies using DCs pulsed with live vaccine conditions and each of the components and determine their effect on DCs and Treg incubated with such DCs. 2. Characterize the in vivo role of CpG ODNs in modulating Treg function on the Lm/C57BI/6 model. We will vaccinate mice and extract DCs and Treg at different time points to study their function and phenotype. We will use those cells to reconstitute RAG -/- and determine their phenotype. [unreadable] [unreadable]