Targeting Dendritic Cells as a Good Alternative to Combat Leishmania spp.

Abstract

LEISHMANIASIS: GLOBAL BURDEN, CLINICAL FORMS, AND CURRENT STRATEGIES OF CONTROL Leishmaniasis is an important group of neglected diseases caused by more than 20 spp. of protozoan from the genus Leishmania. It is transmitted by sandfly bite (1), and impacts populations by inducing disfiguration, loss of productivity, and a burden estimated at 2,357.000 disabilityadjusted life years (DALY) (2). Ninetyeight countries have reported cases of leishmaniasis, and over 350 million people are living at risk, with 0.2–0.4 and 0.7– 1.2 million cases of VL and CL annually, respectively (3). Three main clinical forms are known: visceral (VL, more lethal, e.g., L. donovani and L. infantum), cutaneous (CL, more common, e.g., L. major), and mucocutaneous (MCL). Strategies to limit these diseases are controlling the vectors and chemotherapy of affected individuals, but these approaches have a high cost and led to resistant parasites and vectors (4). Thus, there is an urgent need of vaccines and more effective therapies for leishmaniasis, otherwise the number of cases and resistant strains will probably continue to rise. Since they have a key capacity to initiate and maintain an immune response, dendritic cells (DCs) have been seen as an important target for the control of different diseases, such as leishmaniasis. Thus, in this article we present the principal strategies to efficiently induce activation of DCs in the context of leishmaniasis. DENDRITIC CELLS AS THE MAIN TARGET OF VACCINES AGAINST LEISHMANIA The major task for a vaccine is to correctly induce the immune system to develop a protective response against one specific pathogen. In the case of leishmaniasis, this protection comes from Th1 CD4 T cells producing IFN-γ, TNF, and IL-12, which have been associated with disease control, macrophage activation, and elimination of parasites (5). However, to initiate this response, antigen presenting cells (APCs), present in different tissues of the body, must be activated to induce a proper response to eliminate or control the parasite. DCs are highly specialized APCs of the immune system capable of priming naive T cells, and mounting a T-cell response upon pathogen entry in the body. Distinct subsets of DCs are associated with lineages and receptor expression patterns (6), and they develop from hematopoietic stem cells stimulated with fms-like tyrosine kinase 3 ligand (Flt3L) or with granulocyte/macrophage colony-stimulating factor (GM-CSF) (7). The majority of DCs develop from myeloid precursors, whereas plasmacytoid DC (pDC) develops from lymphoid precursors and shares many features with B cells (8). To aid in their function, DCs express different toll-like receptors (TLR), which bind to common molecules associated with pathogens, and have been target for the development of new vaccine adjuvants. DCs express a large variety of receptors involved with uptake of molecules and pathogens, such as DC-SIGN (CD209) and DEC205 (CD205) (9). Immature DCs have a high endocytic capacity, which leads to pathogen or pathogen’s antigens degradation, processing, and finally loading of major histocompatibility complex (MHC) molecules. Later, mature DCs lose their high capacity of endocytosis, and change efforts to up-regulate the expression of several receptors for cytokines, MHC, adhesion, and co-stimulatory molecules, such as CD80, CD86, and CD40. It is estimated that each mature DC expresses around 106–107 MHC Class II and 105 MHC Class I molecules, and “fix” a repertoire of peptides bounded onto MHC Class II to present to T cells (10). Eventually, DCs acquire capacity to activate a specific T-cell response against the pathogen that induced its activation (11). The last years were marked by an increase in the knowledge on the role and function of DCs in the immune system, and thus, the emergence of potential applications based on its manipulation. Starting on the field of cancer, which finally led to the US FDA approval of a DC-based vaccine against prostate cancer (Sipuleucel-T, Provenge®) (12), applications were quickly transferred to the field of infectious diseases with very encouraging clinical results against HIV (13). Although prospective results for infectious diseases were achieved, there is no DC vaccine or therapy for any infectious diseases that are currently available or in the pipeline (14, 15). Most of the results were gathered by