IL-12 is necessary for the killing of parasites by macrophages, as it allows for upregulation of inducible nitric oxide synthase (iNOS or NOS2) and NO synthesis and subsequent parasite elimination [22, 23] by promoting the development of CD4+ T cells and production of IFN- (basic findings around the role of Th1/Th2 cytokines in reference [24]). role in the outcome of the disease either remedy and protection or progression and? even death. Although plenty of data concerning the factors involved in pathogenesis of contamination and the effector mechanisms of the host immune response are collected in animal models and patients?during the last decades, but yet the immune biomarkers of cure/protection or exacerbation in human leishmaniasis are not well defined. It is well known that CL caused by natural contamination or leishmanization induces strong protection against further CL lesion development, which justifies to develop vaccine against leishmaniasis [3]. Wealth of information which is usually accumulated over the past years around the biology of intracellular parasites, map of genome, and numerous experimental studies around the immunology of leishmaniasis, supported search to develop an effective vaccine (reviewed in [4, 5]). In the last decades, numerous vaccine candidates have been introduced as vaccine candidate including whole live, attenuated, genetically modified, killed parasites, and subunits or fusion proteins, but only a few have been tested in clinical trials [4]. The absence of a vaccine against leishmaniasis is usually primarily attributed to the absence of clear understanding of correlates of protection [6]. Moreover, animal models of leishmaniasis do not usually mimic human leishmaniasis [7], and ACY-775 extrapolating results of protection assays obtained with the experimental murine models to humans GFAP is usually doubtful. Methods A literature search using the PubMed, Scopus and Google Scholar databases has been conducted for publications with full text or abstract in English language over the last 45?years. Relevant additional articles identified during review by authors were also included. Search terms included were Leishmania* AND (immune response OR immunology OR protection) or leishmaniasis AND biomarker. The initial search strategy identified more than 10,000 results. To limit search hits, other fields such as title [Ti], title abstract [Tiab], English [lang] and publication 12 months [dp] were used which decreased the number of results to 7897 articles. Based on the title ACY-775 and the abstract, 523 articles including 46 review papers and 477 initial papers were carefully analysed and finally 280 were cited. Macrophages and initiation of Leishmania contamination Macrophages (M) are known as the primary ACY-775 antigen presenting cells (APCs), other phagocytic cells including monocytes, dendritic cells and neutrophils are also recruited to the site of contamination and play important roles (reviewed in [8]). It has been proposed that parasites use neutrophil polymorphonuclear leukocytes (PMNs) as temporary host cells to silently enter macrophages without activation of defence mechanisms (Trojan horse hypothesis) [9]. Subsequently, macrophages phagocytose free parasites and apoptotic PMNs infected with parasites and serve as the definitive host cells and permit parasite growth. However, macrophages are naturally responsible for killing of invading parasites by activation of effective microbicidal mechanisms (reviewed in [10]). The effective elimination of parasites by macrophages and development of protective immune response against require involvement of dendritic cells (DCs) [10]. parasites are able to engage different cell surface receptors?including complement receptors [11, 12], fibronectin receptor [13], Toll-like receptors 2, 3 [14] and 4 [15] and mannose receptor [16] to enter into the host cells. The leishmanial membrane protease gp63 cleaves C3b attached to its surface, converts it to C3bi inactive form which binds to CR3 receptor, and mediate entry of opsonized promastigotes into macrophages. This strategy protects the parasites from lysis by complement activity [17]. parasites are engulfed by macrophages and are eliminated by production of interferon gamma (IFN-), reactive oxygen species (ROS) and nitric oxide (NO) derivatives inside phagolysosome; however, intracellular amastigotes modulate various antimicrobial defense pathways and interfere with a number of critical macrophage functions to sustain and multiply inside the cell (reviewed in [18]). Macrophages successfully phagocytose?parasites, but the production of IL-12 is inhibited by the intracellular parasites [19]. It was shown that internalization of through CR3 receptor, which is ACY-775 a mechanism of silent entry into macrophages, leads to blockade signaling cascade and synthesis of interleukin 12 (IL-12) [20, 21]. IL-12 is necessary for the killing of parasites by macrophages, as it.