Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

Abstract

No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-γ, IL-12, and TNF-α. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4+ and CD8+ T cells and TH2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-β, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on the polarization of antigen-presenting cells and subsequent role of costimulatory and coinhibitory molecules in mediating vaccine-induced immunity using live-attenuated Leishmania parasites as specific examples.

Anti-Leishmanial Vaccines: Assumptions, Approaches, and Annulments

“…Therefore, the binding strengths may be one of the mechanisms through which the cytokines may get affected at IS. For example, the coinhibitory receptor CTLA-4 has a higher affinity to bind to CD86 [197] than CD28, therefore, it outcompetes CD28 binding at IS and may lead to a suppressed T cell instead of activation [198]. In the case of murine VL, CTLA-4 increases TGF-β levels and apoptosis of CD4+ T cells [199].…”

Combination immunotherapy with interleukin‐2 surface‐modified tumor cell vaccine and programmed death receptor‐1 blockade against renal cell carcinoma

“…A number of factors potentially affect the therapeutic effect of vaccines . The present study has not evaluated the role of myeloid cells or stromal tissue in the combination therapy with the SA‐IL‐2‐modified vaccine and PD‐1 blockade.…”

Applications of Nanomaterials in Leishmaniasis: A Focus on Recent Advances and Challenges

“…The other way is that the parasite mediates a cell signaling pathway in macrophages which inhibits T-helper cells' (Th2) cytokine responses, specifically interleukins, IL-5, IL-4, and IL-13, leading to downregulation of the protective immune response [18]. Hence, the parasite has the ability to switch between a proinflammatory Th1-type healing response to an anti-inflammatory Th2-type non-healing response, which prioritizes their survival and growth inside the macrophages [19]. Additionally, the parasite has also the ability to inhibit the intracellular leishmanicidal activity by decreasing the production of reactive oxygen species, nitric oxide, and pro-inflammatory cytokines leading for their better growth and survival by reduced proliferation of CD4+ and CD8+ T cells, which eventually leads to an The leishmanial parasite has ability to take control of the immune system of the affected individuals, which enables the disease condition to persist for a long time and develop into a chronic infection [16].…”

“…Furthermore, several co-inhibitory molecules, such as CTLA-4, PD-L1, CD200, and Tim-3, have shifted the balance of the immune system towards the non-healing Th2 response [19].…”