Cutting-Edge Delivery Systems and Adjuvants in Tolerogenic Vaccines: A Review

Abstract

Conventional therapies for immune-mediated diseases, including autoimmune disorders, transplant reactions, and allergies, have undergone a radical evolution in the last few decades; however, they are still not specific enough to avoid widespread immunosuppression. The idea that vaccine usage could be extended beyond its traditional immunogenic function by encompassing the ability of vaccines to induce antigen-specific tolerance may revolutionize preventive and therapeutic strategies in several clinical fields that deal with immune-mediated disorders. This approach has been supported by improved data relating to the several mechanisms involved in controlling unwanted immune responses and allowing peripheral tolerance. Given these premises, several approaches have been developed to induce peripheral tolerance against the antigens that are involved in the pathological immune response, including allergens, autoantigens, and alloantigens. Technological innovations, such as nucleic acid manipulation and the advent of micro- and nanoparticles, have further supported these novel preventive and therapeutic approaches. This review focuses on the main strategies used in the development of tolerogenic vaccines, including the technological issues used in their design and the role of "inverse adjuvants". Even though most studies are still limited to the preclinical field, the enthusiasm generated by their results has prompted some initial clinical trials, and they show great promise for the future management of immune-mediated pathological conditions.

Keywords: adjuvant; bystander suppression; dendritic cell; immune response; nanoparticles; regulatory T cells; tolerance; tolerogenic vaccine; vaccine delivery strategy.

Figure 1

Tolerance-inducing strategies in tolerogenic vaccines. Mechanisms through which tolerogenic vaccines can induce an antigen-specific tolerogenic phenotype during the immune response. For the sake of simplicity, all vaccines are represented as being delivered through nanoparticles, even though several other delivery modes can be employed. Dimensions are not to scale. First, the antigen is usually endocytosed and processed by DCs; thereafter, the antigen is presented on MHC II and naive T cells. The tolerogenic adjuvant is delivered together with the antigen, and it has an effect on both the DCs and T cells interacting with them. (A) Deprivation of co-stimulatory signals. If the antigen is directly displayed on the MHC II molecule that is being carried by the vaccine, and in the absence of DC mediation and without co-stimulators, the T cell becomes anergic despite antigen recognition. (B) Inhibition of pro-inflammatory stimuli. Delivering the inhibitors of transcription factors that promote inflammation and cell proliferation is an additional strategy that can dampen the T cell response. (C) Induction of a tolerogenic phenotype. Engagement between signaling pathways are able to downregulate T or B cell activation, or it can induce programmed cell death. (D) Mimicry of tolerogenic physiological mechanisms. These strategies harness the physiological “neat death” (apoptosis) of cells; for instance, by displaying the apoptotic marker, PS, thus preventing an inappropriate inflammatory reaction. (E) Nucleic acid-based vaccines. The nanoparticle-delivered DNA coding for the specific antigen, as well as for a tolerogenic molecule, is first incorporated in the DC nucleus, then transcribed into an mRNA molecule, and eventually translated into a protein antigen plus the tolerogenic molecule. The former is loaded on an MHC II and presented to naive T cells, whereas the latter acts both on the DC itself and on naive T cells to induce a tolerogenic phenotype. In mRNA-based vaccines, the mechanism is very similar, with the only difference being that the transcription step is skipped, and therefore, the mRNA molecule is directly translated due to the DC ribosomes. Abbreviations. Ag, antigen; BCR, B cell receptor; CD22, cluster of differentiation 22; IL-10, interleukin-10; mTORC, mammalian target of rapamycin complex; NFκB, nuclear factor-κB; NP, nanoparticle; PC, phosphatidylcholine; TCR, T cell receptor; TGF-β, transforming growth factor-β.

Figure 2

Schematic representation of the phenomenon of epitope spreading. A DC presents two different antigens (Ag-A and Ag-B) to a Treg and an effector CD4+ T cell, respectively. The Treg releases IL-10 and TGF-β, which educates the nearby effector CD4+ T cell so that it becomes a Treg. This results in a downregulation of the immune response towards Ag-B, even though the original tolerogenic stimulus derives from a cell specific Ag-A. Abbreviations: Ag, antigen; DC, dendritic cell; IL-10, interleukin-10; IL-10R, interleukin-10 receptor; MHC II, major histocompatibility complex II; TCR, T cell receptor; TGF-β, transforming growth factor-β; TGF-βR, transforming growth factor-β receptor; Treg, regulatory T cell.