Immunomic Discovery of Adjuvants and Candidate Subunit Vaccines by Darren R. Flower & Yvonne Perrie

Author:Darren R. Flower & Yvonne Perrie
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

8.4.3 Endogenous Immunostimulatory Signals Can also Be Added to Adjuvants

Possible disadvantages of targeting direct DC activation via PRR and injury sensors include undesirable responses such as pain and localized or systemic inflammation. So why not design adjuvants that target downstream pathways and shortcut direct DC activation? As the host-derived signals responsible for T cell priming are more clearly defined, it should become possible to develop effective adjuvants that deliberately trigger pathways downstream of DC activation and thereby prime T cells. Targeting inflammatory pathways to promote immunity has long been an aim in adjuvant design. A classic example was the fusing of C3d to antigen, simulating complement activation during acute inflammation, which covalently “tags” proteins and targets them to B cells, thereby reducing the dose required to promote antibody responses [64].

More recently, two distinct approaches to the use of endogenous signals—as opposed to pathogen-associated or injury signals—in adjuvants can be identified. Firstly, the discovery of chemokines and cytokines combined with advances in recombinant protein manufacturing has resulted in prolonged interest in using endogenous DC activation signals in adjuvants. Secondly, given the potent effects of feedback signals (such as CD40) on DC activation, deliberately targeting this endogenous pathway offers the hope of priming cytotoxic responses without requiring CD4 T cell help. The last two case studies explore the use of DC to understand how to use synthetic endogenous signals to prime immunity.

Case study 4: Blinding DC to microbial stimulation: can endogenous proinflammatory signals replace direct DC activation?

As rapidly as proinflammatory cytokines such as TNFα, IL-1, and IL-12 were identified, they have been produced using recombinant technology and explored for augmenting adjuvant activity [65]. In addition to incorporating recombinant cytokine proteins, they have been genetically engineered into live attenuated viral and bacterial vectors and DNA vaccines. But can endogenous signals replace direct DC activation? Although DCs are potently influenced by endogenous signals including inflammatory cytokines, how effective are indirectly activated DCs for T cell priming?

An elegant experiment designed to answer this question made use of MyD88 knockout mice as a source of DCs that are “blind” to direct TLR stimulation, and therefore can only respond to indirect activation signals. Bone marrow chimeras were made containing both MyD88-sufficient and MyD88-deficient DC, each with different MHC classes and thus able to present antigen to different sets of T cells. By immunizing these mice with protein antigen plus synthetic PRR agonist, the phenotype of T cells primed by direct vs. indirectly activated DC could be simultaneously monitored in the same mouse. Although indirectly activated “blind” DC promoted CD4 expansion, Th1 differentiation was only seen by T cells activated by PRR-sufficient DC that produced IL-12 after direct TLR stimulation [66].

Although triggering inflammation at the site of vaccine injection is sufficient to enhance immunity to vaccine antigens—for example by promoting DC and lymphocyte recruitment—studies like this one suggest that the immune system has highly sophisticated methods to distinguish antigens that are directly linked to PRR triggers from other antigens also present at an inflamed site. This has implications

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