ReviewImmunomodulatory biomaterials
Introduction
Vaccines are one of the most successful interventions for infectious diseases. However, major challenges remain in vaccine design, including improving their efficacy significantly and developing new vaccines for emerging diseases. Current vaccines typically include an antigen or live attenuated microorganism, an adjuvant to enhance the immune response, and a delivery system to target delivery to the right location (Pashine et al., 2005). An adjuvant is an agent that stimulates the immune system, increasing the response to a vaccine, while not having any specific antigenic effect. Adjuvants perform one or more of three main functions. (i) They provide a “depot” for the antigen for slow release; (ii) they facilitate targeting of the antigen to immune cells and enhance phagocytosis, and (iii) they modulate and enhance the type of immune response induced by the antigen alone (Cox et al., 2006, Trujillo-Vargas et al., 2005, Lutsiak et al., 2006, Petrovsky, 2006). Adjuvants may also provide the danger signal the immune system needs in order to respond to the antigen as it would to an active infection (Janeway et al., 2001). Thus, adjuvants play a significant role on every aspect of the immune response.
However, currently very few adjuvants and delivery systems are licensed for human use, with alum being the most common one. Adjuvants and delivery systems play a much more significant role in newer vaccines consisting of isolated antigens as opposed to live microorganisms. However, most current adjuvants only stimulate one immune pathway, as described below. Therefore the development of immunomodulatory biomaterials as adjuvants and delivery systems can have a significant impact on vaccines. This review discusses the current approaches to designing immunomodulatory adjuvants and presents some future research trends in this area. We begin with a brief discussion of the immune response.
Section snippets
Immune response mechanisms
A physiological immune response begins with the antigen presenting cell (APC). This is the crucial step of the activation of the immune system. The best APCs responsible for activation of helper T cells, killer T cells and B cells are dendritic cells (DCs). Immature DCs are found under the skin and mucous membranes where they sample surrounding for possible pathogens through pattern recognition receptors. After detecting pathogen, these cells engulf it via phagocytosis and pinocytosis and
Limitations of current vaccines
Current vaccine designs do not target the DC system. DCs can readily stimulate T cells and can operate at mucosal surfaces, where early protection is needed in many infections, while existing vaccines are weak stimulators of T cells. T-cell activation is only guaranteed by repeated encounters with persistent low levels of antigens (Zinkernagel, 2006). Therefore therapeutic strategies based on modulating the immune response may significantly expand treatment options and circumvent the problem of
Immunomodulators
The list of potential molecular targets for modulators of innate immunity is quite extensive (Germain, 2004). In cancer patients, for example, the immune system is non-specifically stimulated with immunomodulators in addition to treatment (Hanks et al., 2005). Several immunomodulatory agents are currently being investigated as adjuvants. Examples include natural compounds (calf thymic hormones, glucans), synthetic compounds (oligodeoxynucleotides containing CpG motifs, maramyl peptides,
The promise of polymeric biomaterials
The adjuvants discussed above, while promising, suffer from several drawbacks. Pathogens have evolved mechanisms against host immune systems. Moreover, toxicity is a huge concern with several of these adjuvants. Synthetic polymers with specific characteristics can be used as adjuvants and immunomodulators as an alternative to the microbially derived adjuvants currently being investigated. This is a relatively new interdisciplinary area involving a marriage of immunology and materials chemistry.
Discussion and conclusions
In summary, good immunostimulatory vaccine adjuvants activate DCs to mature and migrate to the draining lymph node, coincident with induction of the cytokine profile appropriate to the desired immune response mechanism (i.e., IFN-γ, IL-2, and IL-12 for the Th1 response and IL-4, IL-5, and IL-6 for the Th2 response). Like adjuvants that target DCs, some immunostimulatory vaccine adjuvants also interact with TLR proteins. Regardless of the mechanism of adjuvanticity, vaccine adjuvants must
Acknowledgments
B.N. gratefully acknowledges financial support from the U.S. Department of Defense – Office of Naval Research (ONR Award #N00014-06-1-1176). The authors would like to thank M.J. Wannemuehler, M.J. Kipper, M.P. Torres, and J.H. Wilson-Welder for useful discussions. The authors also wish to acknowledge support from the Institute for Combinatorial Discovery at Iowa State University.
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