Review
Antigen delivery by dendritic cells

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Abstract

Dendritic cells (DC) link the innate and adaptive arms of the immune system and thus orchestrate the immune response to pathogens. A novel immune intervention strategy to control infectious diseases is based on the use of the potent immunostimulatory properties of DC for vaccination and immunotherapy. Recent advances in our understanding of DC biology and the molecular mechanisms by which DC instruct the development of an appropriate immune response to microorganisms provide means for DC-based approaches to manipulate the immune system. In experimental systems, DC vaccination has been documented to mediate protection against a wide spectrum of infectious diseases caused by viral, bacterial, parasitic and fungal pathogens. The protocols for the generation, stimulation and antigen loading of DC are being optimized, and methods for DC targeting in situ are likely to become available soon, thus paving the way for clinical applications of DC-based vaccines.

Introduction

Effective and durable immunity against the diverse types of microbial pathogens that enter our body relies on the co-ordinated action of components of the innate and the adaptive immune system. The specific immune response is driven by antigen-presenting cells that are located in peripheral tissues and thus link the innate arm with the cellular and humoral arms of the immune system (Moll, 2003). Both macrophages and dendritic cells (DC) can process and present microbial antigens to T cells, but have distinct and complementary functions in the regulation of the resulting immune response and the resolution of infection. Macrophages are professional phagocytes and, after appropriate activation, the most important effector cells for pathogen clearance. DC, on the other hand, express high levels of major histocompatibility complex (MHC) class II and co-stimulatory molecules and have the unique ability to stimulate resting T cells. Moreover, DC instruct the development of pathogen-specific CD4+ T helper (Th) cell subsets. This Th cell polarization into Th1 and Th2 cells is critical for balancing the immune response to microorganisms and must be controlled tightly.

A novel approach to vaccination against infectious diseases and therapeutic immune intervention is to exploit DC as ‘nature's adjuvant’ in order to induce pathogen-specific T cells directly in vivo. Such a strategy may be particularly useful in cases of infectious diseases for which conventional therapies have failed or are still not available. This review article focuses on recent findings elucidating the instructive role of DC in the development of an appropriate immune response and highlights the emerging reports on DC-based vaccination against infections that offer new perspectives for manipulations of the immune system for clinical benefit.

Section snippets

Pathogen recognition by dendritic cells

The DC system comprises a network of different subpopulations that are phenotypically and functionally heterogeneous (Shortman and Liu, 2002). The functional properties of a given DC subset do not appear to be fixed, but can be modified by signals from the microenvironment, thus permitting a striking plasticity in response to different microbes (de Jong et al., 2002; Manickasingham et al., 2003). In humans, myeloid DC and plasmacytoid DC have been described. Murine DC express the CD11c integrin

Pathogens trigger the maturation of dendritic cells

In the course of an infection, pathogen encounter causes the maturation of DC not only directly, but also indirectly via the broad spectrum of inflammation-associated factors released in the affected tissues (Josien et al., 2000). Furthermore, DC can be activated by necrotic cells (Gallucci et al., 1999). The DC maturation program is associated with profound changes in the phenotypic and functional characteristics of the cells. Immature DC in peripheral tissues, such as the skin and the mucosal

Dendritic cells control the immune response to infections

DC integrate microbial and inflammatory stimuli and direct the selective development of polarized Th cell responses (Fig. 1). Elucidating the mechanisms by which DC instruct the appropriate type of Th cell response is a major focus of the present research on DC immunobiology. It has been suggested that different DC subsets have an intrinsic tendency to promote either a Th1 or a Th2 response (Moser and Murphy, 2000). However, this rather simplistic concept has been challenged by a number of

The role of dendritic cells in classical vaccine approaches and DNA vaccination

DC are highly specialized in antigen presentation via the MHC class I pathway, which is required for the activation of CD8+ cytotoxic T lymphocytes, and the MHC class II pathway, which forms structures to be recognized by CD4+ Th cells (Guermonprez et al., 2002). In addition, DC express members of the non-polymorphic CD1 family, which are able to present microbial lipid and glycolipid antigens, such as mycobacterial cell wall components, to conventional T cells, a subset of γδT cells and

Novel immune intervention strategies based on dendritic cells

DC are strategically located at epithelial barriers where pathogens gain access to their host. Upon internalization of microorganisms and their transport to secondary lymphoid organs, matured DC present a profile of processed antigens of the pathogen to naive T cells, thus initiating the specific immune response. Furthermore, mature DC are able to retain microbial antigens in immunogenic form for prolonged periods, due to the increased stability of MHC–peptide complexes, and may thus allow the

Immunological parameters determining the efficiency of dendritic cell-based vaccination

The immunological mechanisms underlying the ability of DC to induce protective immune responses in vivo have been studied in several infectious disease models. Exposure to microbial antigen in vitro induces high levels of IL-12 production by DC, and this feature may play a major role in the development of protective immunity associated with Th1 cells (Berberich et al., 2003; Bourguin et al., 1998; d’Ostiani et al., 2000; Flohé et al., 1998; López et al., 2000; Su et al., 1998). Furthermore, the

Approaches to enhance the efficacy of dendritic cell-based vaccination

DC may represent the key to the development of novel vaccination approaches that mimic the course of natural immune responses or trigger de novo responses that have been ignored or suppressed. To optimize DC vaccination, it will be important to design strategies for appropriate activation of DC, improved antigen delivery to DC and in situ targeting of DC.

There is increasing evidence for the profound influence of microbial components and inflammatory factors on DC phenotype and function,

Concluding remarks

During the last decade, considerable insights have been gained into the mechanisms by which DC induce and regulate the fate of immune responses to microbial pathogens. The development of protocols for generating large numbers of DC in vitro from precursor cells has opened new perspectives for DC-based immune intervention strategies. Data from infectious disease models are highly encouraging and results from completed clinical trials with cancer patients demonstrate the safety of DC vaccines.

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