Mini-Review Dendritic cells as vectors for vaccination against infectious diseases

IJMM IJ

Int. J. Med. Microbiol. 291, 323-329 (2001) © Urban & Fischer Verlag http://www.urbanfischer.de/journals/ijmm

Mini-Review Dendritic cells as vectors for vaccination against infectious diseases Heidrun Moll, Christof Berberich Institute for Molecular Biology of Infectious Diseases, University of Würzburg, Würzburg, Germany Received April 20, 2001 · Accepted July 26, 2001

Abstract Antigen presentation by dendritic cells (DCs) is critical for the induction of a specific immune response. The immunotherapeutic potential of antigen-pulsed DCs for the treatment of cancer has been confirmed in a number of experimental tumor models and in several preclinical trials. Recent advances in our understanding of the interaction of microbial pathogens with DCs have provided the basis to explore DCs as vaccine carriers for the induction of protective immune responses to infections. Support for this strategy comes from animal studies demonstrating that DCs, after ex vivo loading with microbial antigens, confer protection against microbial challenges in vivo. This may have important implications for the development of novel strategies for prophylactic or therapeutic immunizations against various microbial pathogens. Key words: vaccination – dendritic cells – T cells – cytokines – parasites

Introduction Effective vaccination requires the induction of the appropriate type of immunity. Protection induced by the currently available vaccines against several viral and bacterial infections appears to be mediated by the humoral immune response through the production of antibodies. However, protective immune responses against intracellular pathogens, such as mycobacteria, Salmonella, Listeria monocytogenes and protozoan parasites of the genus Leishmania, are mediated by T cells, whereas antibodies secreted by B cells play a minor, if any, role. Recent advances in molecular microbiology and immunology have provided a rational basis for the elaboration of parameters that are relevant to the development of efficient vaccines against

these infectious agents, including the identification of protective T cell antigens and novel vaccine delivery systems. The experiences with Mycobacterium bovis Bacillus Calmette Guérin (BCG) vaccination against tuberculosis have shown that ‘classical’ vaccines consisting of attenuated pathogens have variable efficacy and may cause major concerns with respect to safety aspects. Therefore, considerable efforts have been made towards the development of new vaccine concepts based on the subunit principle. Recombinant techniques are now used for the massive production of antigens, for DNA-based immunization strategies and for the design of live vaccine carriers including genetically engineered poxvirus (Cox et al., 1992), vaccinia virus (Perkus et al., 1995), BCG (Stover, 1994), Salmonella (Chatfield

Corresponding author: Heidrun Moll, Institute for Molecular Biology of Infectious Diseases, University of Würzburg, Röntgenring 11, D-97070 Würzburg, Germany. Phone: +49 931 31 2627, Fax: +49 931 31 2578, E-mail: heidrun.moll@ mail.uni-wuerzburg.de 1438-4221/01/291/5-323 $ 15.00/0

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et al., 1994) or Listeria (Shen et al., 1995) carrying foreign antigens. The demonstration that DNA vaccines induce both humoral and broad cellular immune responses (cytotoxic and helper T cell responses) in animal models has prompted optimism that they could become highly effective vaccines against infectious diseases, although their efficacy in clinical trials is still not convincing. The strong immunogenicity of DNA vaccines appears to be largely mediated by professional antigen-presenting cells, in particular dendritic cells (DCs). Following DNA administration into the skin, dermal DCs and epidermal Langerhans cells are assumed to acquire newly synthesized antigen from transfected keratinocytes or, alternatively, by direct transfection (Tuting et al., 1998). Immunostimulatory CpG oligonucleotide sequences present in the plasmid backbone further activate DCs to induce a T cell response (Sato et al., 1996). This review focuses on the role of DCs in the regulation of immune responses to microbial infections and the potential use of DCs as vaccine carriers for prophylactic and therapeutic vaccination against infectious diseases that are controlled by cell-mediated immunity.

Immunobiology of dendritic cells It has long been recognized that the induction of a cellular immune response is dependent on the presentation of antigen and the delivery of co-stimulatory signals to T cells by accessory cells. However, an immune response is not only determined by the quantity and quality of signals that are provided and involves more than merely the stimulation of antigen-specific T cells. The instruction of T cells must be tailored by the antigen-presenting cell to allow the elimination of various types of pathogen. A plethora of data documents the important role of dendritic antigen-presenting cells in orchestrating these processes (Banchereau et al., 2000). Originating from the bone marrow, different types of DCs are present in numerous body compartments, including epithelia (e. g., the epidermis and mucosa), blood, lymph and all lymphoid organs. The major task of immature DCs residing in peripheral tissues, such as Langerhans cells in the epidermis, is to sample invading pathogens, migrate as veiled cells through the lymphatics to the draining lymph nodes, and differentiate into interdigitating DCs that present pathogen-derived antigen to naive T cells. Thus, DCs are regarded as the key initiators of adaptive immunity to infections (Moll, 1993; Reis e Sousa et al., 1999). DCs at different maturational stages vary in phenotype and function. Immature DCs in body-surface tissues can phagocytose pathogens and process antigens

for loading of major histocompatibility complex (MHC) class II molecules. During maturation, while DCs migrate to lymphoid organs in vivo or upon activation of isolated DCs in culture, they lose this ability. At the same time, there is a marked upregulation of MHC class II, from an already high constitutive level, as well as costimulatory and adhesion molecules. This process results in the acquisition of the distinct ability of DCs to trigger a primary T cell response. In addition, recent evidence suggests that there are at least two distinct lineages of DCs, the so-called ‘lymphoid’ and ‘myeloid’ lineages (Pulendran et al., 2001). The myeloid lineage (also referred to as DC1) comprises cells of the Langerhans and interstitial DC pathway, whereas the lymphoid lineage (also termed DC2) gives rise to ‘plasmacytoid’ cells of secondary lymphoid organs, which are characterized by their extensive endoplasmic reticulum resembling that of plasma cells (Grouard et al., 1997). These findings emphasize that DC functions are not fixed, but are regulated by lineage and maturational differences. Furthermore, signals from the local milieu and from microbial pathogens control the nuances of DC phenotypes and the fate of DC-initiated immune responses.

Invasion of dendritic cells by microbial pathogens Consistent with their function as sentinels of the immune system, DCs are particularly frequent in bodysurface tissues, such as the skin or the lung, where microbial pathogens gain access to their host. At these locations, the organisms invade host cells for multiplication and are encountered by cells of the immune system. Prominent examples for the uptake of pathogens by DCs are vector-borne diseases involving the skin as transmission site: leishmaniasis, Chagas’ disease, Dengue fever and Lyme borreliosis. Numerous viruses, bacteria, fungi and protozoan parasites are known to invade DCs (Table 1). In most, but not all cases, exposure to the pathogen induces the maturation of DCs, i. e. the activation of their T cell-stimulatory functions. Several pathogen-associated molecules have been shown to trigger this activation of DCs, including lipopolysaccharide (LPS) and CpG oligodeoxynucleotides from bacteria (De Smedt et al., 1996; Sparwasser et al., 1998). The bacteria-induced stimulation of DCs involves binding to the Toll-like receptor 2 and subsequent activation of the transcription factors ERK kinase and NF-kB (Rescigno et al., 1999; Hertz et al., 2001). DCs can also be activated by secondary mediators of inflammation, such as tumor necrosis factor-α and activated T cells. However, as shown in Table 1, some microorganisms prevent DC maturation as part

DC-based vaccination against infections

of a strategy to evade the host immune response. An even more sophisticated mechanism of dendritic cell dysregulation is used by the malaria parasite Plasmodium falciparum. Infected erythrocytes have been shown to adhere to dendritic cells, thus inhibiting their maturation and T cell-stimulatory potential (Urban et al., 1999). The number and fate of intracellular pathogens in DCs is distinct from that in other cell types. Salmonella and Leishmania are examples for such cell-specific interactions. The uptake of Salmonella typhimurium and its intracellular survival in DCs do not depend on virulence factors which are important in macrophages, such as the PhoP-PhoQ two-component response regulator (Niedergang et al., 2000). In addition, evidence has been presented that these bacteria are targeted to DC compartments lacking lysosomal membrane glycoproteins, whereas in macrophages the Salmonellacontaining vacuoles are positive for these markers (García-del Portillo et al., 2000). These results suggest that DCs are host cells with specialized functions during Salmonella infection. A similiar conclusion may also be drawn from studies with the protozoan parasite Leishmania. The number of parasites ingested by DCs is small compared with macrophages. While Leishmania has been shown to down-regulate parasite clearance and antigen presentation by macrophages, DCs control intracellular parasite replication and efficiently process and present Leishmania antigen (Moll, 2000). Some viruses, including measles virus (MV) and human immunodeficiency virus (HIV), exploit the migratory functions of DCs to facilitate their spreading and replication in the host. For MV, it has been shown that the interaction of CD40 on DCs with its ligand expressed by activated T cells enhances MV replication in DCs, resulting in the induction of apoptosis of both DCs and T cells (Fugier-Vivier et al., 1997). DCs may be early targets of viral infection and also serve as an important reservoir for persistent infections with HIV, contributing to the pathogenesis of disease (Klagge and Schneider-Schaulies, 1999).

Dendritic cells and induction of antimicrobial immune responses In contrast to macrophages, the functions of DCs are not aimed at avid ingestion and clearance of invading microorganisms, but at alerting the immune system. Within a few hours after pathogen encounter, DCs produce high levels of various chemokines in a timeordered fashion (Sallusto et al., 1999; Foti et al., 1999). In this way, they regulate their own migratory capacities and organize the recruitment of other cells, such as mac-

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Table 1. Examples of pathogens invading DCs. Pathogen

Induction of DC maturation*

References

Viruses Measles Dengue HSV Influenza HIV

+ n. d. – + +

Klagge and Schneider-Schaulies, 1999 Wu et al., 2000 Salio et al., 1999 Larsson et al., 2000 Grouard and Clark, 1997

Bacteria C. trachomatis B. burgdorferi S. typhimurium L. monocytogenes M. tuberculosis M. leprae Y. enterocolitica

+ + + + + + –

Ojcius et al., 1998 Filgueira et al., 1996 Svensson et al., 2000 Paschen et al., 2000 Henderson et al., 1997 Sieling et al., 1999 Schoppet et al., 2000

Fungi C. albicans H. capsulatum

+ +

d’Ostiani et al., 2000 Gildea et al., 2001

Protozoa T. gondii T. cruzi L. major L. donovani

+ – + +

Johnson and Sayles, 1997 Van Overtvelt et al., 1999 Moll, 1993 Gorak et al., 1998

* + = activation of DC maturation, – = inhibition of DC maturation, n. d. = not determined.

rophages, granulocytes, natural killer (NK) cells, T cells and more DCs. Thus, DCs contribute to the amplification of innate immune defense mechanisms. In addition, they represent an important link between innate and acquired immunity. Two distinct features underline their superb ability to present microbial antigens to T cells. First, bacteria and protozoan parasites have been shown to support the de novo biosynthesis of MHC class I and class II molecules by DC and to induce a stabilization of these structures. As a result, the half-life of immunogenic MHC-peptide complexes on pathogenactivated DCs is greatly increased (Flohé et al., 1997; Rescigno et al., 1999). Second, DCs constitutively express another type of antigen-presenting molecule: CD1 proteins. The CD1 family of non-polymorphic molecules mediates the MHC-independent presentation of lipid and glycolipid antigens (Matsuda and Kronenberg, 2001). The best-characterized antigens for CD1mediated presentation to T cells are mycobacterial cell wall components, such as mycolic acids and lipoarabinomannan. These antigens have been shown to be recognized by conventional T cells, a subset of γδ T cells and NK T cells. Thus, DCs are well equipped to stimulate a cellular immune response to microbial protein as well as non-protein antigens. Another important aspect is the ability of DCs to modulate the development of CD4+ T helper (Th) cell

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subpopulations. Exposure to microbial stimuli, including bacterial products as well as Toxoplama gondii and Leishmania antigens, elicits the production of interleukin 12 (IL-12) by DCs (Jakob et al., 1998; Reis e Sousa et al., 1997; Gorak et al., 1998; Flohé et al., 1998), which can bias the local microenvironment towards triggering a Th1 response. Th1 cells are characterized by the release of interferon-γ (IFN-γ) that is critical for the activation of macrophages to eliminate intracellular pathogens.

Dendritic cell-based vaccination and therapy The unique capacity of DCs to initiate immune responses and their extraordinary potency in the regulation and maintenance of immunity make them optimal candidates for new vaccination strategies. The concept of DC-based immune interventions emerged first in the field of tumor therapy; it was shown to be successful in rodent models and is now being explored in clinical trials with cancer patients (Dallal and Lotze, 2000). The recent advances in our understanding of the role of DCs in antimicrobial immunity provide the opportunity to use this approach for vaccination against infectious diseases. Numerous protocols are now available for the preparation and antigen loading of DCs, and an increasing number of studies, using preclinical animal models of infections, documents the feasibility of inducing a host-protective T-cell response with these ‘professional’ antigen-presenting cells. Immunity to bacteria The ability of DCs to stimulate both humoral and cellular components of immune responses correlates with the spectrum of their activities in immunization studies. After in vitro pulsing with live Borrelia burgdorferi spirochetes, DCs induced a selective antibody response in vivo to spirochetal antigens, including OspA, -B and -C, and protected mice against a subsequent challenge with tick-transmitted B. burgdorferi (Mbow et al., 1997). The efficacy of DC-based vaccination has also been shown in a mouse model of Chlamydia trachomatis infection of the female genital tract. Mice immunized with DCs that had been pulsed ex vivo with heat-killed chlamydiae shed 3 logs fewer infectious bacteria and were protected from genital tract inflammatory and obstructive disease (Su et al., 1998). Protective immunity correlated with a chlamydial-specific Th1-biased response that closely mimicked the immunity induced by natural infection. The induction of a protective immune response against tuberculosis using BCG-infected DCs was in-

vestigated in an aerosol infection model. Intratracheal administration of infected DCs stimulated a potent T cell response to mycobacterial antigens and production of IFN-γ in the mediastinal lymph nodes, leading to significant protection against aerosol challenge with M. tuberculosis (Demangel et al., 1999). The IFN-γ level was considerably higher and protection was established much faster in mice immunized with BCGinfected DCs than in mice sensitized with BCG alone, indicating that DCs may be useful to enhance vaccination against tuberculosis. Interestingly, it has been observed that DCs pulsed with a HLA-binding motif contained in the 19-kDa lipoprotein of M. tuberculosis can sensitize HLA class I-restricted cytotoxic T cells from human donors in an in vitro vaccination system (Mohagheghpour et al., 1998). This further supports the concept that DC-based strategies can be extended to clinical applications. Immunity to protozoan parasites and fungi The presence of the Th1-promoting cytokine IL-12 is known to be critical for the outcome of many infections caused by intracellular pathogens, including protozoan parasites. Activated DCs produce high levels of IL-12 and this feature may be one key to their ability to promote a protective immune response. Epidermal Langerhans cells loaded with Leishmania major antigens or splenic DCs loaded with T. gondii antigens protected mice against challenge with L. major or T. gondii parasites, respectively (Flohé et al., 1998; Bourguin et al., 1998). In both experimental systems, exposure of DCs to parasite antigens induced the expression of IL-12 that favored the development of Th1 cells in vivo. Moreover, IL-12 plays an important role in natural immunity to these parasites because it stimulates NK cells to release IFN-γ. In the leishmaniasis model, the protection was shown to be long-lived and to be maintained after subsequent infections with the parasites (Flohé et al., 1998). Furthermore, the homing patterns of adoptively transferred DCs were found to be important for their capacity to induce a protective Th1 response because the effectiveness of DC-based vaccination against L. major was dependent on the route of immunization. The interaction of DCs and Candida albicans is influenced by the form of the fungus (d’Ostiani et al., 2000). Although DCs phagocytose both yeast and hyphal forms, only the ingestion of yeasts activated DCs for IL12 production and priming of Th1 cells. In vivo, antifungal protective immunity was generated upon injection of DCs that had been pulsed with Candida yeasts but not hyphae. Thus, DCs appear to discriminate between the virulent and nonvirulent forms of the fungus in terms of the type of immune response elicited.

DC-based vaccination against infections

Antiviral immunity The activation of cytotoxic T cells is essential for immunity to various viral infections. DCs infected with influenza virus have been shown to efficiently stimulate and expand cytotoxic T cells, leading to rapid clearance of even different virus subtypes (Lopez et al., 2000). In another study, DCs that were either pulsed with the lymphocytic choriomeningitis virus (LCMV)specific peptide GP33–41, or were constitutively expressing the respective epitope, were found to induce protection against LCMV in vivo (Ludewig et al., 1998). Notably, very small numbers of DCs (100– 1000) were sufficient to induce an antiviral immune response. The DC-induced immunity developed rapidly, was long-lasting and was not limited by the turnover of peptide-MHC class I complexes. Furthermore, antigenic peptide-presenting DCs most efficiently restimulated cytotoxic memory T cells.

Concluding remarks Our increasing knowledge of the immunobiology of DCs and the possibility to generate sufficient numbers of these potent antigen-presenting cells in vitro from precursor cells has opened new perspectives for the immunotherapy of various infectious diseases. Such an approach would be most promising for controlling those medically important diseases for which conventional immunization strategies have proven to be elusive. It would be impracticable to use ex vivo antigenpulsed autologous DCs for broad-scale prophylactic treatment of humans. Nevertheless, the findings summarized in this review demonstrate that the specific targeting of antigens to DCs may be a key to develop efficacious vaccination strategies. This notion is supported by the observation that the priming of immune responses following DNA vaccination is critically dependent on small numbers of directly transfected DCs (Akbari et al., 1999). Furthermore, the feasibility of DC-based therapeutic vaccination of patients has been documented for the treatment of cancer. An equivalent approach may be for the benefit of those patients in whom conventional anti-infective therapies have failed or who suffer from yet incurable forms of infectious diseases. It will be important (1) to identify protective antigens that are suitable for targeting of DCs and triggering their immunizing properties, (2) to define the best source of DCs, (3) to develop optimal techniques for antigen delivery to DCs and (4) to understand the optimal routes of administration. DCs may be armed for induction of efficient antimicrobial immunity by in vitro pulsing with recombinant microbial antigens or

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by transfection with DNA encoding the respective antigens (or combinations of antigens). Moreover, the efficacy of DC-based immune interventions may be enhanced by administering cytokines or other DC activators in combination with DC vaccination, or by engineering DCs to secrete cytokines (Ahuja et al., 1999). Studies to investigate these possibilities are currently underway.

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