Prospects for dendritic cell vaccination against fungal infections in hematopoietic transplantation☆
Introduction
In the past decades, the frequency of opportunistic fungal infections has increased, and the spectrum of fungal pathogens has changed [1]. The increasing number of susceptible hosts, the introduction of newer modalities for hematopoietic stem cell transplantation (HSCT), the evolution of organ transplantation practices, the use of novel immunosuppressive agents, and current antimicrobial prophylactic strategies have likely contributed to the changing epidemiology of invasive mycoses. The trends in time of onset, spectrum, and frequency of infections due to invasive molds and opportunistic yeasts are unique for different fungi and vary between subsets of immunocompromised hosts [1]. Opportunistic fungal pathogens, which more typically require immunosuppression to infect the host, include Candida albicans, which is a normal inhabitant of the human gut, and Aspergillus fumigatus, which is ubiquitous in the environment [2], [3]. As a pathogen, C. albicans is associated with a wide spectrum of diseases in humans, ranging from allergy, severe intractable mucocutaneous diseases to life-threatening bloodstream infections [2]. Aspergilli are respiratory pathogens, and pulmonary infections are usually acquired through the inhalation of conidia able to reach small airways and the alveolar space, where the impaired host defense mechanisms allow hyphal germination and subsequent tissue invasion. A. fumigatus is associated with a wide spectrum of diseases ranging from benign colonization of the lung and allergy to life-threatening diseases such as invasive pulmonary aspergillosis or allergic bronchopulmonary aspergillosis [3]. Aspergillus species are the most common cause of invasive infections in allogeneic HSCT [3]. Prophylactic antifungal therapy had little effect on disease incidence in these patients [4].
Section snippets
Immunity to fungi
Host defense mechanisms against fungi are numerous and range from relatively primitive and constitutively expressed nonspecific defenses to sophisticated adaptive mechanisms that are specifically induced during infection [5]. Although the role of innate immunity was originally considered to be a process for defense of the host early in infection, it is now clear that there is an important reciprocal relationship between innate and adaptive immune responses. Through the involvement of a set of
DCs as natural adjuvants
Since their original discovery in 1973, DCs have assumed center stage as the key initiator of adaptive immunity [12]. In infections, they are central in the balancing act between immunopathology and protective immunity generated by host–microbe interactions. DCs are strategically located at the interface of potential pathogen entry sites and take up antigen, move into secondary lymphoid tissues, and activate both helper and cytotoxic T cells. Pathogen-mediated activation induces DCs to undergo
In vitro
Efficient responses to the different forms of fungi require different mechanisms of immunity [5]. DCs showed a remarkable functional plasticity in response to the different forms of fungi, being able to discriminate between the different forms in terms of maturation, cytokine production, and induction of Th cell reactivity, in vitro and in vivo [15], [16]. Murine and human DCs, of both myeloid (MDCs) and plasmacytoid (PDCs) subsets, were able to phagocytose Candida yeasts, Aspergillus conidia,
DCs translate fungus-associated information to Th1, Th2, and Treg cells
Upon exposure to Candida or Aspergillus, DCs activated different types of naive CD4+ Th cells in vitro and in vivo [15]. In vitro, CD4+ T murine splenocytes cocultured with yeast- or conidia-pulsed DCs produced high levels of IFN-γ, but not IL-4 or IL-10. In contrast, DCs exposed to hyphae induced low levels of IFN-γ, but high levels of IL-4 and IL-10 [21]. Adoptive transfer in vivo of purified DCs pulsed with yeasts/conidia or hyphae resulted in priming of CD4+ T cells for Th1 or Th2 cytokine
Exploiting DCs as fungal vaccines in hematopoietic transplantation
Fungus-pulsed DCs activated CD4+ Th cell responses upon adoptive transfer into immunocompetent mice [17], [19], [21]. Previous work has demonstrated the dependency of the efficacy of DC delivery in vivo on the subcutaneous route of administration [17]. We found that DCs delivered subcutaneously migrated to the lungs, spleen, thoracic lymph nodes, Peyer patches, and interestingly, thymus of mice, as indicated by the presence of CFSE-labeled cells in these organs. The ability of DCs to migrate to
Conclusions and perspectives
A variety of cytokines, including chemokines and growth factors, proved to be beneficial in experimental and clinical fungal infections [47]. However, establishing the clinical utility of cytokines as therapy for fungal infections in patients has been difficult. The Th1/Th2 balance itself was also found to be the target of immunotherapy. Thus, the deliberate targeting of cells and pathways of cell-mediated immunity to the fungus may represent a useful strategy in developing effective strategies
Acknowledgments
We thank Dr. Lara Bellocchio for superb editorial assistance. This study was supported by the National Research Project on AIDS, contract 50D.27 “Opportunistic Infections and Tuberculosis,” Italy.
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- ☆
This paper is based upon a presentation at a Focused Workshop on Haploidentical Stem Cell Transplantation sponsored by The Leukemia and Lymphoma Society held in Naples, Italy, from July 8 to 10, 2004.